U.S. GOVERNMENT PRINTING OFFICE

WASHINGTON : 

For sale by the Superintendent of Documents, U.S. Government Printing Office

Internet: bookstore.gpo.gov Phone: toll free (866) 512–1800; DC area (202) 512–1800

Fax: (202) 512–2104 Mail: Stop IDCC, Washington, DC 20402–0001

76–491 PDF 2012

REAUTHORIZATION OF PDUFA: WHAT IT MEANS 

FOR JOBS, INNOVATION, AND PATIENTS 

HEARING 

BEFORE THE

SUBCOMMITTEE ON HEALTH 

OF THE

COMMITTEE ON ENERGY AND 

COMMERCE 

HOUSE OF REPRESENTATIVES 

ONE HUNDRED TWELFTH CONGRESS 

SECOND SESSION 

FEBRUARY 1, 2012 

Serial No. 112–110 

( 

Printed for the use of the Committee on Energy and Commerce 

energycommerce.house.gov 

COMMITTEE ON ENERGY AND COMMERCE 

FRED UPTON, Michigan 

Chairman 

JOE BARTON, Texas 

Chairman Emeritus 

CLIFF STEARNS, Florida 

ED WHITFIELD, Kentucky 

JOHN SHIMKUS, Illinois 

JOSEPH R. PITTS, Pennsylvania 

MARY BONO MACK, California 

GREG WALDEN, Oregon 

LEE TERRY, Nebraska 

MIKE ROGERS, Michigan 

SUE WILKINS MYRICK, North Carolina 

Vice Chairman 

JOHN SULLIVAN, Oklahoma 

TIM MURPHY, Pennsylvania 

MICHAEL C. BURGESS, Texas 

MARSHA BLACKBURN, Tennessee 

BRIAN P. BILBRAY, California 

CHARLES F. BASS, New Hampshire 

PHIL GINGREY, Georgia 

STEVE SCALISE, Louisiana 

ROBERT E. LATTA, Ohio 

CATHY MCMORRIS RODGERS, Washington 

GREGG HARPER, Mississippi 

LEONARD LANCE, New Jersey 

BILL CASSIDY, Louisiana 

BRETT GUTHRIE, Kentucky 

PETE OLSON, Texas 

DAVID B. MCKINLEY, West Virginia 

CORY GARDNER, Colorado 

MIKE POMPEO, Kansas 

ADAM KINZINGER, Illinois 

H. MORGAN GRIFFITH, Virginia 

HENRY A. WAXMAN, California 

Ranking Member 

JOHN D. DINGELL, Michigan 

Chairman Emeritus 

EDWARD J. MARKEY, Massachusetts 

EDOLPHUS TOWNS, New York 

FRANK PALLONE, JR., New Jersey 

BOBBY L. RUSH, Illinois 

ANNA G. ESHOO, California 

ELIOT L. ENGEL, New York 

GENE GREEN, Texas 

DIANA DEGETTE, Colorado 

LOIS CAPPS, California 

MICHAEL F. DOYLE, Pennsylvania 

JANICE D. SCHAKOWSKY, Illinois 

CHARLES A. GONZALEZ, Texas 

JAY INSLEE, Washington 

TAMMY BALDWIN, Wisconsin 

MIKE ROSS, Arkansas 

JIM MATHESON, Utah 

G.K. BUTTERFIELD, North Carolina 

JOHN BARROW, Georgia 

DORIS O. MATSUI, California 

DONNA M. CHRISTENSEN, Virgin Islands 

KATHY CASTOR, Florida 

SUBCOMMITTEE ON HEALTH

JOSEPH R. PITTS, Pennsylvania 

Chairman 

MICHAEL C. BURGESS, Texas 

Vice Chairman 

ED WHITFIELD, Kentucky 

JOHN SHIMKUS, Illinois 

MIKE ROGERS, Michigan 

SUE WILKINS MYRICK, North Carolina 

TIM MURPHY, Pennsylvania 

MARSHA BLACKBURN, Tennessee 

PHIL GINGREY, Georgia 

ROBERT E. LATTA, Ohio 

CATHY MCMORRIS RODGERS, Washington 

LEONARD LANCE, New Jersey 

BILL CASSIDY, Louisiana 

BRETT GUTHRIE, Kentucky 

JOE BARTON, Texas 

FRED UPTON, Michigan (ex officio) 

FRANK PALLONE, JR., New Jersey 

Ranking Member 

JOHN D. DINGELL, Michigan 

EDOLPHUS TOWNS, New York 

ELIOT L. ENGEL, New York 

LOIS CAPPS, California 

JANICE D. SCHAKOWSKY, Illinois 

CHARLES A. GONZALEZ, Texas 

TAMMY BALDWIN, Wisconsin 

MIKE ROSS, Arkansas 

JIM MATHESON, Utah 

HENRY A. WAXMAN, California (ex officio) 

(II) 

(III) 

C O N T E N T S 

Page 

Hon. Joseph R. Pitts, a Representative in Congress from the Commonwealth 

of Pennsylvania, opening statement ................................................................... 1 

Prepared statement ................................................................................................. 3 

Hon. Michael C. Burgess, a Representative in Congress from the State of 

Texas, opening statement .................................................................................... 5 

Prepared statement .......................................................................................... 6 

Hon. Henry A. Waxman, a Representative in Congress from the State of 

California, opening statement ............................................................................. 8 

Hon. Leonard Lance, a Representative in Congress from the State of New 

Jersey, opening statement ................................................................................... 9 

Prepared statement .......................................................................................... 11 

Hon. Tim Murphy, a Representative in Congress from the Commonwealth 

of Pennsylvania, opening statement ................................................................... 12 

Hon. Phil Gingrey, a Representative in Congress from the State of Georgia, 

opening statement ................................................................................................ 12 

Prepared statement .......................................................................................... 14 

Hon. Frank Pallone, Jr., a Representative in Congress from the State of 

New Jersey, opening statement .......................................................................... 15 

Hon. John D. Dingell, a Representative in Congress from the State of Michigan, prepared statement ...................................................................................... 59 

Hon. Anna G. Eshoo, a Representative in Congress from the State of California, prepared statement .................................................................................. 79 

Hon. Marsha Blackburn, a Representative in Congress from the State of 

Tennessee, prepared statement .......................................................................... 202 

WITNESSES

Margaret A. Hamburg, Commissioner, Food and Drug Administration ............. 16 

Prepared statement .......................................................................................... 19 

Answers to submitted questions ...................................................................... 203 

Geno Germano, President and General Manager, Specialty Care and Oncology, Pfizer, Inc. ..................................................................................................... 100 

Prepared statement .......................................................................................... 103 

Answers to submitted questions ...................................................................... 237 

David L. Gollaher, President and Chief Executive Officer, California 

Healthcare Institute ............................................................................................. 113 

Prepared statement .......................................................................................... 115 

Answers to submitted questions ...................................................................... 240 

Richard F. Pops, Chairman and Chief Executive Officer, Alkermes, on Behalf 

of Biotechnology Industry Organization ............................................................. 123 

Prepared statement .......................................................................................... 125 

Answers to submitted questions ...................................................................... 243 

David E. Wheadon, Senior Vice President, Scientific and Regulatory Affairs, 

Pharmaceutical Research and Manufacturers of America ............................... 137 

Prepared statement .......................................................................................... 139 

Answers to submitted questions ...................................................................... 247 

Allan Coukell, Director of Medical Programs, Pew Health Group, The Pew 

Charitable Trusts ................................................................................................. 154 

Prepared statement .......................................................................................... 156 

Answers to submitted questions 1 ...................................................................

Diane Endquist Dorman, Vice President, Public Policy, National Organization 

for Rare Disorders ................................................................................................ 162 

Prepared statement .......................................................................................... 164 

Answers to submitted questions ...................................................................... 251 

Page

IV 

Daniel A.C. Frattarelli, Chair of Pediatrics, Oakwood Hospital and Medical 

Center, on Behalf of the American Academy of Pediatrics’ Committee on 

Drugs ..................................................................................................................... 175 

Prepared statement .......................................................................................... 177 

Answers to submitted questions ...................................................................... 255 

SUBMITTED MATERIAL

Summary, undated, of H.R. 1483, the Drug Safety Enhancement Act of 2011, 

submitted by Mr. Dingell .................................................................................... 62 

Statement, dated February 1, 2012, of the National Community Pharmacists 

Association, submitted by Mr. Pitts ................................................................... 89 

Statement, dated February 1, 2012, of the National Association of Chain 

Drug Stores, submitted by Mr. Pitts .................................................................. 92 

1Mr. Coukell did not answer submitted questions for the record. 

(1) 

REAUTHORIZATION OF PDUFA: WHAT IT 

MEANS FOR JOBS, INNOVATION, AND PATIENTS 

WEDNESDAY, FEBRUARY 1, 2012 

HOUSE OF REPRESENTATIVES, 

SUBCOMMITTEE ON HEALTH, 

COMMITTEE ON ENERGY AND COMMERCE, 

Washington, DC. 

The subcommittee met, pursuant to call, at 10:02 a.m., in room 

2123 of the Rayburn House Office Building, Hon. Joseph R. Pitts 

(chairman of the subcommittee) presiding. 

Members present: Representatives Pitts, Burgess, Shimkus, Rogers, Myrick, Murphy, Gingrey, Latta, Lance, Cassidy, Guthrie, 

Bilbray, Griffith, Pallone, Dingell, Towns, Capps, Schakowsky, 

Gonzalez, Ross, Matheson, Markey, Eshoo, Christensen, and Waxman (ex officio). 

Staff present: Clay Alspach, Counsel, Health; Michael 

Beckerman, Deputy Staff Director; Mike Bloomquist, General 

Counsel; Anita Bradley, Senior Policy Advisor to Chairman Emeritus; Andy Duberstein, Deputy Press Secretary; Paul Edattel, Professional Staff Member, Health; Debbee Keller, Press Secretary; 

Ryan Long, Chief Counsel, Health; Carly McWilliams, Legislative 

Clerk; John O’Shea, Professional Staff Member, Health; Heidi Stirrup, Health Policy Coordinator; Alli Corr, Democratic Policy Analyst; Eric Flamm, FDA Detailee; Karen Lightfoot, Democratic Communications Director and Senior Policy Advisor; Karen Nelson, 

Democratic Deputy Committee Staff Director for Health; and Rachel Sher, Democratic Senior Counsel. 

OPENING STATEMENT OF HON. JOSEPH R. PITTS, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH 

OF PENNSYLVANIA 

Mr. PITTS. The subcommittee will come to order. The chair recognizes himself for 5 minutes for an opening statement. 

Today, we will discuss reauthorizations of the Prescription Drug 

User Fee Act, PDUFA, the Best Pharmaceuticals for Children Act, 

BPCA, and the Pediatric Research Equity Act, PREA, all of which 

expire September 30 of this year. We will also discuss pharmaceutical supply chain issues. 

PDUFA was first authorized by Congress in 1992 with the goal 

of expediting human drug applications through the FDA approval 

process. Under the act and its subsequent reauthorizations, the 

drug industry pays user fees to FDA, and FDA commits to meet 

2 

certain performance goals. I am pleased that the industry and FDA 

have reached an agreement for PDUFA V, and I look forward to 

hearing more of the details from our witnesses. Under the agreement, industry would pay over $700 million in fiscal year 2013, and 

higher amounts in the remaining 4 years. 

The PDUFA V agreement is designed to speed new drugs to patients awaiting treatments and cures, while ensuring the highest 

safety standards. It is also designed to make the approval process 

more timely, predictable, and certain for drug sponsors and the 

venture capitalists who fund new drug research. 

Among the highlights, the agreement increases the communication between FDA and drug sponsors, specifically building contacts 

and meetings into the regulatory review process. To increase the efficiency and predictability of the review process, a new 60-day validation period will be used for FDA and drug sponsors to communicate, interact and plan before the clock officially starts. 

We are also here to discuss the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. BPCA gives FDA 

the authority to extend a 6-month period of market exclusivity to 

a manufacturer in return for specific studies on pediatric use. 

Under PREA, a manufacturer of a new drug or biologic is required 

to submit studies of a drug’s safety and effectiveness when used by 

children. 

Most prescription drugs have never been the subject of studies 

specifically designed to test their effects on children. Yet, when no 

pediatric-approved drugs exist for an illness, doctors often prescribe 

these medications to children, relying on the safety and effectiveness demonstrated with adults, in the absence of clinical data on 

how the drug may work in a child. As a father and grandfather, 

I view reauthorizing BPCA and PREA as a step toward obtaining 

that data and ensuring that our children and grandchildren receive 

the correct medications and correct dosages when they are ill. 

We should not forget that Americans are the most innovative 

people on earth, and the United States leads the world in new drug 

development. Some 4 million jobs in the United States are directly 

or indirectly supported by the drug industry. 

If the goals of the PDUFA V agreement are realized, we will continue to be the world leader in new, safe and effective life-saving 

and life-enhancing drugs; American patients will have timely access to treatments and cures for everyday maladies, chronic illnesses, and terminal diseases; and we will keep good, well-paying 

jobs here in the United States. 

[The prepared statement of Mr. Pitts follows:] 

3 


76491.001

Opening Statement of the Honorable Joseph R. Pitts 

Subcommittee on Health 

Reauthorization of PDUFA: What It Means for Jobs, Innovation, and Patients 

February 1,2012 

Today, we will discuss reauthorizations of the Prescription Drug User Fee Act (PDUFA), the Best 

Pharmaceuticals for Children Act (BPCA), and the Pediatric Research Equity Act (PREA), all of which 

expire September 30th of this year. 

We will also discuss pharmaceutical supply chain issues. 

PDUFA was first authorized by Congress in 1992 with the goal of expediting human drug applications 

through the FDA approval process. 

Under the Act and its subsequent reauthorizations, the drug industry pays user fees to FDA and FDA 

commits to meet certain performance goals. 

! am pleased that the industry and FDA have reached an agreement for PDUFA V, and [ look forward to 

hearing more of the details from our witnesses. 

Under the agreement, industry would pay over $700 million in FY20 13, and higher amounts in the 

remaining four years. 

The PDUF A V agreement is designed to speed new drugs to patients awaiting treatments and cures, while 

ensuring the highest safety standards. 

It is also designed to make the approval process more timely, predictable, and celtain for drug sponsors and 

the venture capitalists who fund new drug research. 

Among the highlights, the agreement increases the communication between FDA and drug sponsors, 

specifically building contacts and meetings into the regulatory review process. 

To increase the efficiency and predictability of the review process, a new 60-day validation period will be 

used for FDA and drug sponsors to communicate, interact, and plan before the clock officially starts. 

We are also here to discnss the Best Pharmaceuticals for Children Act and the Pediatric Research Equity 

Act. 

BPCA gives FDA the authority to extend a six-month period of market exclusivity to a manufacturer, in 

return for specific studies on pediatric use. 

Under PREA, a manufacturer ofa new drug or biologic is-required to submit studies ofa drug's safety and 

effectiveness when used by children. 

Most prescription drugs have never been the subject of studies specifically designed to test their effects on 

children. 

Yet, when no pediatric-approved drugs exist for an illness, doctors often prescribe these medications to 

children, relying on the safety and effectiveness demonstrated with adults, in the absence of clinical data on 

how the drug may work in a child. 

As a father and grandfather. I view reauthorizing BPCA and PREA as a step toward obtaining that data and 

ensuring that our children and grandchildren receive the corrcct medications and correct dosages when they 

are ill. 
4 


76491.002

We should not forget that Americans are the most innovative people on earth, and the United States leads 

the world in new drug development. Some four million jobs in the U.S. are directly or indirectly supported 

by the drug industry. 

If the goals of the PDUFA V agreement are realized: 

We will continue to be the world leader in new, safe, and effective life-saving and life-enhancing 

drugs; 

American patients will have timely access to treatments and cures for everyday maladies, chronic 

illnesses, and terminal diseases; 

• and we will keep good, well-paying jobs here in the U.S. 
5 

Mr. PITTS. I would like to thank all of our witnesses for coming 

today and now yield to the vice chairman, Dr. Burgess. 

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A 

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS 

Mr. BURGESS. Thank you, Mr. Chairman and Madam Commissioner. Thank you very much for being here. Thank you for the 

hospitality you have shown to me and my staff on the two times 

we ventured out to the FDA during your tenure. I certainly appreciate the time you spent with us. 

We are here to talk about the User Fee Act reauthorizations, but 

we are also here to ask some questions about how the FDA as a 

whole is successfully accomplishing its mission. If we don’t understand where we are, it is hard to know where we are trying to go, 

and this committee has already laid an aggressive schedule and 

foundation for the user fee reauthorizations. Certainly, today’s 

hearing is going to be a big part of that because it is an issue of 

patient safety, and we are all for patient safety. That is not a partisan issue. We are also all for creation of American jobs. That is 

not a partisan issue, or should not be a partisan issue either. 

And the big question I have is the lack of predictability driving 

American drug manufacturers out of the country. We are trying to 

encourage job growth and innovation in this country. Does the 

FDA’s slow approval process send venture capitalists elsewhere 

where they can find more stability? Is there a way to continue to 

streamline the approval process of single-molecule drugs where you 

have the most regulatory experience? 

The FDA must have the infrastructure and programs in place in 

order that innovations are dealt with in a fashion that assures 

safety for the patient and a straightforward and streamlined approved process. 

Mr. Chairman, I thank you for the recognition. I will yield back 

the balance of my time. 

[The prepared statement of Mr. Burgess follows:] 

6 


76491.003

Congressman Michael C. Burgess, M.D. 

Opening Statement 

Reauthorization ofPDUFA: What It Means for Jobs, Innovation, and Patients 

Energy & Commerce Committee: Health Subcommittee 

February 1,2012 

Thank you Mr. Chairman, 

As the time approaches for the reauthorization of PDUF A it is essential we look 

not only if the FDA is meeting the goals outlined in statute, but if the agency as a whole 

is successfully accomplishing its mission. Where we are is just as important as where we 

want to go. 

This Committee has already laid an aggressive foundation for the User Fee 

Reauthorizations. Today we have Commissioner Hamburg and I look forward to further 

advancing many of the issues that will impact all the agreements, and certainly PDUFAthe subject oftoday's hearing is no exception. 

These Agreements present us with tremendous opportunity as we all want a strong and 

efficient FDA that provides both clarity for companies on approval and a watchdog for 

American patients and thus need not fall subject to unnecessary partisanship. 

Lack of predictability is driving American drug manufactures out of the country. When 

we are trying to desperately encourage job growth and innovation in this country, slow 

FDA approval process sends venture capitalists elsewhere where they can tind more 

stability. 

FDA can continue to streamline the approval process of single molecule drugs- which 

they have the most regulatory experience. 
7 


76491.004

FDA must have the infrastructure and programs in place to ensure all innovations are 

dealt with in a fashion that ensures safety for the patient as well as a straightforward and 

stream I ined approval process. 

But if we can't handle the fundamentals, then we have a big problem. 

I look forward to working with this subcommittee throughout the reauthorization process 

and having a constructive dialogue with FDA to make sure we gel on the right path. 

Thank you and I yield back. 
8 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

ranking member of the full committee, Mr. Waxman, for 5 minutes. 

OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF CALIFORNIA 

Mr. WAXMAN. Thank you, Mr. Chairman, and thank you, Mr. 

Pallone, for allowing me to give my statement at this point. 

Today, we begin, once again, the process of reauthorizing the 

UFAs and our pediatric drug testing laws. I have been a part of 

this process since the inception of each of these programs, starting 

first with the Prescription Drug User Fee Act in 1992. In every reauthorization, we have worked together on a bipartisan basis. Of 

course, that is how it should be, given the role these laws play in 

helping FDA fulfill its vital public health mission. 

The drug and device user fee programs ensure that FDA gets 

critical dollars to allow the agency to complete its premarket review in a timely manner so that patients have access to therapies 

at the earliest possible time. The Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act give FDA the authority to obtain information about the use of drugs in children. 

And this year, for the first time, we will be establishing two new 

programs to help speed FDA’s review of low-cost generics and 

biosimilars. 

As we begin this process, these are the primary goals we need 

to keep in mind. We must reauthorize and establish these essential 

programs in a timely way so that FDA can do its job protecting the 

health and safety of American patients. It would be irresponsible 

to allow this legislation to become a vehicle for the wish lists of 

members seeking to move their own controversial bills. I hope we 

should continue the long tradition of UFA bipartisanship and work 

together to ensure this does not happen. 

I am concerned, however, about some of the bills our counterparts across the aisle have suggested will be under consideration. 

Some of these bills would prevent FDA from insisting on adequate 

data from clinical trials and forcing it to approve drugs and devices 

on an incomplete record. These proposals would prove disastrous 

for the safety and efficacy of our drugs and devices. Another would 

enrich the pharmaceutical industry by gutting the time-tested system of incentives provided under Hatch-Waxman. The cost of this 

windfall would fall on the backs of American patients who under 

that proposal would be forced to pay monopoly drug prices for 15 

years. 

Another controversial proposal the majority intends to consider 

would fundamentally reform FDA’s mission by adding things like 

‘‘economic growth, innovation, competitiveness, and job creation’’ to 

the agency’s priorities. The title of this hearing suggested our colleagues across the aisle also believe that creating jobs should be 

one of FDA’s many responsibilities. I hope we would all agree that 

FDA should not take jobs into consideration when it is reviewing 

the safety and effectiveness of a new medicine. We want FDA to 

ensure that our drugs and devices are safe and effective. Whether 

jobs will be created is simply not a part of that scientific public 

health equation. As a matter of fact, some of the new drugs, if they 

9 

are higher priced and don’t do any more than the older drugs, may 

be a financial burden and one could then evaluate that at FDA, 

which is also not FDA’s appropriate role. 

It appears that many of these proposals are driven by rhetoric 

insisting that FDA has become too demanding of companies seeking to market their drugs and devices. As a result, innovation and 

jobs are being driven abroad. When we examine claims as serious 

as these, we must insist on data and on facts. Biased anecdotes 

from individual constituent companies do not qualify as fact. I am 

aware of no reliable data showing that these claims are true. To 

the contrary, I am aware of some studies showing, for example, 

that FDA actually approves drugs faster than our counterparts in 

Europe. I am also aware of a study showing that FDA is quite 

flexible in its requirements in reviewing orphan drug applications. 

NORD is here today and will testify on this study. 

We should all be united in the goal of ensuring that we have a 

strong, well-resourced FDA that is armed with a full complement 

of authorities to protect us from unsafe drugs and to assure that 

those drugs work. That is FDA’s fundamental mission, and it is in 

no one’s interest to have a weak FDA. American consumers depend 

on FDA. If Americans lose confidence in the FDA, they will lose 

confidence in the pharmaceutical and medical device industries as 

well. 

One final point. I appreciate that we are looking at the increasing globalization of our drug supply as a feature of our hearing. It 

is critically important issue. FDA has indicated that it needs an 

updated set of tools to deal with this dramatically different marketplace, and I look forward to hearing more on this issue from our 

witnesses today. 

Mr. Dingell, Mr. Pallone, Ms. DeGette and I have proposed legislation, the Drug Safety Enhancement Act, that will go a long way 

toward providing FDA with these much-needed resources and authorities. 

Thank you, Mr. Chairman. I yield back the balance of my time. 

Mr. PITTS. The chair thanks the gentleman and now recognizes 

the gentleman from New Jersey, Mr. Lance, for 5 minutes. 

OPENING STATEMENT OF HON. LEONARD LANCE, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW JERSEY 

Mr. LANCE. Thank you, Mr. Chairman. 

Congress first authorized PDUFA in response to lagging approval 

times for prescription drugs at the FDA. Under the agreement, the 

FDA collects funds from drug sponsors to help expedite the human 

drug approval process. Not only has PDUFA improved the approval 

times of drugs, but the past authorizations have led to improved 

safety policies, better communication and improved regulatory 

processes at the FDA. 

The current reauthorization, PDUFA V, includes provisions to 

provide the FDA with tools to make safe and effective new medicines available to patients in a more efficient, consistent and timely 

manner while maintaining the high review standards for safety 

and efficacy. Additionally, the agreement contains new provisions 

to address problems that have arisen since PDUFA IV. This inVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00013 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
10 

cludes the implementation of a new benefit risk framework, patient-focused drug development, standardization of the risk evaluation and mitigation strategies, and a new implementation plan for 

the rare-disease program, something that is close to my heart. 

I look forward to hearing from the panels on their views on the 

agreement and working with my colleagues on both sides of the 

aisle on the committee to reauthorize this vitally important legislation. 

Thank you, Mr. Chairman, and I yield the balance of my time 

to Dr. Murphy. 

[The prepared statement of Mr. Lance follows:] 

11 


76491.005

Opening Statement of the Honorable Leonard Lance 

Subcommittee on Health 

Reauthorization of PDUFA: What It Means for Jobs, Innovation, and Patients 

February 1, 2012 

Thank you Mr. Chairman. 

Congress first authorized the Prescription Drug User Fee Act (PDUFA) in response 

to lagging approval times for prescription drugs at the US Food and Drug 

Administration (FDA.) Under the agreement, the FDA collects funds from drug 

sponsors to help expedite the human drug approval process. 

Not only has the PDUFA legislation improved the approval times of drugs, but the 

past three authorizations have led to improved safety policies, better 

communication and improved regulatory processes at the FDA. 

The current reauthorization, PDUFA V, includes provisions to provide the FDA 

with tools to make safe and effective new medicines available to patients in a more 

efficient, consistent and timely manner while maintaining the high review 

standards for safety and efficacy. 

Additionally, the agreement contains new provisions to address problems that have 

arisen since PDUFA IV. This includes the implementation of a new benefit-risk 

framework, patient-focused drug development, standardization of the Risk 

Evaluation and Mitigation Strategies and a new implementation plan for the Rare 

Disease Program, an area I am particularly interested in. 

I look forward to hearing from the panels on their views on the agreement and 

working with my colleagues on the committee to reauthorize this vitally important 

legislation. 

Thank you, I yield back my time. 
12 

OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA 

Mr. MURPHY. I thank the gentleman for yielding. 

As this committee begins the processing of reauthorizing the Prescription Drug User Fee Act, it is important to look back at where 

we were when this was first enacted. 

Prior to the first PDUFA agreement in 1992, it took almost 2 

years for the FDA to review new drug applications and roughly 70 

percent of all new drugs were entering the market overseas before 

they became available to U.S. patients. By 2007, review time for 

new drugs had been reduced to just over 1 year. The backlog of applications that had been built up prior to PDUFA had been cleared, 

and today, 50 percent of new drugs are now marketed in the 

United States first, making us the world leader in bringing new 

treatments to market. 

The certainty and transparency provided to drug manufacturers 

as a result of PDUFA have been key drivers of economic development in the biopharmaceutical sector. In 2009, the industry was directly supporting almost 650,000 jobs and as many as 4 million 

jobs indirectly while boasting a total economic impact of $918 billion annually. 

Now industry and the FDA have come together and negotiated 

an agreement that seeks to expand transparency and consistency 

in the drug approval process while continuing to ensure patient 

safety. As this committee reviews this agreement, we must have 

three priority goals: one, ensuring the safety of patients; two, facilitating access to new treatments for patients as soon and as safely 

as possible; and three, establishing a review process that continues 

to allow U.S. pharmaceutical jobs to flourish. Let us gather the 

facts on these three essential goals and work together towards a 

bill that saves lives and saves jobs. 

With that, Mr. Chairman, I will yield to Dr. Gingrey of Georgia. 

OPENING STATEMENT OF HON. PHIL GINGREY, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF GEORGIA 

Mr. GINGREY. Mr. Chairman, I thank the gentleman from Pennsylvania for yielding to me. 

The reauthorization of the FDA user fee program presents Congress with the opportunity to improve upon the current U.S. drug 

and device approval pathway. These hearings also present us with 

an opportunity to work together for patients and businesses back 

home in our districts who tell us that reform is long overdue. I look 

forward to working with my colleagues on both sides of the aisle 

to accomplish this worthy goal. 

To Dr. Hamburg, a special welcome. It is good to see you before 

this subcommittee again, Dr. Hamburg. You and I have spent time 

talking over the past year and a half about the potential that regulatory science holds as well as the need to spur antibiotic drug development, and I want to commend you for your leadership in these 

fields and personally thank you for your support of our efforts on 

Generating Antibiotic Incentives Now, the GAIN Act, H.R. 2182. 

My GAIN Act original cosponsors, Gene Green, Ed Whitfield, Diana 

DeGette, John Shimkus, Anna Eshoo, Mike Rogers, and the latest 

13 

edition, and not the least, Ed Markey, thank you for your efforts 

and that of your staff on the GAIN Act. This is truly a bipartisan 

piece of legislation. We created it together. We have advocated for 

it together, and it is because of our combined efforts that it has a 

real chance of becoming law. 

Finally, thank you to the long list of GAIN Act supporters, and 

specifically, the Pew Charitable Trust, which I see will be testifying 

on the second panel. 

With that, Mr. Chairman, I thank you for the time and I yield 

back. 

[The prepared statement of Mr. Gingrey follows:] 

14 


76491.006

Opening Statement of the Honorable Phil Gingrey 

Committee on Energy and Commerce 

Snbcommittee on Health 

February I, 2012 

Reauthorization of PDUFA: What It Means for Jobs, Innovation, and Patients 

The reauthorization of the FDA user fee programs presents Congress with the 

opportunity to improve upon the current U.S. drug & device approval pathway. These 

hearings also present us with an opportunity to work together for patients and businesses 

back home in our districts who tell us that reform is long overdue. I look forward to 

working with my colleagues on both sides of the aisle to accomplish this worthy goal. 

To Dr. Hamburg, a special welcome. It is good to see you before this 

subcommittee again. You and I have spent some time talking over the past year and a 

half about the potential that regulatory science holds as well as the need to spur antibiotic 

drug development. I want to commend you for your leadership in these fields and 

personally thank you for your support of our efforts on the Generating Antibiotic 

Ineentives Now (GAIN) Act - H.R.2182. 

To my GAIN Act co-authors Gene Green, Ed Whitfield, Diana DeGette, John 

Shimkus, Anna Eshoo, & Mike Rogers - thank you for the efforts of you and your staff 

on the GAIN Act. This is truly a bipartisan piece of legislation. We created it together, 

we have advocated for it together, and it is because of our combined efforts that it has a 

real chance of becoming law. Finally, thank you to the long list of GAIN Act supporters 

and specifically the PEW Charitable Trust - which [ see will be testifying on the second 

panel. 
15 

Mr. PITTS. The chair thanks the gentleman and yields to the 

ranking member of the subcommittee, Mr. Pallone, for 5 minutes. 

OPENING STATEMENT OF HON. FRANK PALLONE, JR., A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW JERSEY 

Mr. PALLONE. Thank you, Chairman Pitts, and I welcome today’s 

hearing and I am very much looking forward to working together 

on the critical business of this subcommittee. 

This is the beginning of a multi-month process in this subcommittee that will involve many hearings, lengthy deliberations, 

negotiations amongst members and staff, and final legislation on 

critical FDA policy. 

The User Fee Acts, which has become known as the UFAs, will 

include reauthorizations of some successful and some not as successful FDA programs. This will be our subcommittee’s opportunity 

of working alongside the FDA, industry and other stakeholders to 

build upon and improve these critical programs. It will also include 

some new programs such as a generic drug user fee program that 

I am optimistic will help to advance generic drug utilization in this 

country. 

But today’s hearing will focus on the reauthorization of the Prescription Drug User Fee Act, otherwise known as PDUFA. Originally authorized in 1992, PDUFA has provided FDA with the additional resources it needs to efficiently review an application for a 

new drug or biologic to enter the marketplace. 

I would like to first applaud the FDA and the brand drug industry for coming together on this thorough and responsible agreement. PDUFA has been a remarkable success, giving patients access to safe, effective and breakthrough medical treatments while 

supporting the advancement of science and promoting a thriving 

pharmaceutical industry in the United States, and I know that we 

all agree that failure to reauthorize PDUFA in a timely manner 

would be extraordinarily disruptive and a misstep for all parties involved, so I look forward to hearing from our witnesses about the 

important compromises made in this agreement and how it will 

help to strengthen the PDUFA program overall. 

That said, I would like to note that as we set out to reauthorize 

this program for a fourth time, an important issue remains unresolved, and that is the growing globalization of the drug marketplace. I believe that Americans deserve the confidence that the 

drugs they rely on will help them get better and not make them 

more sick. That is why along with Mr. Dingell, Mr. Waxman and 

Ms. DeGette, I will be advocating for critical provisions of the Drug 

Safety Enhancement Act to be included in these reauthorizations. 

The bill would equip the FDA with the increased authorities and 

resources it needs to keep pace with an increasingly international 

marketplace of products. It is imperative that the FDA play a role 

in improving quality and safety standards of manufacturing facilities abroad. This legislation process presents a unique opportunity 

for this subcommittee to make extraordinary changes to enhance 

our drug safety laws, and it is my hope that my colleagues on both 

sides of the aisle, consumer advocates and the regulated industry, 

16 

can all come together to ensure we address the safety of the Nation’s drug supply in a meaningful way. 

Also under discussion today is the reauthorization of two pediatric programs, the Best Pharmaceuticals for Children Act, BPCA, 

and the Pediatric Research Equity Act, PREA, which are designed 

to provide necessary research on the appropriate use of prescription 

drugs in pediatric populations. These programs have been crucial 

in the successful cultivation of important research used by doctors 

and parents to better determine what kind of drug therapy is 

safest and most appropriate for a child. Above all else, we must ensure that the prescriptions our children use are tested appropriately and deemed safe. I believe that we can all agree that we 

have an enormous responsibility to our children to make certain 

that they have access to the best possible medical treatment. BPCA 

and PREA are two different but complementary approaches towards accomplishing that goal. 

Now, the regulatory authority granted to FDA under PREA is 

linked to the expiration of BPCA and thus will also expire at the 

end of this fiscal year. I understand there are proposals being offered by some members on the subcommittee that would sunset the 

expirations on both programs, and I have some concerns with that 

approach, so I am eager to hear from our witnesses about their 

views on the linkage and expiration of these programs. 

Now it is time for us to get to work on these critical issues. It 

is my hope that our subcommittee can work in a bipartisan manner 

and produce strong consensus legislation, and again, I want to 

thank all our witnesses for being here today, including Dr. Hamburg, who I have to say with regard to Dr. Hamburg, she has been 

incredibly cooperative, come to my district and I know other districts to talk about the FDA, and I do believe we have made substantial progress under your leadership, so I want to commend you 

for that. Thanks. 

I yield back, Mr. Chairman. 

Mr. PITTS. The chair thanks the gentleman. 

We have two panels today. Our first panel will have just one witness, Dr. Margaret Hamburg, the Commissioner of FDA, and we 

are happy to have you with us today. 

Dr. Hamburg, you are recognized for 5 minutes for your opening 

statement. 

STATEMENT OF MARGARET A. HAMBURG, COMMISSIONER, 

FOOD AND DRUG ADMINISTRATION 

Ms. HAMBURG. Good morning, Mr. Chairman and members of the 

subcommittee. I am Dr. Margaret Hamburg, Commissioner of Food 

and Drugs, and I really do appreciate this opportunity to discuss 

the reauthorization of both the Prescription Drug User Fee Act and 

legislation to promote pediatric drug testing, laws that will expire 

if not reauthorized this year. I will also talk about FDA’s efforts 

to promote science and innovation as well as the continuing challenges of ensuring the safety of medical products in a global marketplace. 

I am joined today by Dr. Theresa Mullin, who is the Director of 

the Office of Planning and Informatics in the Center for Drug Evaluation and Research, and Deborah Autor, Deputy Commissioner for 

17 

Global Regulatory Operations and Policy. Dr. Mullin actually 

served as FDA’s lead negotiator during the recent PDUFA reauthorization discussions and leads our long-range planning efforts 

within the Center for Drug Evaluation and Research. I have also 

charged Ms. Autor, Deb Autor, in a new role recently to really help 

the agency to adapt to the challenges of globalization and import 

safety as the Deputy Commissioner of a newly organized entity to 

really focus on these important challenges. Both are very distinguished and they are available to help answer some of the questions that you may have based on their ample experience and 

knowledge. 

I am pleased to report that we have transmitted our recommendations for three user fee programs to help fund our prescription drug, generic drug and biosimilar review programs to 

Congress ahead of schedule. I am also very placed to announce this 

morning that FDA and industry have also agreed in principle to a 

user fee program for medical devices. 

Congress first enacted the Prescription Drug User Fee Act, also 

known as PDUFA, back in 1992, as was noted. Before PDUFA, 

FDA’s review process was understaffed, unpredictable and slow. 

Patients in the United States often had to wait for new products 

that were already available in foreign countries. PDUFA revolutionized the drug approval process by providing the funding necessary for us to conduct faster, more predictable reviews. 

In the nearly 20 years since PDUFA was first enacted, FDA has 

approved over 1,500 new drugs and biologics. In the last fiscal 

year, FDA approved 35 new groundbreaking medicines, actually 

the largest number second to only one other year in the last couple 

of decades. We were able to approve two new treatments for hepatitis C, groundbreaking medicines using more advanced science, 

targeting molecular targets linking diagnostics and therapeutics. 

We approved the first drug for Hodgkin’s lymphoma in 30 years 

and the first drug for lupus in 50 years, and just this week we approved innovative new drugs to treat cystic fibrosis and skin cancer, and we did it ahead of our PDUFA performance goals. The 

United States now in fact leads the world in the introduction of 

novel drugs. 

We look forward to working with the subcommittee on the fifth 

authorization of PDUFA. In keeping with the requirements Congress put into place, we negotiated this new PDUFA agreement 

with industry while regularly consulting consumer, patient and 

health care professional organizations. The agreement contains several enhancements that address the concerns raised by industry 

and public stakeholders as well as the agency’s priorities. These enhancements include initiatives to improve communication between 

FDA and industry to speed up drug development, advance the 

science behind drug regulation, particularly around rare diseases, 

enhance the way FDA evaluates the risks and benefits of therapies, 

modernize FDA’s drug safety system, and require electronic submission and standardize the format of the data that we receive. Together, these improvements, along with additional funding industry 

will be providing under the agreement, will allow us to maintain 

our Nation’s leadership in drug development while preserving our 

high standards for safety and efficacy. 

18 

On the same timetable for reauthorization as PDUFA are two 

laws designed to ensure that drugs are appropriately tested for 

their use in children, entitled the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, also known as 

BPCA and PREA. These two laws have dramatically improved our 

understanding of the safety and efficacy of drugs prescribed for our 

children, and I want to thank Representatives Mike Rogers and 

Anna Eshoo, who are leading the reauthorization efforts on these 

important laws. 

Before enactment of BPCA in 1997, all too often, health care professionals were forced to rely on imprecise and ineffective methods 

to provide medications for children such as adjusting dosing based 

on weight or crushing pills and mixing them in food. But today, as 

a result of BPCA and PREA, approximately 400 drugs have been 

studied and labeled specifically for pediatric use. We welcome the 

opportunity to work with Congress to reauthorize these successful 

programs. 

Lastly, I will turn to the challenges posed by globalization and 

FDA’s efforts to meet these challenges. Today, approximately 40 

percent of the drugs Americans take are manufactured outside our 

borders and up to 80 percent of the active pharmaceutical ingredients in those drugs come from foreign sources. Over the next decade, FDA will transform itself from a domestic agency operating in 

a globalized world to a truly global agency fully prepared for a regulatory environment in which product safety and quality knows no 

borders. 

To achieve this transformation, the agency is developing a new, 

more international operating model that relies on strengthening 

collaboration, improved information sharing and gathering, datadriven risk analytics, and the smart allocation of resources. We are 

eager to work with Congress to ensure that our regulatory authorities keep pace with an increasingly globalized world. 

So I thank you for the opportunity to testify today and I am 

happy to address any questions that you may have. 

[The prepared statement of Ms. Hamburg follows:] 

19 


76491.007

,.,. "''''''r~ 

( ~ DEPARTMENT OF HEALTH AND HUMAN SERVICES 

,~"z""" 

STATEMENT 

OF 

Food and Drug Administration 

Silver Spring. MD 20993 

MARGARET A. HAMBURG, M.D. 

COMMISSIONER OF FOOD AND DRUGS 

FOOD AND DRUG ADMINISTRATION 

DEPARTMENT OF HEALTH AND HUMAN SERVICES 

BEFORE THE 

SUBCOMMITTEE ON HEALTH 

COMMITTEE ON ENERGY AND COMMERCE 

U.S. HOUSE OF REPRESENTATIVES 

"REAUTHORIZATION OF PDUFA: WHAT IT MEANS FOR JOBS, 

INNOVATION, AND PATIENTS" 

February 1,2012 

RELEASE ONLY UPON DELIVERY 
20 


76491.008

INTRODUCTION 

Mr. Chainnan and' Members of the Committee, I am Dr. Margaret Hamburg, 

Commissioner of Food and Drugs at the Food and Drug Administration (FDA or the Agency). 

I am pleased to be here today to discuss the tiHh authorization of the Prescription Drug User 

Fee Act (PDUFA), also referred to as "PDUFA Y," and the renewal of legislation to promote 

pediatric drug testing. I will also talk about FDA's efforts to promote the science and 

innovation necessary to ensure that we are fully equipped to address the public health issues 

of the 21 st century and the continuing challenges of a global marketplace. 

Background on PDUF A 

FDA considers the timely review of the safety and effectiveness of New Drug 

Applications (NDA) and Biologics License Applications (BLA) to be central to the Agency's 

mission to protect and promote the public health. Prior to enactment of PDUFA in 1992, 

FDA's review process was understaffed. unpredictable, and slow. FDA lacked sufficient staff 

to perform timely reviews, or develop procedures and standards to make the process more 

rigorous, consistent, and predictable. Access to new medicines for U.S. patients lagged 

behind other countries. As a result of concerns expressed by both industry and patients, 

Congress enacted PDUF A, which provided the added funds through user fees that enabled 

FDA to hire additional reviewers and support staff and upgrade its information technology 

systems. At the same time, FDA committed to complete reviews in a predictable time frame. 

2 
21 


76491.009

These changes revolutionized the drug approval process in the United States and enabled 

FDA to speed the application review process for new drugs, without compromising the 

Agency's high standards for demonstration of safety, efficacy, and quality of new drugs prior 

to approval. 

Three fees are collected under PDUF A: application fees, establishment fees, and 

product fees. An application fee must be submitted when certain NDAs or BLAs are 

submitted. Product and establishment fees are due annually. The total revenue amounts 

derived from each of the categories-application fees, establishment fees, and product feesare set by the statute for each fiscal year (FY). PDUFA permits waivers under certain 

circumstances, including a waiver of the application fee for small businesses and orphan 

drugs. 

Of the total $931,845.581 obligated in support or the process for the review of human 

drug applications in FY 20 I 0, PDUF A fees funded 62 percent, with the remainder funded 

through appropriations. 

PDUF A Achievements 

PDUF A has produced significant benefits for public health, providing patients faster 

access to over 1,500 new drugs and biologics, since enactment in 1992, including treatments 

for cancer, infectious diseases, neurological and psychiatric disorders, and cardiovascular 

diseases. In FY 2011, FDA approved 35 new, groundbreaking medicines, including two 

treatments for hepatitis C, a drug for late-stage prostate cancer, the first drug for Hodgkin's 

3 
22 


76491.010

lymphoma in 30 years, and the first drug for lupus in 50 years. Oflhe 35 innovative drugs 

approved in FY 2011. 34 met their PDUFA target dates for review. 

Su/Jstantial(v Reduced Review Times 

PDUFA provides FDA with a source of stable, consistent funding that has made 

possible our efforts to focus on promoting innovative therapies and help bring to market 

critical products for patients. 

According to researchers at the Tufts Center for the Study of Drug Development, the 

time required for the FDA approval phase of new drug development (i.e., time from 

submission until approval) has bcen cut since the enactment of PDUFA, 1 from an average of 

2.0 years for the approval phase at the stmi of PDUFA to an average of 1.1 years more 

recently. 

FDA aims to review priority drugs more quickly, in six months vs. 10 months for 

standard drugs. Priority drugs are generally targeted at severe illnesses with few or no 

available therapeutic options. FDA reviewers give these drugs priority attention throughout 

development, working with sponsors to determine the most efficient way to collect the data 

needed to provide evidence of safety and effectiveness. 

Reversal of the "Drug Lag" 

Importantly, PDUFA has led to the reversal of the drug Jag that prompted its creation. 

Since the enactment ofPDUFA, FDA has steadily increased the speed of Americans' access 

to important new drugs compared to the European Union (EU) and the world as a whole. Of 

I Milne, Christopher-Paul (20 I 0). PDUFA and the Mission to Roth Protect and Promote Public 11ealth 

[PowerPoint slides]. Presentation at the FDA PDUFA Public Meeting, Rockville. MD. 

4 
23 


76491.011

the 35 innovative drugs approved in FY 2011, 24 (almost 70 percent) were approved by FDA 

before any other regulatory agency in the world, including the European Medicines Agency, 

Of 57 novel drugs approved by both FDA and the EU between 2006 and 20 I 0,43 (75 

percent) were approved first in the United States, 

Figure I below shows that since the late I 990s, the United States has regularly led the 

world in the first introduction of new active drug substances. 2 Preliminary data show that in 

2011, over half of all new active drug substances were tirst launched in the United States. 

Figure 1. U.S. Share of New Active Substances (NAS) First Launched on the World 

Market 

70% 

60% 

50% 

40% 

30% 

20% 

10% 

0% 

§ g 8 g 8 § g 8 : N N N N N N N N N 

Year of NAS First Launch Worldwide 

In recent ycars, FDA's drug review timcs also have been. on average, significantly 

faster than those in the EU. It is ditTicult to compare length of approvals for FY 2011 because 

many of the drugs approved in the United States have not yet been approved in the EU. A 

comparison of drugs approved in the United States and thc EU between 2006 and 2010 is 

illustrative. however. For priority drugs approved betwecn2006 and 2010. FDA's median 

'Scrip NeE Review/Scrip Yearbook/Scrip Magazine (1982 ·20()5), PharmaProjects R&D Annual Review 

(2006-20 I 0), New active substances include novel chemical or biological substances not previollsly approved to 

treat any disease. There is a close, but not complete overlap, between new active substances and new molecular 

entities: IlC\V active suhstances exclude raciiopilarmaccuticais. 

5 
24 


76491.012

time to approval was six months (183 days). more than twice as fast as the EU. which took a 

median time of 13.2 months (403 days). For standard drug reviews. FDA's median time to 

approval was 13 months (396 days). 53 days fasterthanthc EU lime of 14.7 months (449 

days). 

A recent at1iclc in the journal Health A/Ii/irs also compared cancer drugs approved in 

the United States and EU fi'OlTI 2003 through 20 10. Thirty-five cancer drugs were approved 

by the United States or the EU li'om October 2003 through December 20 I O. Of those. FDA 

approved 32--in an average time of 8.6 months (261 days). The EU approved only 26 of 

these products. and its average time was 12.2 months (373 days). This difference in approval 

times is not due to safety issues with these products. All 23 cancer drugs approved by both 

agencies during this period were approved first in the United States.] 

!'rovidil1f; Guidance 10 Induslrv 

Increased resources provided by user fees have enabled FDA to provide a large body 

of technical guidance to industry that clarified the drug development pathway for many 

diseases and to meet with companies during drug development to provide critical advice on 

specific development programs. In the past five years alone. FDA has held over 7.000 

meetings within a short time after a sponsor's request. Innovations in drug development are 

being advanced by many new companies as well as more established ones, and new sponsors 

may need, and often seek. more regulatory guidance during development. In FY 2009. more 

than half of the meetings FDA held with companies at the early investigational stage and 

3 "Despite Criticism Of The FDA Review Process, New Cancer Drugs Reach Patients Sooner ln The United 

States Than In Europe," .)(lJtumtha Ii, Rober!s. ,/(/ID. Allen. and l::/len /' S;gal. fh',dlh A{f(Jirs, .lUff(;' 20/}, 

6 
25 


76491.013

midway through the clinical trial process were with companies that had no approved product 

on the U.S. market. 

Weighing Benefit and Risk 

It should be noted that FDA assesses the benefit-risk of new drugs on a case-by-case 

basis, considering the degree of unmet medical need and the severity and morbidity of the 

condition the drug is intended to treat. This approach has been critical to increasing patient 

access to new drugs for cancer and rare and other serious diseases. where existing therapies 

have been few and limited in their effectiveness. Some of these products have serious side 

effects but they were approved because the benefit outweighed the risk. For examplc, in 

March oflast year, FDA approved Yervoy (ipilimumab) for the treatmcnt ofunresectable or 

metastatic melanoma. Yervoy also poses a risk of serious side effects in 12.9 percent of 

patients treated with Yervoy. including severe to fatal autoimmune reactions. However, FDA 

decided that the benefits of Yervoy outweighed its risks, especially considering that no other 

melanoma treatment has been shown to prolong a patient's life. 

As discussed in more detail below, PDUF A V will enable FDA to develop an 

enhanced. structured approach to benefit-risk assessments that accurately and concisely 

describes the benefit and risk considerations in the Agency's drug regulatory decisionmaking. 

5)Jeeding Access 

PDUFA funds help support the lise of existing programs to expedite the approval of 

certain promising investigational drugs, and also to make them available to the very ill as 

7 
26 


76491.014

early in the development process as possible, without unduly jeopardizing patient safety, We 

are committed to using these programs to speed therapies to patients while upholding our high 

standards of safety and efficacy, Balancing these two objectives requires that we continue to 

evaluate our use of the tools available to us and consider whether additional tools would be 

helpful. 

The most important of these programs are Priority Review (discussed earlier), 

Accelerated Approval, and Fast Track. In 1992, FDA instituted the Accelerated Approval 

process, which aJlows earlier approval of drugs that treat serious diseases and that fiJI an 

un met medical need based on a surrogate endpoint that is reasonably likely to predict clinical 

benefit, but is not fully validated to do so, or, in some cases, an effect on a clinical endpoint 

other than survival or irreversible morbidity. A surrogate endpoint is a marker-a laboratory 

measurement, or physical sign-that is used in clinical trials as an indirect or substitute 

measurement for a clinically meaningful outcome, such as survival or symptom improvement. 

For cxample, viral load is a surrogate endpoint for approval of drugs for the treatment of 

HIV/AlDS. The use ofa surrogate endpoint can considerably shorten the time to approval, 

allowing more rapid patient access to promising new treatments for serious or life-threatening 

diseases. Accelerated Approval is givcn on the condition that post-marketing clinical trials 

verify the anticipated clinical benefit. Over 80 new critical products have been approved 

under Accelerated Approval since the program was established, including nearly 30 drugs to 

treat cancer. Three of the 30 new molecular entities (NMEs) approved in 20 II were approved 

under Accelerated Approval. NMEs represent the truly innovative new medicines. 

8 
27 


76491.015

Once a drug receives Fast Track designation, early and frequent communications 

between FDA and a drug company are encouraged throughout the entire drug development 

and review process. The frequency of communications ensures that questions and issues are 

resolved quickly, oftcn leading to earlier drug approval and access by patients. 

FDA also recognizes circumstances in which there is public health value in making 

products available prior to marketing approval. A promising but not yet fully evaluated 

treatment may sometimes represent the best choice for individuals with serious or lifethreatening diseases, who lack a satisfactory therapy. 

FDA allows for access to investigational products through multiple mechanisms. 

Clinical trials are the best mechanism for a patient to receive an investigational drug, because 

they provide a range of patient protections and benefits and they maximize the gathering of 

useful information about the product, which benefits the entire patient population. However, 

there are times when an individual cannot enroll in a clinical trial. In some cases, the patient 

may gain access to an investigational therapy through one of the alternative mechanisms, and 

FDA's Office of Special Health Issues assists patients and their doctors in this endeavor. 

Challenges for the Current Drug Program 

Although we can report many important successes with the current program, new 

challenges have also emerged that offer an opportunity for further enhancement. While new 

authorities from the Food and Drug Administration Amendments Act of2007 (FDAAA) have 

strengthened drug safety, they have put strains on FDA's ability to meet premarket review 

performance goals and address post-market review activities. In addition, there has been a 

significant increase in the number of foreign sites included in clinical trials to tcst drug safety 

9 
28 


76491.016

and effectiveness, and an increase in the number of foreign facilities used in manufacturing 

new drugs for the U.S. market. While foreign sites can play an important role in enabling 

access to new drugs, the need to travel much farther to conduct pre-approval inspections for 

clinical trials and manufacturing sites overseas has created additional challenges for 

completion of FDA's review within the existing PDUFA review performance goals, while at 

the same time trying to communicate with sponsors to see if identified issues can be resolved 

before the review performance goal date. 

Despite these challenges, FDA has maintained strong performance in meeting the 

PDUF A application review goals, with the exception of a dip in FY 2008-09, when staff 

resources were shifted within the discretion afforded FDA to ensure timely implcmentation of 

all of the new FDAAA provisions that affected activities in the new drug review process. 

Recent pcrformance data show that FDA has returned to meeting or exceeding goals for 

review of marketing applications under PDUFA. This is shown in Figure 3. 

10 
29 


76491.017

;; 

0 

'Y' 

:e " 

.~ 

II> 

" 2 

,. 

.11 

0. 

c. 

<t 

(; 

:If. 

100% 

90% 

80% 

70% 

60% 

50% 

40% 

30% 

20% 

10%. 

0% 

COER POUFA Application Review Performance 

(NDAs, BLAs, Efficacy Supplements} 2005 ·2011 

Quart,,! of POUfA Due Date 

COER data as of 11130/201 L Figures reflact aggregate performance for all NOAs, BlAs, and 

Efficacy Supplements based on the month of the POUFA review goa! 

However, FDA wants to meet not only the leller, but also tbe spirit of the PDUFA 

program. That is, we want to speed patient access to drugs sbown to be safe and effective for 

the indicated uses while also meeting our PDUFA goals. 

The NDAIBLA approval phase of drug development is reported to have the highest 

success rate of any phase of drug developmcnt. That is. the percentage of drugs that fail after 

the sponsor submits an NDA/BLA to FDA is less than the percentages that fail in preclinical 

development, and each phase of clinical developmcnt. At the same time, it is critical to our 

public health mission that we work with industry and other stakeholders to take steps to 

reduce unccrtainty and increase the success of all phases of drug development. We must 

leverage advances in science and technology to make sure that we have the knowledge and 

tools we need to rapidly and meaningfully evaluate medical products. The science of 

11 
30 


76491.018

developing new tools, standards, and approaches to assess the safety, efficacy, quality, and 

performance of FDA-regulated products--known as regulatory science-is about more than 

just speeding drug development prior to the point at which FDA receives an application for 

review and approval. It also gives us the scientific tools to modernize and streamline our 

regulatory process. With so much at stake for public health, FDA has made advances in 

regulatory science a top priority. The Agency is both supporting mission-critical science at 

FDA and exploring a range of new partnerships with the National Institutes of Health (NIH) 

and academic institutions to develop the science needed to maximize advances in biomedical 

research and bring the development and assessment of promising new therapies and devices 

into the 21 st century. With tbis effort, FDA is poised to support a wave of innovation to 

transform medicine and save lives. 

For example, FDA is working to improve the science behind certain clinical trial 

designs. Recent advances in two clinical trial designs-called non-inferiority and adaptive 

designs-have required FDA to conduct more complex reviews of clinical trial protocols and 

new marketing applications. Improving the scientilic bases of these trial designs should add 

efficiency to the drug review process. encourage the development of novel products, and 

speed new therapies to patients. 

FDA has also taken steps to help facilitate the development and approval of safe and 

effective drugs for Americans with rare diseases. Therapies for rare diseases-those affecting 

fewer than 200,000 people in the United States-represent the most rapidly expanding area of 

drug development. Although each disease affects a relatively small population, collectively, 

rare diseases affect about 25 million Americans. Approximately one-third of the NMEs and 

new biological products approved in the last live years have been drugs for rare diseases. 

12 
31 


76491.019

Because orthe small numbers of patients who suffer from each disease, FDA often allows 

11on-traditional approaches to establishing safety and effectiveness. For example, FDA 

approved Voraxaze (glucarpidase) in January 2012 to treat patients with toxic methotrexate 

levels in their blood due to kidney failure, which affects a small population of patients each 

year. Methotrexate is a commonly used cancer chemotherapy drug normally eliminated from 

the body by the kidneys. Patients receiving high doses of methotrexate may develop kidney 

failure. Voraxaze was approved based on data in 22 patients from a single clinical trial, 

which showed decreased levels of methotrexate in the blood. Prior to the approval of 

Voraxaze, there were no effective therapics for the treatment of toxic mcthotrexate levels in 

patients with renal failure. 

Just yesterday, January 31,2012, FDA approved Kalydeco (ivacaftor) to treat patients 

age 6 or older with Cystic Fibrosis (CF) and who have a specific genetic defect (0551 D 

mutation). CF occurs in approximately 30,000 children and adults in the United States. The 

0551 D mutation occurs in approximately 4 percent of patients with CF, totaling 

approximately 1,200 patients in the United States. CF is a serious inherited disease that 

affects the lungs and other organs in the body, leading to breathing and digestive problems, 

trouble gaining weight, and other problems. There is no cure for CF, and despite progress in 

the treatment of the disease, most patients with CF have shortcned life spans and do not live 

beyond their mid-30's. Ivacaftor was given a Priority Review by FDA. Due to the results of 

these studies showing a significant benefit to patients with CF with the G551 D mutation. 

ivacaftor was reviewed and approved by FDA in approximately half of the six-month Priority 

Review period. Ivacaftor will be the first mcdicine that targets the underlying cause of CF; 

currently, therapy is aimed at treating symptoms or complications of the disease. 

13 
32 


76491.020

PDUFA Reauthorization 

In PDUFA IV, Congress directed FDA to take additional steps to ensure that public 

stakeholders, including consumer, patient, and health care professional organizations, would 

have adequate opportunity to provide input to the reauthorization and any program 

enhancements for PDUFA V, Congress directed tbe Agency to hold an initial public meeting 

and then to meet with public stakeholders periodically, while conducting negotiations with 

industry to hear their views on the reauthorization and their suggestions I'llI' changes to the 

PDUFA performance goals, PDUFA IV also required that minutes from negotiation sessions 

held with industry be made public. 

Based on a public meeting held in April 20 I 0, input from a public docket, and the 

Agency's own internal analyses of program challenge areas, FDA developed a set of potential 

proposed enhancements for PDUFA V and in .Iuly 2010, began negotiations with industry and 

parallel discussions with public stakeholders. These discussions concluded in May 2011 and 

we held a public meeting on October 24, 20 II, where we solicited comments on the proposed 

recommendations. We also opened a public docket for comments. We considered these 

comments, and on January 13,2012. we transmitted the final recommendations to Congress. 

We are very pleased to report that the enhancements for PDUFA V address many of 

the top priorities identified by public stakeholders, the top concerns identified by industry, and 

the most important challenges identified within FDA. I will briefly summarize these 

enhancements. 

14 
33 


76491.021

A. Review Programfbr New Drug Applications, New Molecular Entities, and Original 

Biologics License Applications 

FDA's existing review perfonllance goals for priority and standard applications-six 

and 10 months respectively-were established in 1997. Since that time, additional 

requirements in the drug review process have made those goals increasingly challenging to 

meet, particularly for more complex applications like new molecular entity (NME) NDAs and 

original BLAs. FDA also recognizes that increasing communication between the Agency and 

sponsors during the application review has the potential to increase efficiency in the review 

process. 

To address the desire for increased communication and greater efficiency in the 

review process, we agreed to an enhancement to FDA's review program for NME NDAs and 

original BLAs in PDUFA V. This program includes pre-submission meetings, mid-cycle 

communications, and late-cycle meetings between FDA and sponsors for these appl ications. 

To accommodate this increased interaction during regulatory review, as agreed to with 

industry, FDA's review clock would begin after the 60-day administrative filing review 

period for this subset of applications. The impact of these modifications on the efficiency of 

drug rev iew for this subset of applications wi II be assessed during PD UF A V. 

B. Enhancing RegulatOl:V Science and Expediting Drug Development 

The following five enhancements focus on regulatory science and expediting drug 

development. 

15 
34 


76491.022

I. Promoting Innovation Through Enhanced Communication Between FDA and Sponsors 

During Drug Development 

FDA recognizes that timely interactive communication with sponsors can help foster 

efficient and effective drug development. In some eases. a sponsor's questions may be 

complex enough to require a formal meeting with FDA, but in other instances, a question may 

be relatively straightforward such that a response can be provided more quickly. However, 

our review staff's workload and other competing public health priorities can make it 

challenging to develop an Agency response to matters outside of the formal meeting process. 

This enhancement involves a dedicated drug development communication and training 

staff, focused on improving communication between FDA and sponsors during development. 

This staff will be responsible for identifying best practices for communication between the 

Agency and sponsors, training review staff, and disseminating best practices through 

published guidance. 

2. Methods for Meta-analysis 

A meta-analysis typically attempts to combine thc data or findings from multiple 

completed studies to explore drug benefits and risks and, in some cases, uncover what might 

be a potential safety signal in a premarket or post-market context. However, there is no 

consensus on best practices in conducting a meta-analysis. With the growing availability of 

clinical trial data, an increasing number of meta-analyses are being conducted based on 

varying sets of data and assumptions. If such studies conducted outside FDA find a potential 

safety signal, FDA will work to try to confirm-or correct-the information about a potential 

hann. To do this, FDA must work quickly to conduct its own meta-analyses to include 

publicly available data and the raw clinical trial data submitted by drug sponsors that would 

16 
35 


76491.023

typically not be available to outside researchers. This is resource-intensive work and often 

exceeds the Ageney's on-board scientific and computational capacity. causing delays in FDA 

findings that prolong public uncertainty. 

PD UF A V enhancements include the development of a dedicated staff to evaluate best 

practices and limitations in meta-analysis methods. Through a rigorous public comment 

proccss, FDA would develop guidance on best practices and the Agency's approach to mctaanalysis in regulatory review and decision-making. 

3. Biomarkers and Pharmacogenomics 

Phannacogenomics and the application of qualified biomarkers have the potential to 

decrease drug development time by helping to demonstrate benefits. establish unmet medical 

needs. and identify patients who are predisposed to adverse events. FDA provides regulatory 

advice on the use of biomarkers to facilitate the assessment of human safety in early phase 

clinical studies. to support claims of efficacy, and to establish the optimal dose selection for 

pivotal efficacy studies. This is an area of new science where the Agency has seen a marked 

increase in sponsor submissions to FDA. In the 2008-2010 period, the Agency experienced a 

nearly four-fold increase in this type of review work. 

PDUFA V enhancements include augmenting the Agency's clinical. clinical 

pharmacology, and statistical capacity to adequately address submissions that propose to 

utilize biomarkers or pharmaeogenomic markers. The Agency would also hold a public 

meeting to discuss potential strategies to facilitate scientific exchanges on biomarker issues 

between FDA and drug manufacturers. 

17 
36 


76491.024

4. Use of Patient-reported Outcomes 

Assessments of study endpoints known as paticnt-reported outcomcs (PROs) are 

increasingly an important part of successful drug development. PROs measure treatment 

benefit or risk in medical product clinical trials from the patients' point of view. They are 

critical in understanding drug benefits and harm from the patients' perspective. However, 

PROs require rigorous evaluation and statistical design and analysis to ensure reliability to 

support claims of clinical benefit. Early consultation between FDA and drug sponsors can 

ensure that endpoints are well-defined and reliable. However. the Agency does not have the 

capacity to meet the current demand from industry. 

PDUFA V enhancements include an initiative to improve FDA's clinical and 

statistical capacity (0 address submissions involving PROs and other endpoint assessment 

tools. including providing consultation during the early stages of drug development. In 

addition, FDA will convene a public meeting to discuss standards for PRO qualification, new 

theories in endpoint measuremcnt, and the implications for multi-national trials. 

5. Development of Drugs for Rare Diseases 

FDA's oversight of rare disease drug development is complex and resource intensive. 

Rare discases are a highly diverse collection of disorders, their natural histories are often not 

well-described, only small population sizes are often available for study, and they do not 

usually have well-defined outcome mcasures. This makes the design, execution, and 

interpretation of clinical trials for rare diseases difficult and time consuming, requiring 

frequent interaction between FDA and drug sponsors. If recent trends in orphan designations 

18 
37 


76491.025

are any indication, FDA can expect an increase in investigational activity and marketing 

applications for orphan products in the future. 

Another PDUF A V enhancement includes FDA facilitation ofrare disease drug 

development by issuing relevant guidance, increasing the Agency's outreach efforts to the 

rare disease patient community, and providing specialized training in rare disease drug 

development for sponsors and FDA staff. 

C. Enhancing Benefit-Risk Assessment 

FDA has been developing an enhanced, structured approach to benefit-risk 

assessments that accurately and concisely describes the benefit and risk considerations in the 

Agency's drug regulatory decision-making. Paft of FDA 's decision-making lies in thinking 

about the context of the decision-an understanding of the condition treated and the unmet 

medical need. Patients who live with a disease have a direct stake in the outcome of drug 

review. The FDA drug review process could benefit from a more systematic and expansive 

approach to obtaining the patient perspective on disease severity and the potential gaps or 

limitations in available treatments in a therapeutic area. 

PDUF A V cnhancements include expanded implementation of FDA's benefit-risk 

framework in the drug review process. including holding public workshops to discuss the 

application of frameworks for considering benefits and risks that arc most appropriate for the 

regulatory setting. FDA would also conduct a scries of public meetings between its review 

divisions and the relevant patient advocacy communities to review the medical products 

available tor specific indications or disease states that will be chosen through a public process. 

19 
38 


76491.026

D. Enhancement and Modernization of the FDA Drug Sof'ely System 

The enhancements for PDUF A V include two post-market, safety-focused initiatives. 

1. Standardizing Risk Evaluation and Mitigation Strategies 

FDAAA gave FDA authority to require a Risk Evaluation and Mitigation Strategy 

(REMS) when FDA finds that a REMS is necessary to ensure that the benefits of a drug 

outweigh its risks. Some REMS are more restrictive types of risk managcment programs that 

include elements to assure safe use (ET ASU). These programs can require such tools as 

prescriber training or certification, pharmacy training or certification, dispcnsing in certain 

health care settings, documentation of safe use conditions, required patient monitoring, or 

patient registries. ETASU REMS can be challenging to implement and evaluate, involving 

cooperation of all segments of the health care system. Our experience with REMS to date 

suggests that the development of multiple individual programs has the potential to create 

burdens on the health care system and, in some cases, could limit appropriate patient access to 

impoliant therapies. 

PDUF A V enhancements initiate a public process to explore strategies and initiate 

projects to standardize REMS with the goal of reducing burden on practitioners, patients, and 

others in the health care setting. Additionally, FDA will conduct public workshops and 

develop guidance on methods for assessing the effectiveness of REMS and the impact on 

patient access and burden on the health care system. 

20 
39 


76491.027

2. Using the Sentinel Initiative to Evaluate Drug Safety Issues 

FDA's Sentinel Initiative is a long-term program designed to build and implement a 

national electronic system for monitoring the safety of FDA-approved medical products. 

FDAAA required FDA to collaborate with federal, academic, and private entities to develop 

methods to obtain access to disparate data sources and validated means to link and analyze 

safety data to monitor the safety of drugs after they reach the market, an activity also known 

as "active post-market drug safety surveillance." FDA will use user fee funds to conduct a 

series of activities to determine the feasibility of using Sentinel to evaluate drug safety issues 

that may require regulatory action, e.g .. labeling changes, post-marketing requirements, or 

post-marketing commitments. This may shorten the time it takes to better understand new or 

emerging drug safety issues. PDUFA V enhancements will enable FDA to initiate a series of 

projects to establish the use of active post-market drug safety surveillance in evaluating postmarket safety signals in population-based databases. By leveraging public and private health 

care data sources to quickly evaluate drug safety issues, this work may reduce the Agency's 

reliance on required post-marketing studies and clinical trials. 

E. Required Electronic Submissions and Standardization of Electronic Application Data 

The predictability of the FDA review process relies heavily on the quality of sponsor 

submissions. The Agency currently receives submissions of original applications and 

supplements in formats ranging from paper-only to electronic-only, as well as hybrids of the 

two media. The variability and unpredictability of submitted formats and clinical data layout 

present major obstacles to conducting a timely, eftlcient, and rigorous review within current 

21 
40 


76491.028

PDUFA goal time frames. A lack of standardized data also limits FDA's ability to transition 

to more standardized approaches to benefit-risk assessment and impedes conduct of safety 

analyses that inform FDA decisions related to REMS and other post-marketing requirements. 

PDUFA V enhancements include a phased-in requirement for standardized, fully electronic 

submissions during PDUFA V for all marketing and investigational applications. Through 

partnership with open standards development organizations, the Agency would also conduct a 

public process to develop standardized terminology for clinical and non-clinical data 

submitted in marketing and investigational applications. 

F. User Fee Increase/iJr PDUFA V 

The cost of the agreed upon PD UF A V enhancements translates to an overall increase 

in fees of approximately six percent. 

G. P DUFA V EnhancementsfiJr a Modified Inflation Adjuster and Additional Evaluations of 

the Workload Adjusler 

In calculating user fees for each new fiscal year, FDA adjusts the base revenue amount 

by inflation and workload as specified in the statute. PDUFA V enhancements include a 

moditication to the inflation adjuster to accurately account for changes in its costs related to 

payroll compensation and benefits as well as changes in non-payroll costs. In addition, FDA 

will continue evaluating the workload adjuster that was developed during the PDUF A IV 

negotiations to ensure that it continues to adequately capture changes in FDA's workload. 

22 
41 


76491.029

Best Pharmaceuticals for Children Act (Pediatric Research Equity Act 

Background 

The Best Pharmaceuticals for Children Act (BPCA), enacted in [997 as part of the 

Food and Drug Administration Modernization Act (FDAMA) and reauthorized in 2002 and 

2007, provides incentives to manufacturers who voluntarily conduct studies of drugs in 

children. This law provides six months of additional exclusivity for a drug (active moiety), in 

return for conducting pediatric studies in response to a written request (WR) issued by FDA. 

To qualify for pediatric exclusivity, the pediatric studies must "fairly respond" to a WR issued 

by FDA that describes the needed pediatric studies (including, for example, indications to be 

studied or number of patients). The Patient Protection and Affordable Care Act (Affordable 

Care Act) extended availability of pediatric exclusivity to biological products but, due to the 

recent nature of this change. no biological product has received pediatric exclusivity to date. 

The Pediatric Research Equity Act (PREA), enacted in 2003, works in concert with 

BPCA. PREA provides FDA the authority to require pediatric studies under certain 

conditions. PREA requires pediatric assessments of drugs and biological products for the 

same indications previously approved or pending approval. when the sponsor submits an 

application or supplemental application to FDA for a new indication, new dosing regimen, 

new active ingredient, new dosage form. or new route of administration. 

Both BPCA and PREA expire September 30,2012. ifnot reauthorize_d. 

23 
42 


76491.030

Needfilr Pediatric lnfbrmation 

Before enactment of BPCA in 1997, approximately 80 percent of medication labels in 

the Physician's Desk Reference did not have pediatric-use information-data to establish the 

correct dose for pediatric patients or confirm safety or efficacy in the pediatric population. 

All too often health care professionals were forced to rely on imprecise and inefTective 

methods to provide medications for children, such as adjusting dosing based on weight or 

crushing pills and mixing them in food. Pediatric patients are subject to many of the same 

diseases as adults and are, by necessity, often treated with the same drugs and biological 

products as adults. Inadequate dosing information may expose pediatric patients to 

overdosing or underdosing. Overdosing may increase the risk of adverse reactions that could 

be avoided with an appropriate pediatric dose: underdosing may lead to ineffective treatment. 

The lack of pediatric-specific safety information in product labeling also means caretakers 

and health care professionals are unable to monitor for and manage pediatric-specific adverse 

events. In situations where younger pediatric populations cannot take the adult formulation of 

a product. the failure to develop a pediatric formulation that can be used by young children 

(e.g., a liquid or chewable tablet) also can deny children access to important medications. 

Success of BPL'A and PR}<,'A 

Together, BPCA and PREA have generated pediatric studies on many drugs and 

helped to provide important new safety. effectiveness, and dosing information for drugs used 

in children. Both statutes continue to foster an environment that promotes pediatric studies 

and to build an infrastructure for pediatric trials that was previously non-existent. 

24 
43 


76491.031

Over the past 15 years. approximately 400 drugs have been studied and labeled for 

pediatric use under these two laws. Since 1997. BPCA. the exclusivity incentive program, 

has generated labeling changes for 250 products. The labeling for 120 products has been 

updated to include new information, expanding use ofthc product to a broader pediatric 

population; the labeling of 29 products had specific dosing adjustments; the labeling of 69 

products was changed to show that the products were found not to be safe and efTective for 

children; and 55 products had new or enhanced pediatric safety information added to the 

labeling.4 

Since PREA was enacted, FDA has approved approximately 1,450 NDAs and 

supplemental NDAs that fell within the scope of PRE A (i.e., applications fix new active 

ingredients, new dosagc forms, new indications, new routes of administration, or new dosing 

regimens). These approvals have resulted in approximately 231 labeling changes involving 

pediatric studies linked to PREA assessments. In addition, FDA has approved approximately 

105 BLAs and supplemental BLAs that fell within the scope of PREA. 

Examples of New Pediatric In/ormation Generated by BPCA and PREA 

Migraine headaches - Axert (almotriptan) was studied and labeled for agc 12 years 

and older. Before enactment of BPCA and PREA, no medieations were studied and 

labeled for migraines in children. 

• Diabetes Apidra (insulin gluilsine recombinant) has been studied and labeled down 

to age 4 for Type I diabetes. 

" These numbers add up to a number greater than 205 because some products had more than one change to the 

labeling. 

25 
44 


76491.032

• Arthritis Actemra (tocilizumab) has been studied and labeled down to age 2 for 

Active Systemic Juvenile Idiopathic Arthritis (SJIA). 

• Pain - Otirmev/acetaminophen injection has been studied and labeled down to age 2 

for mild-to-moderate pain/moderate-to-severe pain with adjunctive opioid analgesics 

and reduction of fever. 

• Brain Tumors - Afinitor (everolimus) has been studied and labeled down to age 3 for 

subependymal giant cell astrocytoma (S EGA) associated with tuberous sclerosis (TS). 

BPCA and PREA require review of adverse event reports on a regular basis. To date, 

adverse event reviews have been presented to the Pediatric Advisory Committee (PAC) for 

129 products. In addition, as directed by BPCA, FDA has worked with NIH and the 

Foundation for the National Institutes of Health (FNIH) to facilitate the study of off-patent 

drugs not eligible for exclusivity under BPCA. 

Despite the successes of these two programs, there is more work to be done. There is still 

a large number of drug and biological products that are inadequately labeled for children. 

More broadly, long-teml safety and effects on growth, learning, and behavior are critically 

important to the safe use of certain medications and continue to be understudied. Due to 

technical challenges and the need for sequential studies, slow but deliberate progress is being 

made studying the safety and efficacy of approved therapies used to treat neonates (age birth 

to one month). These issues are still of concern, as it is this youngest population that is 

undergoing marked physiologic and developmental changes, which are affected by drug 

therapies. 

26 
45 


76491.033

FDA welcomes the opportunity to work with Congress to ensure that the~benefits of an 

incentive program can continue, in conjunction with FDA's authority to require mandatory 

studies, as Congress considers the reauthorization of the BPCA and PREA programs. 

Challenges Posed by Globalization 

In addition to reauthorizing PDUFA, FDA is also committed to meeting challenges 

posed by increased globalization. When President Franklin Delano Roosevelt established the 

modern FDA in 1938, the percentage of food and medical products imported into the United 

States was minimal. Today, approximately 40 percent of the drugs Americans take are 

manufactured outside our borders, and up to 80 percent of the active pharmaceutical 

ingredients in those drugs comes from foreign sources. In July 2011, FDA published a special 

report, "Pathway to Global Product Safety and Quality," our global strategy and action plan 

that will allow us to more effectively oversee the safety of all products that reach U.S. 

consumers in the future. As detailed in the plan, over the next decade, FDA will fiJCus on 

strengthened collaboration, improved information sharing and gathering, data-driven risk 

analytics, and the smart allocation of resources through partnerships with counterpart 

regulatory agencies, other government entities, international organizations, and other key 

stakeholders, including industry. 

Toward this goal, I created a directorate in July 2012, focused on grappling with the 

truly global nature of to day's food and drug production and supply. I appointed a Deputy 

Commissioner for Global Regulatory Operations and Policy to provide broad direction and 

support to FDA's Otlice of Regulatory Affairs and Otlke oflnternational Programs, with a 

mandate from me to make response to the challenges of globalization and impoli safety a top 

27 
46 


76491.034

priority in the years to come and to ensure that we fully integrate our domestic and 

international programs to best promote and protect the health of the public. 

CONCLUSION 

PDUFA IV expires on September 30, 2012, and FDA is ready to work with you to 

ensure timely reauthorization of this critical program. I f we are to sustain and build on our 

record of accomplishments, it is critical that the reauthorization occur seamlessly without any 

gap between the expiration of the old law and the enactment of PD UF A V. 

Thank you for your contributions to the continued success of PDUFA and to the 

mission of FDA. I am happy to answer questions you may have. 

28 
47 

Mr. PITTS. The chair thanks the gentlelady and I will now begin 

the questioning and recognize myself for 5 minutes for that purpose. 

Commissioner, I believe the PDUFA agreement contains helpful 

improvements to the drug review process, and I am particularly interested in the process improvements for the review of new molecular entities. Would you explain these improvements and how they 

will add to the predictability and transparency of the review process? 

Ms. HAMBURG. Well, there are a number of important elements. 

One is, you know, to really focus on the transparency, consistency 

and predictability issues that are so important to industry that you 

mentioned through enhanced communication and sitting down 

early in the process and midway through the process to really 

make sure that we all understand where we are, where we are 

going, what are the expectations, and to be able to, you know, 

much more rapidly surface issues as they emerge and address them 

so that we can, you know, really streamline the process and avoid 

unnecessary delays or confusion. 

Mr. PITTS. I understand that FDA and the industry have a tentative agreement on the medical device user fees. As you know, 

Chairman Upton and I have set a deadline of reauthorizing the 

user fees by the end of June. I think my colleagues on the other 

side of the aisle would agree that reauthorizing the user fees by the 

end of June is in the best interest of the FDA and the American 

people. We received the three other user fee proposals by January 

15 but we did not receive the medical device user fee proposal as 

required under statute. Given the need to reauthorize the user fees 

as soon as possible, when will the FDA send us the legislative language and the proposed agreement for the Medical Device User Fee 

Act so this committee can begin its work? Could you give us a specific date? And how does the Administration plan to expedite the 

process so the committee can get the device information as soon as 

possible? 

Ms. HAMBURG. Well, we are really delighted to be able to come 

before you this morning and say that we have an agreement in 

principle, and that was actually just announced within the last 

hours. There are still some i’s to dot and t’s to cross. We will move 

as swiftly as we can to be able to present it to all of you to begin 

to work on it. We do want to follow the process that Congress laid 

for us of course, though, which does require that the recommendations be presented at a public meeting and also that a docket be 

opened with at least 30 days of comment. As soon as we have finalized this agreement and we are very nearly there, we will begin 

that process, and while I can’t specify an exact date, we are very 

mindful of the timeframe that you have set forward and are very 

appreciative of that timeframe that you have set forward, and we 

are very eager to move this as swiftly and as surely as possible. 

This is an important agreement and one that we are very, very 

pleased to be able soon to finalize and move to this next stage. 

Mr. PITTS. Thank you. Companies that want to manufacture prescription drugs in the United States are at a competitive disadvantage because there are manufacturing plants in China with very 

little oversight. Now, there is a 2-year inspection requirement for 

48 

domestic manufacturers but no similar requirement for foreign 

manufacturers including those located in China. Shouldn’t we ensure that our regulatory oversight system does not create an uneven playing field for American manufacturers? Wouldn’t a riskbased inspections approach make more sense in ensuring resources 

are spent inspecting higher-risk facilities like those in China rather 

than setting arbitrary statutory requirements? 

Ms. HAMBURG. Well, I think the issue of how we can really respond to the globalized world that we live in where there are manufacturing facilities around the world that are making products 

coming into the United States is one of the most important challenges before us and certainly one of the priorities that I have 

taken on during my tenure as Commissioner. We very much need 

to rethink many of the ways that we have traditionally done business. Many of our authorities were actually put in place in a world 

that looks very different back when President Roosevelt created the 

modern FDA in 1938. Most drugs were in fact produced in this 

country and that is certainly not the case anymore. 

So we are both trying to expand our ability to do inspections 

internationally, which are more complex and a bit more costly. We 

certainly are trying to introduce risk-based approaches so that we 

use our limited resources as widely as possible. We are also trying 

to work more closely with regulatory counterparts who share this 

challenge of having to do inspections in many more places and 

many more countries so that we can actually share information and 

begin to in many instances, you know, rely on the work of others 

to leverage resources towards the goal of expanding our presence 

internationally and, as you say, leveling the playing field so that 

people who have manufacturing overseas don’t have to wait longer 

than those that are producing domestically. We also think that by 

more coordination with regulatory authorities, we can reduce the 

burden on industry by having more harmonization of standards, 

approaches and expectations and perhaps reducing the overall 

number of inspections that they will be subject to. 

Mr. PITTS. The chair thanks the gentlelady and yields to the 

ranking member, Mr. Pallone, for 5 minutes for questions. 

Mr. PALLONE. Thank you, Mr. Chairman. 

Dr. Hamburg, in your testimony you mention the challenges 

posed by increasing the global marketplace. As you know, Mr. Dingell, Ms. DeGette, Mr. Waxman and I have introduced a bill, the 

Drug Safety Enhancement Act, that gives FDA some authorities 

and an infusion of resources to address these challenges. Could you 

comment on the bill and whether FDA supports the bill? Some 

have asserted that FDA already has the authority to do some of the 

things that are included in the bill and that FDA could just proceed 

with its current authority. Can you comment to what extent that 

is true and whether having explicit new authority would be helpful? 

Ms. HAMBURG. You know, we really do feel, as I mentioned, that 

the ability to respond to the challenges of a globalized world is 

among the most important issues before us and that we really have 

increased vulnerabilities and increased demands that, you know, 

really threaten our ability to fulfill our critical mission to ensure 

the safety of products that the American people use and count on, 

49 

so we are very eager to work with the members of this committee 

and Members of Congress more broadly to identify authorities that 

will make a difference in our ability to better ensure the safety of 

the supply chain and these important products that are being manufactured and distributed on a global basis to enable us to do better screening of products coming into this country, to be able to act 

when we identify products that are coming in that may pose a risk 

in terms of safety and quality, so we are very, very interested in 

the work that you are doing, appreciate your leadership and stand 

ready to provide whatever information that we can. 

Mr. PALLONE. Thank you. A topic that has garnered a lot of attention over the years is the issue surrounding conflicts of interest 

on FDA’s advisory panels. Obviously, if the advisory committee is 

to be credible and useful, it has to have a limited number of members who have conflicts. In the 2007 legislation, we included a provision that prohibited FDA from seating more than a certain percentage of conflicted advisory committee members, but both before 

and since the 2007 law, FDA has encountered difficulty trying to 

fill advisory committees with qualified and unconflicted members, 

and many have asserted that the waiver caps are to blame, but my 

understanding is that FDA has not come close to hitting those 

caps. So I am concerned about reports of weakened advisory committees because I think they are very important. 

I wanted to ask you, do you agree that FDA has indeed encountered problems in filling advisory committees in recent years, and 

what is the impact, if so, of these vacancies on the ability of FDA 

to obtain expertise? Have there been instances in which the advisory committee meetings were delayed because FDA could not identify a sufficient number of outside experts, and to what extent are 

the waiver caps the problem or, you know, related to this? 

Ms. HAMBURG. Well, this is a very important issue and one, you 

know, that very much goes to our ability to bring the best possible 

science to bear on our decision making. We also must have a process that has integrity, and so we have been, you know, working on 

this issue, talking with stakeholders and reviewing our policies and 

experience. It is one of those issues unfortunately in a way that the 

more you get into it, the thornier and more complex it gets, and 

on the one hand, there are people who would like to see us step 

away and relax some of our conflict-of-interest policies so that we 

can bring those individuals who are most expert to the table to 

serve on our advisory committees, and there are others on the 

other end of the spectrum who are very, very concerned that we 

need to have individuals who do not have—— 

Mr. PALLONE. I am just trying to—because my time—specifically, 

have there been problems filling these advisory committees in recent years? 

Ms. HAMBURG. At the present time, as you noted, we are not 

bumping up against our cap in terms of waivers, and we have actually been making an aggressive effort to fill empty slots on our advisory committees and have made progress. It is a challenge to get 

people on our advisory committees for many reasons, both that it 

is a huge time commitment and—— 

Mr. PALLONE. Do you have any ideas about what you could do 

to improve it—— 

50 

Ms. HAMBURG. Well, I think—— 

Mr. PALLONE [continuing]. And whether we could help in some 

way with the legislation? 

Ms. HAMBURG. You know, we have been looking at this pretty 

closely and we don’t at the moment see major areas where a legislative fix is required but I think it is something that we want to 

continue to work on. The input and engagement with our various 

stakeholders is absolutely crucial, and, you know, the role of the 

advisory committees is, you know, very foundational to a lot of 

what we do and so we want to make sure that we have the right 

balance of expertise without conflict of interest that might compromise the value of the input of those individuals, and we do 

think that transparency is a very important aspect of moving forward on this, and that is a strategy that enables often individuals 

to be able to bring their expertise with fuller understanding also 

though of their engagement either with sponsors of a product or an 

industry or positions that they have taken in the past on related 

issues. 

Mr. PALLONE. I thank you. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from New Jersey, Mr. Lance, for 5 minutes for questions. 

Mr. LANCE. Thank you, Mr. Chairman, and good morning to you, 

Dr. Hamburg. I have not had the privilege of meeting you previously, and it is my honor to do so. 

On the front of advancing personalized medicine, what steps 

might the FDA be taking to modernize the current regulatory 

structure? I have a bill in the hopper, the Modern Cures Act, that 

I believe might be able to be helpful in this area. 

Ms. HAMBURG. Well, it is such an important area and we certainly are on the cusp of dramatic advances in terms of opportunities for care and treatment, and we are already seeing breakthroughs including a new therapy that was announced yesterday 

for cystic fibrosis where we are able to really see a therapy targeted to individuals with a particular genetic marker and really 

treat the underlying pathway of a disease in a new way. 

With respect to activities at the FDA to enable us to really realize the potential of personalized medicine, a major area of focus is 

the investments in advancing regulatory science that we have embarked on with our colleagues in industry and academia, and I am 

very happy that a focus on new investments in regulatory science 

is part of the PDUFA V agreement because I think that will enable 

us to further develop the tools that will matter to both drug development and regulatory review and enable us to really target therapies for the people who will respond or for the people who will have 

unacceptable adverse consequences of therapy. We can also stratify 

populations and learn who will benefit and who will perhaps have 

unacceptable risks. 

Mr. LANCE. Thank you. 

Ms. HAMBURG. There is one other thing. I have also reorganized 

the agency in order to try to bring new leadership in, and we have 

a Deputy Commissioner for Medical Products who has a background in personalized medicine, and he will be working across 

51 

drugs, biologics and devices to coordinate activities, which is very 

important to make personalized medicine real. 

Mr. LANCE. Thank you. 

Ms. HAMBURG. I am sorry. 

Mr. LANCE. I look forward to working with you on that. 

Section 9 of the goals letter, enhancing regulatory science and expediting drug development, includes a subsection on advancing development of drugs for rare diseases. Specifically, the proposal provides for by the end of fiscal year 2013 that the FDA will complete 

a staffing and implementation plan for the CDER rare disease program within the Office of New Drugs and a CBER rare disease liaison within the Office of Center Director, and the FDA will increase 

by five the staff of the CDER rare disease program and will establish and fill the CBER rare disease liaison position. Would you 

please indicate to the committee assurances that you can provide 

that these additional staff will lead to greater efficiency and not 

create an additional layer of delay with no or limited value? 

Ms. HAMBURG. You know, I think that we are moving in a direction that is very positive and will help support and extend our efforts in the rare and neglected disease area. I think it is an area 

where we have made terrific progress in terms of being able to 

work with sponsors to identify new promising drug candidates and 

move them through the system where we have been able to apply 

new and better science and more flexible regulatory tools, innovative clinical trial designs being one important aspect of that, and 

I think you will have the opportunity to hear more about that. 

But I think the new proposal in the PDUFA agreement will enable us to have some individuals who are really focused on some 

of the unique needs and concerns in the rare and neglected disease 

areas and to be able to work across many components of the agency 

to ensure that we are doing all that we can, bringing the best possible science to bear and never forgetting this important aspect of 

drug development and getting new products to the people who need 

them. 

Mr. LANCE. Thank you, Commissioner. And finally, on biomarkers, innovative drug development is increasingly dependent on the 

use of new biomarkers of disease to target the right patients. What 

is the FDA doing to encourage the use of biomarkers in drug development? 

Ms. HAMBURG. It is such a key aspect of how we can bring new 

and better science to bear on drug development and drug review. 

We already have been, you know, quite involved in biomarker development including through the biomarker consortium that brings 

industry and academia together with government, both FDA and 

NIH, to try to identify and validate biomarkers for regulatory use. 

Biomarkers have an essential role to play in identifying potential 

toxicities so that if a drug is going to fail, it can fail early and we 

can speed the process. Biomarkers have a critical role to play in 

terms of serving as surrogate end points for clinical trials so that 

we can get important information about whether a drug is working 

or not without having to have extended trials and follow the whole 

course of the disease to give us early indications, and in other 

ways, you know, really gives us tools to accelerate the drug development process and the review process. It is an area that industry 

52 

shares our excitement and enthusiasm about the opportunities in 

science, and I think its inclusion in the PDUFA V agreement reflects that we think that by focusing on this area, we can really 

make huge strides forward. 

Mr. LANCE. Thank you, Mr. Chairman. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentlelady from California, Ms. Capps, for 5 minutes for questions. 

Mrs. CAPPS. Thank you, Mr. Chairman. 

Thank you so much for your testimony, Dr. Hamburg, and for 

being with us today. You and your team have done such terrific 

work coming together on the PDUFA V agreement, and I look forward to working with you to move this bill forward. I also wanted 

to acknowledge that while these user fee agreements are a critical 

piece to ensuring that the FDA has the resources to do its job and 

continue to be the gold standard in this work around the world, at 

the same time we here in Congress must not shirk our responsibility to adequately fund the agency so that you can do that work, 

and I hope that in our bipartisan agreement that we will also work 

across the aisle during the appropriations process to do just that. 

I hope to get to two topics in this very fast-moving 5 minutes 

that I have. In your testimony, Dr. Hamburg, you mentioned the 

Sentinel system for postmarket surveillance. This program holds 

great promise for more efficient and effective postmarket surveillance to protect the public’s health, save money on research and 

curb potential drug recalls. Your testimony says that PDUFA V 

will allow user fees, and this is a quote, ‘‘to determine the feasibility of using Sentinel to evaluate drug safety issues that may require regulatory action.’’ Would you explain just a little bit more, 

not too long, about what that means? How do the goals described 

in PDUFA V differ or expand upon the pilot projects that have already been completed in PDUFA IV? 

Ms. HAMBURG. Well, of course, FDAAA began us on the path of 

really strengthening our postmarketing surveillance capabilities 

and focusing on safety in the postmarket setting, and what we 

hope to be able to accomplish now with PDUFA V is to really use 

the data available in the postmarket setting and the data management and analytic tools to be able to very quickly ask and get answers to questions of an emerging drug safety concern. If we hear 

that a particular drug might be associated with an elevated risk of 

another kind of problem, we can query the database, and we are 

now up to 100 million patient lives in the database, and can answer that will help us to determine the level of concern associated 

with an emerging safety issue and help us decide, do we really 

need to ask for additional clinical studies to further evaluate the 

safety risk or are we comfortable with a determination that it 

doesn’t appear to be a true correlation. 

Mrs. CAPPS. I understand. That is important. Do you have the 

authority—should you need to expand the scale of this program, do 

you have the authority on your own to evaluate and make decisions 

along the way? 

Ms. HAMBURG. I believe that we have all the authorities that we 

need, and obviously PDUFA V will help to give us additional resources that we need, and part of what is exciting about what we 

are doing as well is that it is a real partnership working with the 

53 

private sector and the broader patient community in terms of being 

able to access important data, which of course is utilized in a patient-confidential manner but—— 

Mrs. CAPPS. Great. 

Ms. HAMBURG [continuing]. We do now have these large information resources that enable us to do things that we couldn’t do before. 

Mrs. CAPPS. Great. Another topic, in your testimony you touched 

on the scale-up of electronic submissions to the agency, and in July 

I asked your colleague, Janet Woodcock, about reports that clinical 

trial data submitted to the FDA do not routinely reporting based 

on sex or other important demographics. As you may know, this 

issue is one we have long struggled with. It is a key component of 

a bill that I have, my Heart for Women Act. In her response, she 

noted that while she couldn’t confirm these reports, the use of electronic submissions would make it easier for the FDA to identify if 

companies are indeed submitting the disaggregated data as required by law. Can you tell me where the agency is at this moment 

on moving toward an electronic-only submission system and what 

are the benchmarks put forward in PDUFA V for that kind of 

adoption? 

Ms. HAMBURG. Yes. Well, we are very excited about this component of PDUFA V. It has many benefits, both streamlining and 

modernizing our systems to help speed review and reduce burdens 

ultimately on both industry and our staff, but it has the additional 

benefit that it will enable us to deal with data in much more targeted ways and to be able to ask and answer critical questions 

around such important matters as gender and race and age and 

other factors that we very much need to understand more deeply 

to be able to provide the best possible products and the best possible care to our citizens. 

Mrs. CAPPS. Thank you very much. I yield back. 

Mr. PITTS. The chair thanks the gentlelady and recognizes the 

gentleman, Dr. Burgess, for 5 minutes for questions. 

Mr. BURGESS. Thank you, Commissioner, again for being here. 

Commissioner, we need your help. Last year, February 2011, this 

committee sent a letter regarding documents from the Food and 

Drug Administration relating to the issue of contaminated heparin, 

and you recall that national tragedy was prior to your becoming 

Commissioner but at the same time we are having difficulty coming to a conclusion on that, and while I recognize that you talked 

about the issues of globalization, you are no longer going to be a 

domestic agency but a global agency, I mean, here is where you 

have to show value because you had a compound manufactured in 

communist China that was used to adulterate a biologically derived 

product, heparin, a blood thinner. This hypersulfated chondroitin 

sulfate that was used to contaminate the heparin was a molecule 

that was produced in a lab and patented in the People’s Republic 

of China and found its way into our drug supply with loss of life 

in dialysis centers when people were administered a bolus of heparin. 

Last year, February 23rd, the committee sent a letter. Your Office of Legislative Affairs has documents from at least four employees but we don’t have them at the committee level. In November, 

54 

your agency committed to a timetable to complete the production 

of heparin documents by the end of January 2012. We are there 

but we don’t have any documents. So what has been happening 

over at your Office of Legislative Affairs for over 6 months? This 

is a poor reflection on the agency and one where our committee and 

you all need to work together and it is not happening. 

Ms. HAMBURG. Well, as you point out, heparin was a very serious 

event that we all take very seriously in terms of the initial response at the time but also making sure that we have the systems 

in place to prevent that particular problem from occurring again or 

other similar problems. I am surprised by what you say. I am eager 

to work directly with you to make sure you are getting what you 

need because my sense was that our staff was spending literally 

thousands of hours culling through documents for you, answering 

questions, briefing committee staff on these issues, that we had 

sent up some 50,000 pages of documents. But if you—— 

Mr. BURGESS. If I may interrupt, that may be the case but we 

don’t have them, so over the next 2 weeks can we elicit your help 

in getting this committee and the Subcommittee on Oversight and 

Investigation the information that it needs? 

Ms. HAMBURG. Absolutely. I commit to working very closely with 

you to make sure that you are getting the materials that you are 

requesting and need. 

Mr. BURGESS. Well, we are grateful for the more sophisticated 

testing that would reveal this problem in the future for new heparin but if there is someone out there who seeks value in contaminating our drug supply chain, it may not be heparin next time, it 

may be something else, and I don’t have a sense that we understand what happened when this adulteration occurred. 

We are all concerned about drug shortages. You hear about it. It 

is in the newspapers. There is a particular chemotherapeutic agent 

named Doxil which you are probably familiar with that has the 

company apparently involved in the manufacture of Doxil has said 

they are not going to make any more, so now we are in a tough 

spot because other companies are willing to take up that slack but 

all remaining Doxil has to be used for treating patients. It can’t be 

used for doing the clinical trials, randomized clinical trials that 

would be necessary. So what options do we have in this very rare 

situation to allow the patients who are depending upon that 

chemotherapeutic agent to continue to receive it and at the same 

time speed the approval of generic doses of Doxil? 

Ms. HAMBURG. Well, I am not familiar with all the details of the 

particular case of Doxil that you raise. But it is speaks to a set of 

important issues around drug shortages in terms of, you know, 

really needing to work closely with companies to get early warning 

when decisions are made to discontinue manufacturing or if they 

believe that there is an emerging quality or manufacturing concern 

to help identify other sources of available product to treat the conditions that patients may have when there are potential shortages 

and to help work with sponsors to expedite the standing up of manufacturing capability. 

Mr. BURGESS. Right. We appreciate this is a complex problem, a 

multifactorial problem, but in this specific instance what we’re askVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00058 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
55 

ing is, Can you use your flexibility on the issue of bioequivalents 

to help get these patients the drugs that they so desperately need? 

Ms. HAMBURG. You know, as I said, I don’t know enough about 

the specifics in terms of the option in that case so I would not want 

to comment in the setting. I will certainly go back and make sure 

that the people with the direct knowledge and expertise address 

that. 

Mr. BURGESS. We will follow up with that. Thank you. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentlelady from Illinois, Ms. Schakowsky, for 5 minutes for questions. 

Ms. SCHAKOWSKY. Thank you, Mr. Chairman, and thank you, Dr. 

Hamburg, for being here. I have four questions and I am going to 

get right to them, but I do want to associate myself with Ms. 

Capps’ complimentary remarks to you and also the need to make 

sure that we adequately fund the FDA. 

My first question is this. There was a 2010 report from the HHS 

Office of Inspector General which found that ‘‘80 percent of approved marketing applications for drugs and biologics contain data 

from foreign clinical trials.’’ So my question is, does the FDA have 

adequate resources to do clinical trial oversight in places like 

China and Peru? 

Ms. HAMBURG. Well, this is part of the overall growing demands 

on FDA in terms of oversight of both foreign manufacturing facilities and research that is being done in other countries. It certainly 

is something that we are putting time and attention to. We are 

working both with the regulatory authorities in a wide range of 

countries—— 

Ms. SCHAKOWSKY. Do you have the resources to—— 

Ms. HAMBURG. We need additional resources in order to be really 

provide the level of oversight that we think is necessary and appropriate, and we need some new models for doing business as well 

in terms of coordination with regulatory authorities sharing information and also increasing regulatory oversight capacity in many 

countries to ensure good clinical practice. 

Ms. SCHAKOWSKY. So it is authority and resources, right? 

Ms. HAMBURG. Indeed. 

Ms. SCHAKOWSKY. I have been very interested in the issue of cosmetic safety, and here is my question. It relates to authority. If the 

FDA had reason to believe a cosmetic product was harmful, could 

it issue a mandatory recall of that product? 

Ms. HAMBURG. I believe that we could work with the company 

to encourage a voluntary recall, but in order to pursue a mandatory 

recall, we would have to engage with the court system and pursue 

it through that venue. 

Ms. SCHAKOWSKY. There has been a lot of publicity around the 

product, the hair straightener product, Brazilian Blowout, and I 

know that the FDA wrote to the manufacturer to inform them they 

had determined their products to be both misbranded and adulterated, but apparently it is still being used in salons across the 

United States. So do you plan any further actions against the manufacturer of Brazilian Blowout? 

Ms. HAMBURG. It is my understanding that we are involved in 

some continuing discussions with the manufacturers trying to betVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00059 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
56 

ter understand the issues involved and working with them around 

our concerns. I also believe that OSHA is engaged on this issue in 

terms of some of the workplace health concerns around the people 

that are providing the services in those beauty salons. 

Ms. SCHAKOWSKY. Right, the employees there, OSHA has moved 

in on their behalf. 

Now, I want to ask you about the ubiquitous advertising, directto-consumer advertising that we see on television. Some of them, 

I have to tell you, seem like if you really listen to all the cautionary 

things, it is like ‘‘and death could result’’ it seems like always at 

the end. It is almost humorous to me while you see people skipping 

through the flower fields. Anyway, what I am asking is that do you 

actually have any resources for direct-to-consumer advertising 

monitoring to ensure that consumers do have a balanced understanding of the drugs and the risks advertised to them, the accuracy of those? Where are you with monitoring those direct-to-consumer ads? 

Ms. HAMBURG. Well, we do have a group that is charged with 

working on the oversight of direct-to-consumer advertising and 

there is a process that involves the screening of the direct-to-consumer advertisements. 

Ms. SCHAKOWSKY. But you didn’t have fees for that, right? 

Ms. HAMBURG. We don’t have fees associated with that. I gather 

that in the last PDUFA negotiation, this has been identified as possible area of focus, but actually including it was moved away from 

for a number of reasons that I think may have included the willingness to match or include budget authority. I am not sure of all the 

details but it was considered in PDUFA IV but—— 

Ms. SCHAKOWSKY. Let me just say—— 

Ms. HAMBURG [continuing]. But it is not part of PDUFA V. 

Ms. SCHAKOWSKY. Given the prevalence of those ads on television, it seems to me that that would be a major focus, and I hope 

we can work together to make that happen. Thank you. 

Ms. HAMBURG. Thank you. 

Mr. PITTS. The chair thanks the gentlelady and recognizes the 

gentleman from Kentucky, Mr. Guthrie, for 5 minutes for questions. 

Mr. GUTHRIE. Thanks, Dr. Hamburg. Thanks for coming. It is 

nice to have you here today. I have a related question, I want to 

get to another question, and it is related because it is user fee related. On the Tobacco Control Act, I have a question on that. The 

concern is, there is a user fee by tobacco companies to fund the 

Center for Tobacco Products, and my understanding, there is not 

transparency in the use of that money in terms of performance reporting or financial reporting like it is in PDUFA, you have to account for where that money is being used. My understanding is, 

there is not a report, not required statutorily for you to issue a report. I wonder if you have any comment on the transparency or use 

of those funds. 

Ms. HAMBURG. Well, the user fees that are involved in supporting the tobacco program and its activities are scrutinized, and 

we have developed, you know, very strict oversight mechanisms 

and firewalls in terms of their targeted use for tobacco program activities, but you are correct that the legislation did not require the 

57 

same kind of performance reporting as for other user fees, and, you 

know, I think that are obviously—I would certainly understand 

that Congress would like to know more about how those user fees 

are being utilized. I would say that, you know, we take, as I said, 

the oversight of those resources and their appropriate use very seriously and do have a stringent process that is involved with that. 

Mr. GUTHRIE. Yes, I don’t think anybody has commented that 

you all were using it improperly, just that they don’t have the access to the information that you do. So if I implied that, I apologize. But just the idea that other user fee programs, and maybe we 

should have financial reporting. Of course, Congress didn’t ask you 

to do that when we passed that bill before. 

The one thing, and I have been kind of focused on a little bit is 

this use of guidance documents, so I know it is not right on PDUFA 

but while we are here talking about that, and just a couple of examples, and I’m not getting into the details of specifics, but just 

like draft guidance for industry and FDA staff commercially distributed in vitro diagnostic products. I know that is very detailed. 

But when that was issued and it went forward, there were citations 

about 2 weeks after guidance document. Well, first it was brought 

forth as nonbinding, not for implementation, but my understanding 

is that the FDA has to take an action citing that guidance document I guess 2 weeks after implementation. So the question is, and 

I want to leave you time to respond, essentially the Administrative 

Procedures Act has the rulemaking process and there is some concern that FDA is using the guidance documents in a way that 

should be through the whole rulemaking process and comments. A 

lot of stakeholders have brought that to our attention. Do you have 

any comment on the use of guidance documents as binding even 

though they say nonbinding? 

Ms. HAMBURG. Well, you know, we have found a lot of interest 

from the industries that we regulate in the role of guidance. There 

may be some mixed views, but I will tell you that what I generally 

hear is that guidance is very useful in giving an indication of 

where the agency is, where we are going and thinking about a particular problem. While they are not binding in the same way that 

rulemaking is, they are much quicker to put forward and they are 

welcomed. In fact, one of the things that I think came up in the 

PDUFA negotiations was examining ways to actually support the 

guidance production system because there are a lot of areas, personalized medicine being one, where it would be helpful to sponsors 

of products to have more guidance in order to know what directions 

to pursue and get the insight into our thinking and approaches. So 

I think that it is overall my sense is very useful but I think it does 

sometimes create an uncomfortable situation where people don’t 

know whether it is an enforcement document or whether it is simply guidance. 

Mr. GUTHRIE. See, I don’t disagree with anything you said there 

at all. I think that you are absolutely right. People want some direction because the rulemaking process does take time so where is 

the direction we need to go in the interim, but I guess the concern 

is when they become treated like rules, that they didn’t actually go 

through the Procedures Act, and that is a just a concern that we 

have. 

58 

Thanks. I yield back. 

Mr. PITTS. The chair thanks the gentleman and yields to the 

ranking member emeritus from Michigan, Mr. Dingell, for 5 minutes for questions. 

Mr. DINGELL. Mr. Chairman, I thank you. I commend you for 

this hearing. It is very much needed, and significant reform of food 

and drug laws is very much needed. 

I ask unanimous consent my opening statement be inserted into 

the record at this point. 

Mr. PITTS. Without objection. 

[The prepared statement of Mr. Dingell follows:] 

59 


76491.035

Statement from Representative John D. Dingell 

House Committee on Energy and Commerce 

Subcommittee on Health 

"Reauthorization ofPDUFA: What It Means t()f Jobs. Innovation. and Patients," 

February l. 2012 

I want to thank the Chairman for holding today's hearing on the reauthorization of the Prescription Drug 

User Fee Act (PDUFA). Legislation updating FDA's authority to protect American people from unsafe 

pharmaceuticals is desperately needed as shown from a large number of scandals in recent years. 

This hearing is a critical tlrst step in crafting legislation that will affect millions of Americans who take 

prescription medication. FDA has the tremendous responsibility of ensuring these medications are safe and 

effective for use, and ensuring patients have access to innovative new treatments in a timely fashion. 

The agreement proposed by FDA and the industry will help to achieve this goal by ensuring FDA has 

adequate funding: to hire review and inspection staff needed for drug approvals. to improve the 

communication between FDA and industry during the approval process to ensure a more predictable and 

efficient process, and to improve regulatory science at the FDA, 

One way that we can strengthen this proposed agreement is by focusing on the safety of our drug supply 

chain. What many Americans don't realize is the staggering fact that the number of drug products being 

manufactured outside of the United States doubled between 2001 and 2008. A globalized drug supply 

demands a globalized FDA that can enforce and oversee the quality of drugs entering our market from both 

domestic and foreign drug manufacturers. 

This Committee has heard previously ti'om Dr. Janet Woodcock, Director of the Center for Drug Evaluation 

and Research, that FDA does not have the authorities it needs to oversee our drug supply. Currently FDA 

does not have the authority to require a manufacturer to notify FDA if they know that a dn.g has been 

adulterated, to recall drugs that the FDA believes are causing harm to the puhlic's health, to refuse or seize 

imported drugs that are unsafe or counterfeited at the border, or to require a drug manufacturer to know their 

suppliers. 

Further. we must ensure FDA has the resources needed to conduct comparable inspections of domestic and 

foreign drug manufacturers. FDA is now required to inspect domestic drug facilities once every two years, 

but docs not have a similar requirement in the law for foreign drug Hlcilities. I would hope my colleagues 

would agree that we must hold foreign drug manufacturers to the same high standards we hold domestic drug 

manufacturers. 

H.R. 1483, the Drug Safety Enhancement Act, builds on the success of the food safety reform law - H.R. 

2751, the FDA Food Safety Modernization Act enacted by Congress last year and we have the opportunity 

to do the same thing for pharmaceuticals that we did for food. FDA must have updated authorities and 

needed resources to properly oversee a globalized drug supply. 

With the PDUFA expiring at the end of this tiscal year, this Committee must work quickly and efficiently to 

ensure that we pass legislation that will reauthorize this program in order to avoid any personnel disruptions 

at the FDA. The hardworking employees of the FDA are looking for Congress to do our job, so that they can 

continue to do theirs. 

flook t;)fward to working with the Chairman and my colleagues on the other side of the aisle on 

reauthorization. Thank you. 
60 

Mr. DINGELL. I would like to begin by making a couple of observations. We have renewed PDUFA on a number of occasions and 

have expanded to a number of other activities by Food and Drug 

for a fee is now paid willingly by the industry. Each time this legislation has been extended, it has been extended with the active support of the industry. I authored PDUFA for some very interesting 

reasons. This committee conducted an extensive investigation of 

Food and Drug involving some serious misbehavior, accepting of 

gratuities and things of that kind, because of the fact that the 

agency did not have the resources to properly handle the issuance 

of permits for new pharmaceuticals, and the end result was, there 

were huge numbers of complaints from industry and some very unfortunate corruption existed in the agency. 

One of the interesting things, and I hope my colleagues will listen to this, about PDUFA and one of the reasons that it and its 

half sisters and brothers have been supported by the industry is 

that a good pharmaceutical brings into the manufacturer, or did at 

the time it was first put in place, about $250 million a year, and 

if each time that a company found that it is delayed in putting a 

pharmaceutical to work and getting approved, that company finds 

that it has massive losses, massive losses stemming from the fact 

that it cannot market while its patent, which exists for 17 years, 

is running. Food and Drug does not have the resources to do this. 

Now, Food and Drug is also moving forward to see to it that they 

have legislation which would enable them to begin to collect fees 

for certain changes in the law with regard to other pharmaceutical 

regulatory activities by that agency. These would impose the same 

burden on foreign manufacturers, who are now bringing in huge 

amounts of counterfeits and other unfortunate things into this 

country, to the great detriment and the hurt not only of our law 

but also of American manufacturers and Americans who are being 

poisoned. I would observe that we had a rather hideous example 

of this when a lot of Americans were killed or seriously hurt by 

heparin which came in. 

So these questions first of all to Commissioner Hamburg. Has 

the law kept up with the changing environment? Yes or no. 

Ms. HAMBURG. No. 

Mr. DINGELL. It is badly in need of change, is it not? 

Ms. HAMBURG. Yes. 

Mr. DINGELL. And you have a number of changes which you will 

suggest for the record on this matter. Is that not so? 

Ms. HAMBURG. We would love to work with you on this. 

Mr. DINGELL. But the answer is yes? 

Ms. HAMBURG. Yes. 

Mr. DINGELL. It is also so that these will enable you to address 

not only changes in domestic production and the law as regards to 

domestic production but also with regard to the foreigners who are 

now sending in huge amounts of unsafe pharmaceuticals that you 

simply do not have the resources to address. Is that not so? 

Ms. HAMBURG. It is correct. 

Mr. DINGELL. Unfortunately, yes. Now, does Food and Drug have 

the authorities, the resources to adequately oversee such a heavily 

outsourced drug industry? 

Ms. HAMBURG. We don’t currently have the resources—— 

61 

Mr. DINGELL. You don’t have the resources, do you? 

Ms. HAMBURG [continuing]. To fulfill as we would like our mission. 

Mr. DINGELL. Good. I am giving you easy questions. These are 

all yeses or nos. 

Ms. HAMBURG. It is hard to answer just yes or no. 

Mr. DINGELL. Unless I indicate otherwise. 

Now, will you submit for the record the key authorities that FDA 

needs to oversee the drug supply chain? 

Ms. HAMBURG. With pleasure. 

Mr. DINGELL. Now, one of the additional problems that you have 

is that the components are now coming in from overseas. In the 

case of heparin, it was the components which caused the damage 

to the health of the American people, was it not? 

Ms. HAMBURG. We believe that the contaminant was introduced 

into the crude heparin preparation, yes. 

Mr. DINGELL. Thank you. 

Now, I have, Mr. Chairman, an analysis of H.R. 1483, the Drug 

Safety Enhancement Act of 2011, and I would ask unanimous consent that it be inserted into the record at this point. 

Mr. PITTS. Without objection. 

[The information follows:] 

62 


76491.036

H.R. 1483, the Drug Safety Enhancement Act of2011 

Forty percent of ph ann ace utica Is and 80 percent of active pharmaceutical ingredients for the US 

market are now produced in foreign countries, often China and India. Such facilities often operate 

under lower standards than US manufacturers. creating safety risks and an uneven playing field. 

The Drug Safety and Enhancement Act seeks to hold manufacturers responsible for the safety of 

pharmaceuticals manufactured in foreign countries for the US market and ensuring that the FDA 

provides oversight of foreign manufacturers equivalent to that exercised on domestic companies. 

This bill will: 

Require manufacturers to implement improved quality and safety standards, including 

stronger supply chain management 

• Require manufacturers to notify FDA of counterfeits or safety concerns and to list 

country of origin of drugs and drug components 

• Strengthen oversight of importers and customs brokers 

Give FDA needed authorities inclnding mandato}}, recall authority, subpoena power, 

and clear extraterritorial jnrisdiction. 

Strengthen criminal and civil penalties to better deter crime 

Increase FDA inspections of foreign manufacturing to pnt it on par with domestic 

facilities 

Create new funding mechanisms for FDA inspectional activities, so globalization 

doesn't create burden on US taxpayers 

Require all manufacturers to implement basic qnality and safety standards, including stronger 

supply chain management 

Companies selling drugs in the US market must implement quality system to ensure the safety 

and integrity of their products. including drug ingredients manufactured by a contractor or 

supplier. Quality systems should include management responsibilities, quality responsibilities. 

risk management. and supply chain management. 

Companies must be able to document their supply chains, and demonstrate quality control 

Companies must perform on-site audits of suppliers before beginning to purchase product from 

lhat supplier, and must implement quality agreements with suppliers 

Require manufacturers to notify FDA of concerns about counterfeits or manufacturing defects 

that put Americans at risk, and to list country of origin of drugs and drug components 

Companies must notify the FDA wben use of or exposure to drug may result in illness or injury 

to humans or animals; signiticant loss or then; reasonable probability that a drug has been or is 

being counterfeited; repeated failures by a component manufacturer to ensure compliance with 

quality systems; any incident causing a drug to be mistaken for. or its labeling applied to, 

another drug; and any contamination or significant chemical or physical change or deterioration 

after distribution. or any failure of a distributed lot to meet established speeitications. 
63 


76491.037

Require manufacturers of finished drug products to list on their web sites the countries of origin 

for their finished drugs as 'and the active ingredients in those drugs. 

Strengthen oversight of importers and customs brokers 

Require importcrs and customs brokers to register with the FDA, and pemlit FDA to require 

additional documentation at importation. Create an impOlier registration fee to support 

oversight activities 

Rcquire the Secretary to create good importcr practice regulations 

Givc FDA needcd authorities including mandatory recall authority, subpoena power, and clear 

cxtraterritorial jurisdiction. 

Give FDA the power to order a drug recall) allowing for an industry appeals process (as exists 

for food and medical devices) 

Give FDA power of subpoena for documents and witnesses) as with other regulatory agencies 

Allow FDA to destroy imported drugs at the border valued less than $2,000 that pose a health 

threat (so they don't get turned away, only to come back in through another port) 

Creatc protections to allow FDA to exchange information with othcr regulators and rcceive 

information from whistlcblowers 

Allow the FDA to exchangc confidential information in a protected manncr with other agencies 

and foreign governments, and to thc public where warranted. 

Crcate protections for industry whistleblowers that wish to aJcl1 FDA to violations ofthe 

rFDCA and the Public Health Service Act. 

Strengthen penalties to bettcr detcl· crime and noncompliance 

Increase criminal penalties for knowing violations of the Federal Food, Drug, and Cosmetic 

Act to up to 10 years in prison and tines in accordance with title 18 of US Code. Knowing 

violations should include adulteration, misbranding, refusal of inspection, and counterfeiting 

Create eivil penalties 01'$500,000 per violation per day for drug-related violations of the 

FFDCA, Cap penalties at $10,000,000 for a single proceeding that covers a number of 

violations 

Add asset forfeiture as a punitive measure for drug-related violations of the FFDCA 

Increase FDA inspections of foreign manufacturing sites and improve oversight systems 

Require that all plants making finished drugs or active ingredients be inspected once every two 

years (or every four years if appropriate) - a standard mOre like that used inside the US 

Make delay or refusal of an inspection a prohibited act 

To facilitate tracking and oversight, require submission of unique [0 numbers by 

manufacturing establishments, importers, and customs brokers. 

Create a dedicated foreign inspectorate within FDA 

Create new industry registration fees to support FilA inspectional activitics 

Fees will be set at the amount necessary to support increased drug safcty activities and ensure 

that the added costs of manufacturing moving to low-cost countries does not create extra 

burden for taxpayers. 
64 

Mr. DINGELL. Madam Commissioner, one last question. You are 

familiar with the provisions of 1483. They are significantly similar 

to the additional powers and resources that Food and Drug received in the last couple Congresses ago to address the question of 

food safety, and you are finding that those new authorities are 

working very well there, are you not? 

Ms. HAMBURG. Those new authorities are very, very important. 

We of course are struggling to fully implement the demands of the 

Food Safety Modernization Act but we are moving forward, and the 

additional authorities really are able to put us in a position to do 

things that are very, very important to prevent problems and address them swiftly. 

Mr. DINGELL. And they particularly allow you to control imports 

and to address the question of possible seizure of unsafe pharmaceuticals which you had previously no capacity to address. Is that 

not so? 

Ms. HAMBURG. That is correct. 

Mr. DINGELL. Mr. Chairman, I have used more time than I am 

entitled to. Thank you for your courtesy. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from Georgia, Dr. Gingrey, for 5 minutes for questions. 

Mr. GINGREY. Mr. Chairman, thank you. 

Dr. Hamburg, I love you just as much as the chairman emeritus 

does. He said he had some easy questions for you. In that spirit, 

I definitely have one that I think is easy but another one that may 

not be quite so easy. First, for the easier of the two, I am holding 

in my hand a news report that ran yesterday from U.S. News and 

World Report, and it reads, ‘‘Antibiotic-resistant bacteria found in 

37 United States states.’’ Can you tell me your thoughts on the 

magnitude of the threat that antibiotic-resistant bacteria pose to 

the United States patients? 

Ms. HAMBURG. Antibiotic resistance, as you well know, is a huge 

and growing problem and one that we must take very seriously. We 

are seeing across various, you know, classes of antibiotics more and 

more resistance. That is greatly worrisome in terms of, you know, 

rendering important tools for controlling disease and preventing 

spread. We are seeing them, you know, rendered useless, increasing the burden of disease and the costs of care and potentially putting us in a position in some instances where we don’t have the 

kinds of therapeutic interventions that we have come to expect, so 

it is something we need to address and we need to address it together, and FDA has a critical role to play. 

Mr. GINGREY. And I really appreciate that. I will put in more 

plug for the GAIN Act. So much for the easier of the two. 

Now, this next question is not meant to be unfriendly at all but 

I think it is very important. Ranking Member of the Health Subcommittee, Mr. Pallone, sort of addressed this earlier. I want to follow up on what he said, though. 

A number of constituencies, both patients’ groups and industry, 

recognize there are great advancements in our understanding of 

the human genome and science behind biologics. These same constituencies, however, have shared with me their concerns regarding 

current conflict-of-interest rules governing the FDA. Their contention is this: If the rules are not changed to take into these emergVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00068 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
65 

ing sciences nor the limited number of individuals who understand 

these emerging sciences, these sciences may progress beyond the 

FDA’s ability to understand how to properly assess the science. 

And I understand that currently the cap on the waivers for these 

conflict-of-interest rules has not been reached but I also understand that there are maybe a number of obesity drugs, as an example, within the FDA review process that have been stalled because 

of a preconceived lack of understanding of the science behind the 

drugs. I will cut right to the chase. Simply put, I do not believe the 

FDA cap is the issue here. I just want to understand this. Is it the 

FDA’s contention that changes to the current conflict-of-interest 

rules governing the FDA advisory panels would not benefit the 

FDA, patient groups or businesses when considering whether to invest in new drug development? 

Ms. HAMBURG. Well, I think your question raises a number of 

really important points and of course goes beyond simply the conflict-of-interest rules and the advisory committees but how do we 

bring in the best possible expertise as we pursue our regulatory 

oversight of critical products to address critical medical and public 

health needs, and advisory committees are one important element 

of that but there are other ways that we do it as well. 

You know, for example, you mentioned obesity drugs. Well, we 

have a working relationship now spearheaded out of George Washington University where we are trying to bring together critical 

partners to help us think through how we can really improve our 

regulatory pathways for obesity reduction drugs including, you 

know, health care providers, scientific experts and patients. So I 

think there are different ways to bring in expertise, and part of 

what is exciting in PDUFA V, I think, is the focus on investments 

in regulatory science, which is an important venue for bringing the 

right expertise together, framing the right questions and making 

sure that we bring the best minds to bear in getting the critical answers. 

Mr. GINGREY. Well, let me interrupt you because I am just about 

out of time, and I am encouraged to hear that and I thank you for 

that response, but that is why I am supportive, quite honestly, of 

my colleague from Texas, Dr. Burgess’s bill in regard to lifting 

these caps on waiver so that we have that expertise and maybe we 

approach it from two aspects, but thank you very much, Dr. Hamburg, and Mr. Chairman, I yield back. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from Arkansas, Mr. Ross, for 5 minutes for questions. 

Mr. ROSS. Thank you, Mr. Chairman, and Commissioner Hamburg, thank you for joining us today. 

I believe that keeping a safe, affordable emergency inhaler available without a prescription, specifically Primatene Mist, is critical 

for asthmatics. Therefore, I am a little confused as to why the FDA 

took Primatene Mist off the market after December 31st of last 

year. Primatene has been available for over 40 years, and now, because of an environmental issue, not a health issue but an EPA environmental issue, the FDA has pulled Primatene from retail 

shelves and will not allow the existing supply chain to be sold. 

Here is why this concerns me. If the FDA allowed the existing supply to be sold, asthmatics could have access to an over-the-counter 

66 

emergency inhaler for at least the next few months until another 

affordable over-the-counter emergency inhaler without harmful environmental impacts, as alleged by the EPA, is approved. Not only 

did the FDA deny access to the Primatene Mist in our supply chain 

but you have now stopped the phase III studies for development of 

an over-the-counter replacement for Primatene, and now Americans are without an OTC emergency inhaler and probably will be 

for the rest of the year when there are at least a million units of 

this inhaler sitting in a warehouse in California. 

So Americans now have to go see a doctor. If they get a prescription, then they have got to get it filled if they can afford it as a 

substitute for this over-the-counter product, and here is where it 

really hits home for me. I represent a very large, a very rural, a 

very poor district, and Primatene Mist can be purchased over the 

counter for asthmatic patients for 20 bucks and prescription 

albuterol is costing those same patients 50 to 65 bucks, and the 

cost is not only to consumers but also to the government. It is estimated it is costing our government, the federal government, between $300 million and $1.1 billion due to asthmatics’ increased 

hospitalizations, ER visits and an increased cost of going from the 

over-the-counter inhaler to one that requires a prescription, and of 

course, much of this cost of the $300 million to $1.1 billion obviously is coming from Medicare and Medicaid because there is not 

another OTC emergency inhaler. 

So these figures are taken from the FDA’s final rule ordering the 

removal of Primatene Mist based on not 2012 but 2008 cost estimates. So when we say it is costing the government $300 million 

to $1.1 billion, those are probably low numbers, and I believe that 

the denial letter from the EPA states it deferred to the FDA in denying the sale of the last remaining units. In other words, the EPA 

left it up to FDA. FDA chose not to. A lot of folks where I come 

from, they can’t afford a $50 substitute for a $20 product that they 

have been taking for way too many years because of their asthmatic condition. 

And so I would ask or suggest that you look into resolving this 

issue by considering releasing the remaining units of Primatene 

Mist and expedite the development of an emergency over-thecounter inhaler for asthma that is affordable and back on the U.S. 

market as soon as possible, and I would love to get your comments 

and thoughts on that. 

Ms. HAMBURG. Well, it is obviously a complicated issue, but I 

think it is important to understand the broader context and the 

medical issues here. As part of the Montreal convention, there was 

a move—there was an environmental issue, as you point out, to remove chlorofluorocarbons from various products including asthma 

inhalers. It has been a very long transition period and we have 

been working with the various manufacturers of asthma inhalers 

to transition towards other delivery vehicles that don’t have the 

CFCs. Of course, the manufacturer of Primatene Mist has been 

part of these discussions and they were given an extended period, 

some additional time for transition and we had indicated that we 

would welcome an application for another product. 

But in terms of the concerns you raise about the public health 

of individuals, I want to make it clear that there really is—we enVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00070 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
67 

gaged in a very broad process of consensus development about the 

medical necessity of this product, talking with health care providers, scientific experts, public health professionals and patients 

and patient groups, and there is great concern about Primatene 

Mist or over-the-counter epinephrine-based—solely epinephrine 

asthma inhaler being used without the oversight and management 

of a medical provider and is really in the best interest of patients 

that have asthma, which can be a very serious and life-threatening 

condition, to have a medical provider. There are better treatments 

for the management of asthma overall. The epinephrine inhaler is 

a transient effect that briefly improves moderate symptoms but 

doesn’t address the underlying cause of the asthma, and so we really think that in the best interest of individuals having access to a 

medical provider, going to a community health center where you 

pay on the basis of your ability to pay, local free clinic or public 

hospital or there are also sponsored programs to make medicines 

available at cheaper rates by various companies is important to the 

overall health and wellbeing of individuals suffering from asthma. 

I recognize the inconvenience of not being able to get an over-thecounter product for immediate relief if you don’t have your prescription inhaler with you, etc. We really tried to make it a smooth 

phase-out process with ample warning and information, both to enable patients to find alternative products and health care providers 

and to ensure that the health of individuals would be protected. 

But I understand the issues that you are raising and the concerns 

that you have. 

Mr. ROSS. Well, it is not about convenience, it is not about trying 

to sell these million units that are in a warehouse in California. It 

is about having a product that people can afford. Too many of my 

folks can’t afford to go to a doctor. They can’t afford a $50 inhaler. 

They are having a tough time affording a $20 inhaler. I am just 

saying we ought to continue—whatever CFCs are out there, they 

have been out there and people have been on this stuff forever in 

order to be able to breathe, and we ought to find a way to be able 

to let them continue to get it until another over-the-counter product that is EPA approved can be developed. Otherwise they can’t 

afford it. They are going without it. They are showing up in the 

emergency room and it is costing our government well over a billion dollars as we make this transition. 

Mr. PITTS. The gentleman’s time is expired. The chairman 

thanks the gentleman and recognizes the gentleman from Ohio, 

Mr. Latta, for 5 minutes for questions. 

Mr. LATTA. Well, thank you, Mr. Chairman, and Commissioner, 

thanks very much for being with us today. I really appreciate it, 

and very interesting testimony today. 

I would like to just kind of switch a little bit over on the pediatric side, and I see in your testimony you state, you know, that 

both these statutes, the BPCA and the PREA, continue to foster an 

environment that promotes pediatric studies and builds an infrastructure for pediatric trials that previously were nonexistence. If 

I could, I would just like of like to—from experience I have had, 

I have talked to a lot of pediatric docs, researchers, hospitals and 

parents of children that have severe illnesses, and I guess I would 

like to ask you, first of all, what they see is that the adult side 

68 

sometimes is getting more of the dollars that are going in for the 

research, and on the second question, when these drugs are coming 

through, are they getting equal treatment as the adult medicines 

that are going—when the FDA is making its determination decisions? 

Ms. HAMBURG. Well, I think that the BPCA and PREA legislation have been enormously helpful in creating a framework to really focus attention on the importance of doing pediatric studies on 

drugs that had previously really been only studied in adult populations and providing some incentives to move in that direction. We 

still have a considerable ways to go. There are, I think, reasons 

why pediatric trials often are not as likely to be done as adult 

trials that include both the recruitment issues of getting kids into 

trials, both logistics and ethics issues, and—— 

Mr. LATTA. Can I interrupt you right there? To solve that then, 

when you are talking about getting the kids into the trials and also 

the ethics issue, how should we go about trying to get that changed 

or promote to get more children into them so that these drugs can 

be—— 

Ms. HAMBURG. Well, I think that this path is a good one and we 

need to continue these programs and strengthen them as it becomes more routine for drug sponsors to be expected to also examine the drugs in pediatric populations, you know, both creates a 

very different climate where there is now an expectation and a 

commitment and accountability for doing so, and it also, I think, 

helps to expand the opportunities and the expertise for doing pediatric clinical trials. But I think it is an area—obviously it is not 

exclusively within the realm of FDA but where we need to as a nation be continuing to put more attention and resources to create pediatric clinical trial networks, to train the clinical researchers to do 

that work, and to encourage both on the medical product and the 

medical device side more innovation and attention to the needs of 

pediatric populations. 

Mr. LATTA. Let me ask then, in your testimony you say there is 

slow but deliberate process that is being made in setting the safety 

and the efficiency of the approved therapies for certain ages. Would 

you say that would be the same thing, it is trying to get these— 

getting the children into these tests, or how would you address that 

statement in your testimony? 

Ms. HAMBURG. You know, to be honest, I am not quite sure the 

question you are asking, but—— 

Mr. LATTA. You state that slow but deliberate progress is being 

made in these studies and again, is that going back to the whole 

issue of trying to get the children and maybe infants into some of 

these studies and the ethics side? 

Ms. HAMBURG. I see. There definitely are some additional barriers I think to recruiting pediatric patients into clinical trials, and 

we need to work on those, and it is—I think it is, as I said, a 

broader issue of really having the support for the clinical trial networks, the training of the pediatric researchers, the education of 

both families and pediatric community providers about the importance of pediatric clinical trials and the opportunities that they can 

represent for both individual patients and for extending knowledge 

69 

about appropriate pediatric care, so I think it is something that we 

really do need to work on and we need to work on it together. 

Mr. LATTA. Thank you. 

Mr. Chairman, my time is expired and I yield back. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from New York, Mr. Towns, for 5 minutes for questions. 

Mr. TOWNS. Thank you very much, Mr. Chairman, and also the 

ranking member for holding this hearing today. Also, thank you 

very much, Commissioner, for being here. 

PDUFA has been an effective and essential tool in assuring that 

safe, effective drugs are brought to the market in a timely fashion. 

However, we must be certain that we are striking the proper balance between the benefits of speedy approval of new treatments 

and the risk that different patient populations are willing to accept 

in order to gain access to them. 

Let us also keep in mind that different patient groups may be 

willing to tolerate different degrees of risk. This is why it is crucial 

for FDA to communicate with the affected patient population when 

reviewing new treatments. 

In your written testimony, Commissioner, you indicated that the 

FDA takes into consideration the benefits and risks of new drugs 

on a case-by-case basis. Considering the degree of unmet medical 

needs and the severe or morbidity of the conditions the drugs intended to treat when conducting this assessment, do you see the 

input of the patient population affected by the condition? 

Ms. HAMBURG. Well, we do, and one of the exciting things about 

the PDUFA V framework also is a real focus on developing better 

strategies to formalize and systematize how we think about benefitrisk and importantly the engagement of patients and their perspectives, and part of what we hope to accomplish over the next 5 

years, if this PDUFA agreement is reauthorized, is to in a formal 

way through a series of public meetings, four a year over the 5-year 

period to really target different disease conditions and engage with 

the patient community about their perspectives of the available 

drugs, their experience of benefits and risks, what kind of risks 

they are willing to tolerate, etc., and that will be, I think, very, 

very useful, in addition, you know, really building on work that we 

do every day as we look at important products in terms of thinking 

about what are the other options available to patients and how serious, life-threatening, life-disrupting is the condition, and we do 

weigh risks and balance them with benefits, and in our approvals 

we are often willing to accept a considerably high level of risk in 

some cases when there is true benefit to the patient. 

Mr. TOWNS. Thank you very much, and let me say to my colleagues, I hope we recognize the importance of making certain that 

we fund you adequately as we make some demands as we move forward. 

I applaud the agency for instituting the accelerated approval 

process in 1992. Do you feel that the program has been successful, 

particularly in the rare disease space? 

Ms. HAMBURG. You know, it has been a very valuable program 

and we have seen, you know, a high number of drugs move forward 

through the accelerated approval process. We also—and many of 

them, a large percentage have been in the rare and neglected disVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00073 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
70 

ease space. We also often give a full approval straightaway to rare 

and neglected diseases when we have, you know, good science, a 

good product and an impact on the underlying condition that is 

meaningful. So I think we have made enormous progress in the 

last couple of decades moving forward in orphan drugs, rare and 

neglected diseases and have been able to apply a lot of regulatory 

flexibility in how we approve those drugs, and I think you may be 

able to hear more about that in the second panel from the NORD 

representative. 

Mr. TOWNS. Let me ask you, what challenges do you face with 

orphan drugs? What challenges do you actually face? Very quickly. 

Ms. HAMBURG. Well, very often, the challenge is how to do the 

science that enables us to get the answers that we need. If you are 

talking about small numbers of patients, how can you tailor the 

clinical studies so that you can get robust, meaningful answers 

with only a small number of patients. I think historically also there 

were concerns about incentivizing industry to want to work on 

some of these disease areas where there would be limited patient 

numbers, and I think that the orphan drug program and the incentive structure there has helped to shift that dynamic, and I think 

that as we really begin to draw on the advances in science and 

technology today, there are very special opportunities in the rare 

and neglected disease areas to produce the kinds of product like 

the way we were able to approve yesterday for cystic fibrosis. We 

were able to really see a targeted therapy for a particular underlying genetic marker and really provide a breakthrough treatment, 

even though the number of patients with that particular condition 

is quite limited. In this case, we are estimating about 1,200 cystic 

fibrosis patients. 

It is a very exciting time and it is an area where I think there 

is a lot of opportunity, and PDUFA obviously has identified that as 

an area where we can make some real progress. 

Mr. TOWNS. Thank you, Mr. Chairman. I yield back. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentlelady from North Carolina, Ms. Myrick, for 5 minutes for 

questions. 

Mrs. MYRICK. Thank you, Mr. Chairman. 

I appreciate you being here today, and that is kind of along the 

same lines of what I wanted to talk about and that, is, the guidelines for approval of certain drugs. While the FDA is tasked with 

protecting public health, I don’t think it should be in a position of 

withholding or removing approval of drugs that treat fatal illnesses. When a patient is expected to die imminently from a disease, the FDA’s decision of whether or not to approve that drug 

should be made on a different metric than the approval of a drug 

that is intended to treat a less serious condition. 

Your agency does claim to factor this in, and I know you see it 

as part of your mission to move treatment forward for patients, but 

it doesn’t seem to me that you give enough weight to the fact that 

dying patients will tolerate a riskier drug. Sometimes they won’t 

respond and will succumb to the disease but sometimes they respond well, and aggregate clinical data doesn’t always reflect that 

properly. So can you just tell me why the FDA shouldn’t have a 

71 

separate metric for determining approvals for diseases like metastatic or otherwise fatal cancers, ALS and other deadly illnesses? 

Ms. HAMBURG. Well, we do, as we were discussing earlier, you 

know, really take very seriously the importance of balancing risk 

and benefit and recognizing when you have a serious life-threatening illness with no or limited other treatment options. The proposed drug must be viewed in a very different context than if it is 

one of six potential drugs for a disease, you know, that has only 

a very minor impact on the tasks of daily living. So we do take that 

very, very seriously, and if you look at our approvals, it is clear 

that as I said, in some instances, there is significant risk associated 

with a drug that we will approve, but we do at the end of the day 

have to ask the question of, is there an overall benefit to the patient, and that can be very difficult and challenging. But that is, 

you know, an important part of what we are charged with. 

I think, again, you mentioned the sort of stratified populations, 

that there may be some who respond and some who don’t, and that 

is why the deepening of the scientific understanding is so important and to continue to work as PDUFA V, you know, has indicated 

in the area of regulatory science and really identifying how we 

identify—we need to really define who are the subpopulations of responders so that we can target the benefits to the people. 

Mrs. MYRICK. No, I understand. We have talked about that before. That is one that I refer to simply because of people that I 

know who are very successfully being treated with that for other 

than the uses that you had approved. 

Also, with the compassionate use process for terminally ill patients who have very few other clinical options, it doesn’t always 

work very well. Companies understandably worry that patients 

who don’t fit the trial guidelines who have completed the trial for 

their drug will negatively alter their clinical data if they are allowed to take an experimental treatment under a compassionate 

use exception. Yesterday, a 41-year-old ALS patient was in our office, and he saw significant symptom improvement while involved 

in a clinical trial, but his participation in the trial ended and then 

he was denied access to the drug under compassionate use because 

of these concerns. 

So in your opinion, what else can FDA or Congress, for that matter, do to improve the likelihood that patients with no other clinical 

option can access treatment through compassionate use? I mean, 

this is an ongoing problem. I understand where you come from but 

it is also pretty hard to look somebody in the face and say I am 

sorry, I can’t help. 

Ms. HAMBURG. Well, it is, you know, a huge issue and one that 

certainly without knowing the specifics of that instance, you know, 

we do try to work with patients’ families and providers under those 

kinds of circumstances to see if we can help facilitate access to a 

product. 

Mrs. MYRICK. Can we refer him to you? 

Ms. HAMBURG. Pardon me? 

Mrs. MYRICK. Can we refer him to you? 

Ms. HAMBURG. You know, I think you could. You know, I can’t 

make any promises but—— 

Mrs. MYRICK. No, I understand. 

72 

Ms. HAMBURG [continuing]. Absolutely and we can—— 

Mrs. MYRICK. He is so young, you know. 

Ms. HAMBURG. Yes, no, and, you know, it is an area that we need 

as a society to continue to work on. 

Mrs. MYRICK. Well, my time is almost up so I will yield back, Mr. 

Chairman. 

Mr. PITTS. The chair thanks the gentlelady and yields to the gentleman from Utah, Mr. Matheson, 5 minutes for questioning. 

Mr. MATHESON. Thank you, Mr. Chairman, and Dr. Hamburg, 

welcome. Thank you for coming today. 

I would like to focus my questions on a national track and trace 

program or a drug pedigree issue, which I know Mr. Dingell talked 

about and some others as well. You probably know, I have worked 

with my colleague, Mr. Bilbray, and a lot of stakeholders on 

crafting legislation to implement a single national pedigree standard. Last year, February 2011, the FDA held a 2-day track and 

trace public workshop. One of the reoccurring concerns from stakeholders at the workshop was the need for timely guidance on a single national pedigree standard prior to States going off and implementing their own systems. Implementation of a national standard 

could take years to implement. Could you speak to the timeframe 

necessary for Congress, the FDA and industry to act on this? And 

in speaking on that also, if PDUFA passes without a national pedigree solution included, what are the implications for where we are 

going to be in terms of our domestic pharmaceutical supply chain 

over the next 5 or 10 years? 

Ms. HAMBURG. Well, it is a very important question, and since 

I happen to be sitting next to an expert on this topic and you have 

been hearing me talk an awful lot, I think I may actually let my 

colleague, Deputy Commissioner Deb Autor, respond to that because she really has been working on those important issue for a 

very long time. 

Mr. MATHESON. Great. 

Ms. AUTOR. Thank you. Congressman, as you mentioned, we did 

hold a public workshop on track and trace and we have had over 

120 participants in that workshop and a lot of comments that have 

been submitted to the docket on a track and trace system. We are 

working hard on working on those standards, and I would be happy 

to talk to you more about how we can work together towards a national uniform pedigree system. We are concerned that if a national 

system doesn’t go into place, we run the risk of having a patchwork 

of State laws including California’s law that is scheduled to go into 

effect in 2015. We believe track and trace provides very important 

assurances to the integrity of the drug supply by giving us and industry and pharmacies and consumers the information they need 

to know to be assured that their drugs are safe and effective. 

Mr. MATHESON. Do you think the FDA needs further authority 

from Congress in order to implement a national standard? 

Ms. AUTOR. Yes. We have authority now to implement standards 

but it is not clear in the law that those standards will be binding 

on everybody in the industry, and it is not clear that they would 

effectively preempt State law, so in fact, I think national legislation 

on this would be useful. 

Mr. MATHESON. That is good to know. 

73 

Now, the safety of our pharmaceutical supply chain has an important overlap with the drug shortage issue that we have been 

talking about. I saw a survey by the American Hospital Association 

that showed 42 percent of those hospitals facing shortages purchased a more expensive product from a new distributor. However, 

in this instance, there is no meaningful way for that hospital to be 

sure the drug they are buying has traveled a safe and secure path. 

Do you think a single national pedigree standard would help hospitals ensure the integrity of products bought outside their normal 

source of supply? 

Ms. HAMBURG. I think, you know, that the issue of supply chain 

and shortages are linked but they also have many distinct characteristics, and I think that as we are grappling with the drug shortage problem, which is, as you know, a very real problem and growing, you know, we are trying to look at all the critical factors that 

are involved and, you know, they range from issues of limited numbers of manufacturers of a given product to aging production facilities, to cost reimbursement issues, and some of the issues around 

consolidation of providers and manufacturers. 

The issue of the security of the supply chain and quality being 

built into both manufacturing and assurances of quality throughout 

the supply chain obviously play a role in shortages to some degree, 

and also understanding the supply chain is important in understanding what kinds of products and quality products people might 

be accessing in relation to a shortage. So it is a complicated issue. 

Mr. MATHESON. And I know there are a lot of separate issues in 

the two. It just seems to me that in a shortage situation, that—— 

Ms. HAMBURG. In a shortage situation, it is absolutely critical 

that whatever you are using as an alternative product, we can 

know is safe and high quality. 

Mr. MATHESON. Yes, shortages create stress on the system, and 

stress creates opportunity for bad things to happen. 

Mr. Chairman, my time is up. I will yield back. Thanks. 

Mr. PITTS. The chair thanks the gentleman and yields to the gentleman from Louisiana, Dr. Cassidy, for 5 minutes for questions. 

Mr. CASSIDY. Dr. Hamburg, thank you for being here. 

Now, I have learned to say in this job, I know what I have been 

told, not what I know, so let me just preface this by this. I am told 

that there is a difference between calendar days and FDA days, so 

on page 4 of your testimony where you mention that the FDA approval phase of new drug development has shrunk. I heard previously people come and say you have got to be kidding, they kick 

it back to us, they don’t include this, and actually the time has 

grown. I have learned to say what I have been told, not what I 

know, so I come to the font, if you will, to say is that true? Is calendar days actually longer even though FDA days are theoretically 

shorter? 

Ms. HAMBURG. Well, in terms of the way the performance goals 

have historically been structured, you know, in fact, one is looking 

at the FDA time and the clock can be stopped for different kinds 

of activities and ultimately what matters to patients and, you 

know, truly what matters to all of us involved in the process is how 

long does it take for a product to actually get to the person who 

needs it. But I think one of the things that has been very, very enVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00077 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
74 

couraging as we have watched the PDUFA process really take hold 

in terms of the resources capacities and focus of our review activities is that we have seen the number of drugs approved in the first 

cycle increase and it is over 60 percent now, I think, which means 

that we are getting drugs to people in the first review process, 

which is really critical because—— 

Mr. CASSIDY. Now, your answer suggests to me that indeed calendar days may have increased for any given drug but it doesn’t 

go through two cycles so maybe net it is less. 

Ms. HAMBURG. On the drug side, I don’t believe that that is the 

case. The device side, it is a little bit of a different scenario, and 

that is why I was sort of avoiding speaking to specific details, but 

on the drug side, we are seeing changes in the absolute time that 

it takes to get a product to market in really across-the-board way, 

particularly for priority review. 

Mr. CASSIDY. Let me go to my next question. I thank you. We 

will later hear testimony from the Pew Health Group, which kind 

of relates to something which we previously spoke about, that if 

you are a domestic pharmaceutical, you are getting reviewed every 

2 years, and if you are overseas, it may be every decade. And I understand here we are now creating resources but in a previous conversation, you mentioned that union contracts limit the ability of 

FDA to assign people to go overseas to inspect. Now, does this address that issue as well? 

Ms. HAMBURG. You know, I think that the union issue is really 

not central to the discussion. The issue about the increased cost 

complexity demands on the system of increasing the numbers of 

international inspections is, and we are really embarked on a series 

of activities to be able to strengthen our capacity to have a global 

presence and either directly inspect or get inspectional information. 

Mr. CASSIDY. So you imply that, if you will, as a workaround so 

even through the contract may inhibit it, you have a workaround 

in which you could third party it? 

Ms. HAMBURG. You know, I think that the union issue is really 

a non-issue here. We work closely with the union around the activities of union employees. 

Mr. CASSIDY. Now, that is a little bit different than what we 

heard last time in which we were told that people had to volunteer, 

they could not be assigned, and that sort of thing. 

Ms. HAMBURG. Well, we definitely seek volunteers for our foreign 

inspectional activities. We are addressing it in a number of ways. 

We do have a dedicated foreign inspectional cadre that really like 

to travel and have specifically volunteered. 

Mr. CASSIDY. So just a pointed question, knowing that right now 

it is every 10 years or so overseas, if you had tomorrow to say listen, we haven’t inspected them for 5 years, you two are going and 

we expect an inspection report from you in however long it takes 

to do an inspection report, would you be able to do that? 

Ms. HAMBURG. Well, we are dramatically ramping up our foreign 

inspections and we are doing it through both using domestically 

based inspectors who travel overseas. We are doing it through having foreign offices and inspectors who are based in country. We are 

doing it sharing inspectional information with our regulatory counterparts in other countries. 

75 

Mr. CASSIDY. Now, if I may interrupt, because I am almost out 

of time. I don’t mean to be rude. But nonetheless, we are only 

doing it every 10 years. What do you project if we have this hearing 3 years from now that the frequency of inspection of an overseas plant will be by whatever mechanism we assign staff to do so? 

Ms. HAMBURG. We are looking ultimately for parity between our 

domestic inspectional schedule and our foreign inspectional schedule. We want a level playing field, and it is interesting, we are not 

talking today so much about the generic user fee agreement but 

the foreign inspection are a particular issue around generic drugs 

and their manufacture and actually through leadership from the 

generic industry, you know, we have a first-time-ever user fee 

agreement that very much focuses on how can we strengthen the 

resources and programs to meet those demands of foreign inspections. 

Mr. CASSIDY. Mr. Chairman, you have been very generous. 

Thank you. I yield back. 

Mr. PITTS. The chair thanks the gentleman. That concludes the 

questions from the members of the subcommittee. We will go to the 

rest of the members of the committee, and the chair recognizes Dr. 

Christensen from Virgin Islands for 5 minutes for questions. 

Mrs. CHRISTENSEN. Thank you for the opportunity to sit in on 

this important hearing and to be able to ask questions. 

Most of the questions that I had around risk and benefit balancing and how it affects the time I think have already been asked 

several times and answered, so I am not going to ask that one. But 

I have a specific question on supply chain that relates to the territories, and I don’t really expect you to answer it right this minute 

but maybe giving me an opportunity to work with your staff on it. 

The medicines that come to the U.S. Virgin Islands are sometimes 

held by Food and Drug through Customs in Puerto Rico and almost 

always confiscated when they are being sent back to their supplier. 

We are outside of the Customs zone. That is part of the problem. 

But we are part of the United States. Our pharmacists are licensed, trained and licensed in the United States, and we are purchasing from U.S. companies. So what we would like to pursue is 

having a waiver or some special procedure to avoid this problem 

because it is a great burden to my hospitals and my pharmacies 

and of course, it had a deleterious impact on patients’ access to 

clinically important drugs, and I am hoping that as you look 

through a new international regulatory system that we can find a 

way to fix that within that. So again, if you want to comment on 

it, fine, but I think it is—— 

Ms. HAMBURG. Well, only to say thank you for bringing this to 

our attention, and I think that we would like to work with you to 

better understand the nature of what is happening and why and 

what can be done to address it. 

Mrs. CHRISTENSEN. Right. And we have talked in the previous 

administration about it, so some of your staff may know about it, 

but I know it is a fresh one for you. 

Could you tell me how the FDA’s new Office of Minority Health 

works, for example, with the Office of Pediatric Therapeutics to ensure that racial and ethnic minority children are appropriately, 

76 

ethically and adequately included in drug research on children and 

pediatric populations? 

Ms. HAMBURG. Well, we are just standing up this new Office of 

Minority Health. It was actually something—the opportunity to put 

it in place was part of the health care reform act, and it is intended 

to sort of cut across the full range of activities within FDA but with 

a special focus on a set of important scientific, medical and public 

health issues including how can we assure the appropriate representation of racial and ethnic minorities in clinical studies and 

I think there are huge opportunities both to work with our Office 

of Women’s Health and our pediatric offices but to work across, you 

know, all of the medical product areas so that we can really address these critical concerns. 

Mrs. CHRISTENSEN. On BPCA and PREA, often in children, the 

side effects of medicine or anything might not be seen for many 

years. Is there a requirement for the pharmaceutical industry to 

follow children for a certain period of time after they have been involved in clinical trials? 

Ms. HAMBURG. You know, I am not sure that I can give you the 

complete response. We obviously have ongoing efforts to monitor 

adverse events, whether they are near term or long term, and our 

ability to do that in a meaningful way is enhanced by what we 

have been able to do in terms of strengthening our postmarket surveillance activities. In certain disease areas, there might be a particular concern anticipating possible longer-term risks or specific 

side effects in children and it might be part of the structuring of 

the clinical trial at the time of its initiation through PREA to put 

in place certain requirements and expectations about ongoing monitoring. But there may be some additional activities as well that I 

am not fully aware of. 

Mrs. CHRISTENSEN. Maybe we can follow up on some discussions 

with your office around that and see if there is something that 

needs to be done in terms of children and long-term impacts. 

Thank you, Mr. Chairman, I yield back the balance of my time. 

Mr. PITTS. The chair thanks the gentlelady and recognizes the 

gentleman from Virginia, Mr. Griffith, for 5 minutes for questions. 

Mr. GRIFFITH. Thank you, Mr. Chairman, and I know we have 

plowed through some of this territory but I think it is interesting. 

As a member of the committee but not of this subcommittee, it has 

been very educational and I do appreciate you being here, Mr. 

Chairman, and I appreciate you letting me participate. 

But you have heard from both sides of the aisle what I am about 

to say, and that is, we have all been contacted by constituents. 

That is why I am here today. I was contacted by a constituent who 

feels that the strong risk aversion at the FDA is creating at least 

the perception that it is slowing down or stopping the approval of 

new, innovative treatments for cancer and other life-threatening 

terminal diseases. And I like some of the others who have spoken 

here today, and I am not going to make you go through all the 

things you have already testified, are very concerned that if you 

are facing a certain death, you are willing to take more risk, and 

you are wondering why the government is getting in the way. So 

I would ask you first, you have already been over a number of 

things that the FDA is doing to try to make that process better, 

77 

but have you given consideration to creating a waiver process 

where a consumer who is facing one of these diseases can waive liability and any concerns about a particular drug or biologic treatment or whatever in order to get that treatment when they are facing the consequences? Obviously, there has to be a disclaimer of all 

the either known or unknown risks involved, but have you all given 

consideration to doing something like that? Because thank God, I 

have never had to face that and hope I never do, but there are a 

lot of folks out there like the 41-year-old we heard about, and you 

have heard from both sides of the aisle, folks are willing to take 

those risks, particularly when they are younger and particularly if 

they have young children, as I do. You know, I would take those 

risks in a heartbeat if it was going to give me extra time with my 

kids. 

So I am just wondering, have you thought about creating some 

kind of a waiver—ok, this hasn’t been approved but I am willing 

to take that risk? And if you haven’t thought of that, would you? 

And then let me follow up with, and what other things is the FDA 

is doing that you have not already testified to, because I don’t want 

you to have to be like a broken record and go over the things that 

you have already mentioned. 

Ms. HAMBURG. Well, you know, obviously this is such an important point and it is something that goes to the very heart of what 

we do because, you know, our mission really is to try to get the 

best possible treatments to people who need them, and, you know, 

as we have already talked about, we are putting an increasing 

focus on how we think about benefits and risks and weigh them. 

We already do accept, you know—have a much higher tolerance for 

risk when you are talking about a disease that is serious, life 

threatening, has no other treatment. I don’t believe that we have 

really explored the exact proposal that you put forward, and I 

think it would certainly require broader discussions than just within the FDA. And we do have some other programs. Compassionate 

use was mentioned for trying to get drugs to people that are in desperate, life-threatening situations but perhaps, you know, in the interest of time and completeness, you know, we could provide you 

with some additional information about the programs that we are 

undertaking, and we certainly can continue to think about other 

strategies including the one that you mentioned. 

Mr. GRIFFITH. Well, and if you would, and, you know, this is one 

of those things where sometimes folks just sitting around the table 

brainstorming might come up with one of those eureka moments 

and have an epiphany. 

Let me shift a little bit to another question that has come up in 

my district. I represent a rural district. There are many recognized 

off-label uses for approved drugs but—I will pick up Dr. Cassidy’s 

point. But I am told that the FDA severely restricts communications to doctors and patients about these uses. Representing a rural 

district, I have heard about doctors who find it difficult to get the 

information about off-label uses that could benefit many of their 

patients. So what can we do to better, both as the FDA and what 

can we do as Congress to help you better inform doctors, especially 

in rural communities so they know about potential effective offlabel uses of approved treatments? 

78 

Ms. HAMBURG. Well, off-label use, as you know, you know, is an 

important part of many medical practices and FDA doesn’t regulate 

the practice of medicine and off-label use is something that we recognize is happening and frequently I have talked with people within FDA about how can we really collect better information to understand off-label use so that it could inform the broader issues 

around the approved indications for the use of a drug, but I think 

that the big concern is when drug companies are actively marketing an unapproved drug for an off-label use and that is where 

the controversies have been really focused on. 

Mr. GRIFFITH. Yes, ma’am. Thank you for your time. I yield back. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentlelady from California, Ms. Eshoo, for 5 minutes for questions. 

Ms. ESHOO. Thank you, Mr. Chairman, for holding this hearing 

and also for extending both you and the ranking member a legislative courtesy to me to join this hearing today. It has always been 

a great source of pride to me to have served on this subcommittee 

for some 15 years, most of the years that I have been in the Congress, and I miss being here but I look forward to coming back and 

I am glad I am here today. 

I would like to ask unanimous consent that the lovely statement 

that I have be added to the record. 

Mr. PITTS. Without objection. 

[The prepared statement of Ms. Eshoo follows:] 

79 


76491.038

Statement of the Honorable Anna G. Eshoo 

House Committee on Energy and Commerce, Subcommittee on Health 

Hearing on the Prescription Drug User Fee Act, the Best Pharmaceuticals for Children 

Act, and the Pediatric Research Equity Act 

February 1,2012 

Mr. Chairman, thank you for holding this hearing today on the reauthorization of the 

Prescription Drug User Fee Amendments, the Best Pharmaceuticals for Children Act, and the 

Pediatric Research Equity Act. These critically important laws have improved patient access to 

important therapies and our nation's regu latory system. 

The Prescription Drug User Fee Act (PDUFA) was enacted in 1992 when drug review 

times were lagging and FDA simply couldn't keep up with the flood of new drug applications. 

Through user fees paid by applicants, PDUFA gave FDA the resources it needed to hire and 

support more staff. The program has been successful at reducing review-time backlogs and 

expediting safe and effective therapies to patients. 

Along with faster drug approvals, Congress also rccognized the need to study drugs in 

children. Children are not just small adults----drugs react differently in their bodies and must be 

studied accordingly. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric 

Research Equity Act (PREA) are the result of this need. BPCA and PREA have vastly changed 

the medical landscape for those treating children and have resulted in new dosing information, 

new indications of use, new safety information, and new data on effectiveness. The drugs studied 

under these programs treat a range of diseases in children, including cancer, HIVI AIDS, 

diabetes, allergy, and asthma. 

As the original author of BPCA and PREA, I'm proud to report that 426 drug labels have 

been created specifically for children since the passage of these laws. Before BPCA and PREA, 
80 


76491.039

the vast majority of drugs (more than 80 percent) used in children were used off-label, without 

data for their safety and efficacy. Today that number has been reduced to 50 percent. While we 

still have a long way to go, we've made remarkable progress in the last decade. 

Congress has the responsibility to periodically review the program to ensure that pediatric 

needs are being met and the program runs efficiently. Through its design, BPCA was intended 

for reauthorization every 5 yearS- and has been since I introduced it in 2002. The program's 

reward of six-months of market exclusivity for doing additional studies in children is a 

substantial one and should not be taken lightly. Providing 6 months of market exclusivity for 

performing pediatric research is a major incentive, and we owe it to the beneficiaries of this 

program--children-to devote our ongoing timely attention to the issue. 

In this year's reauthorization, it's important for us to look at areas in need of 

improvement. FDA must have the tools it needs to ensure companies are thinking about pediatric 

populations as early as possible in the drug development process, and that they're able to enforce 

timelines that are routinely missed. We should encourage further study into untested age groups, 

like neonates, and we should close loopholes which may allow companies to access the market 

exclusivity incentive without completing additional studies. 

I'm proud of how far these programs have come in improving medical care for children 

and I look forward to working with my colleagues to improve both programs even further. 
81 

Ms. ESHOO. Commissioner Hamburg, it is wonderful to see you. 

I think that you know that I was the original author of both PREA 

and the BPCA, so I come here today with a great sense of pride 

and I welcome the comments and the questions that members have 

asked about both pieces of legislation that the Congress is preparing to reauthorize. 

As you know, PREA was created to ensure that drug companies 

were doing important clinical trials in children, an area which had 

been most frankly woefully underserved before the passage of the 

legislation. And without adequate pediatric labeling, doctors were 

left to guess what the appropriate dosages for children would be. 

I think there was maybe this assumption that was being made that 

children are little adults, and they are not; they are children. So 

I think that this has—we took a very important step with the passage of that legislation, and I think it is why it is crucial for companies to develop their pediatric plans as early in the drug development process as possible. 

Now, I understand that the FDA has draft guidance asking companies to submit their pediatric plans at the end of phase II but 

the PREA statute requires submission at the time of the new drug 

application. I think the sooner that companies focus on pediatric 

populations, the sooner kids will receive the drugs that they need 

in some cases to survive. So can you say with confidence that pediatric study discussions always start as early as the FDA recommends? 

Ms. HAMBURG. Well, first, let me say thank you for your leadership, and before you walked into the room, I had actually made 

note of it in my opening remarks. But BPCA and PREA have been 

very important pieces of legislation and have enabled enormous 

progress in the pediatric therapeutics area. The question you raise, 

you know, is an important one. I know it has been under discussion 

within the agency and beyond, and I think it is sort of an ongoing 

discussion in terms of what is the most appropriate timing, and 

frankly, there probably is no one cookie cutter approach. It probably really does depend on the particular product in question and 

the types of trials required. But I think in general, my sense is that 

early engagement is always helpful and the ability—— 

Ms. ESHOO. I ask because of how the statute reads. Do you have 

any idea what the percentage of pediatric plans are actually completed at the end of phase II? I mean, if you don’t know, maybe 

you can get that to us. 

Ms. HAMBURG. We can get that to you. 

Ms. ESHOO. Now, if a company does not submit its pediatric plan 

by the end of phase II, as the draft guidance recommends, does 

FDA have any enforcement mechanisms to address it? 

Ms. HAMBURG. Now, you know, I want to make sure that I answer your question properly. 

Ms. ESHOO. I ask this because I think it would be helpful to have 

legislation to ensure that companies submit their pediatric plans at 

the end of phase II. In fact, Congressman Markey and I are working on this, and maybe I should just turn the question around. 

Would it be helpful to you to have legislation that addresses what 

I just stated? 

82 

Ms. HAMBURG. Well, we do feel that at least as I understand it 

currently, you know, we have the tool of misbranding as a way of 

trying to respond to when the commitment is not met by the company with respect to completion of the pediatric studies, and that 

does seem like a bit—not quite the right regulatory or—— 

Ms. ESHOO. I can sense it in your voice that there is—— 

Ms. HAMBURG. Yes, it creates a situation—— 

Ms. ESHOO. So you think legislation would be helpful? 

Ms. HAMBURG. I think that looking at that and if there is an approach that could be more targeted and flexible, that that would be 

very useful in terms of pushing companies to complete this important work and doing it in a constructive way that ultimately benefits the patients. 

Ms. ESHOO. Thank you very much, and thank you for your work, 

Mr. Chairman, and our ranking member, thank you again for your 

legislative hospitality. 

Mr. PITTS. The chair thanks the gentlelady and recognizes the 

gentleman from California, Mr. Bilbray, for 5 minutes for questions. 

Mr. BILBRAY. Thank you very much for your courtesy, Mr. Chairman, and I just realized that at least on the other side of the aisle, 

there is a few that may remember the time I served on the committee for 6 years. A whole lot of new faces on this side. 

Doctor, we talk a lot about safety and regulation to protect it. We 

have an over-the-counter consumer product that is connected to 

over 500 deaths a year, and we continue to allow that to be sold 

over the counter. Do you want to explain to this committee why aspirin in its existing form is not more regulated or more restricted 

from consumer use even though there is what some people would 

call a very high death rate related to its use? 

Ms. HAMBURG. Well, you know, aspirin obviously is a widely 

available product that we know has associated risks but also benefits. I don’t think that I am prepared in this setting to discuss the 

whole context of the oversight and regulation of aspirin but I think 

it is an important reminder that even drugs that the average 

American would probably consider sort of safe and routine do have 

consequent risks and they need to be addressed in an ongoing way 

and that the FDA does in fact have a responsibility for the lifecycle 

of products, not just for approval but for monitoring safety, efficacy 

and benefit, overall benefit to patients over the whole course of the 

product’s use. 

Mr. BILBRAY. Now, would it be fair to say, or if you can refer to 

your experts around you or whatever, would it be fair to say on the 

flip side of that issue that aspirin probably can be documented as 

being one of the most lifesaving drugs that have been readily available to the public in the last 30, 40, 50, 60 years? 

Ms. HAMBURG. Aspirin has many benefits on different levels. 

That would be fair to say. 

Mr. BILBRAY. Do you have any idea if there was any other drug 

out there that we could point to that probably has saved as many 

lives as aspirin has? 

Ms. HAMBURG. You know, I am not really prepared to make 

those comparisons or have that—— 

83 

Mr. BILBRAY. I would be very interested if you would take a look 

at the reality we have with aspirin, and I ask you to consider, and 

let us be very frank about it. If this product with its fatality problems came before the FDA today, could our existing system actually process it and get it out onto the market, or is it just one of 

those products that became so institutionalized before our regulatory oversight got where it is today? And my question is, do you 

think aspirin could get through the system today? 

Ms. HAMBURG. Well, I wondered if that might be the ultimate 

question that you would be asking, and I guess that my answer in 

the form of a true bureaucrat is that I wouldn’t be prepared to 

speculate without having really reviewed the information and the 

data, but I understand the issue that you are raising. 

Mr. BILBRAY. I mean, my issue is the fact that if you only look 

at the negatives and if you focus, even if you look at the positives 

but if you focus on the negatives, in today’s life, which usually happens, there are huge opportunities that may be denied, and my biggest concern is that I am looking at this and I don’t see any way 

aspirin would be approved in our system, and how many people 

would die every year in this country and around the world if it 

wasn’t available to the consumer? And I have to ask myself, do we 

know how many other drugs or treatments may be out there that 

have come later that cannot be accessible? So my big question is, 

has anybody ever challenged themselves to say do we have any 

idea how many deaths may be caused because we don’t allow products like aspirin on the market today? 

Ms. HAMBURG. Well, you know, as I was saying earlier in discussions, you know, we look in a very clear-eyed way at risks and benefits of the products that come before us, and I think we are striving now to deepen our strategies for addressing that and, you 

know, we do take a lot of risks. There is a sense that we are very 

risk-adverse. 

Mr. BILBRAY. Doctor, I appreciate that and I am not blaming you. 

I am blaming the fact that the political side, we would raise holy 

hell, you would seeing us standing on the House Floor giving big 

speeches damning you for allowing this on the market, and I just 

want to sensitive that. 

Let me just say one thing. One of the great breakthroughs we did 

with AIDS in the 1990s when I was here was that we changed a 

lot of regulations, and multi-triaging was one of those things that 

we really moved the protocol for AIDS that hadn’t been done for 

other research in other treatments. When it comes to cancer, it 

really appears that multi-triaging and a combination of drugs and 

uses may be one of those things we have learned from the AIDS 

success. Where we going now with FDA improving the ability for 

researchers and for pharmaceuticals to look at multiple drug use 

in the treatment of diseases such as AIDS and do we have an expedited process to try to move that process along? 

Ms. HAMBURG. Well, I began my career in public service working 

on HIV/AIDS drug development and know exactly what you mean 

in terms of the importance of the breakthroughs, and it was really 

a combination of bringing the science together with the resources 

and commitment of industry, academia and the patient groups, and 

we were able to move very forward very swiftly and we were able 

84 

to introduce, you know, some new regulatory approaches, etc. in 

the cancer arena and in other areas as well, other infectious diseases and other disease domains, we have a real opportunity as our 

science has deepened to do some of the kinds of things that you 

were just mentioning, and we actually just recently put out guidance to help industry think in some new ways about testing drugs 

in combination rather than doing one after another after another. 

Mr. BILBRAY. And taking 20 years to do it. 

Ms. HAMBURG. Yes. 

Mr. BILBRAY. Mr. Chairman, I know my time is expired. To my 

colleagues, just to follow up on that, one of those other great successes that my colleagues will remember is that in the AIDS crisis, 

we could do blood tests and monitor virus levels to be able to see 

what cocktails were working rather than what we have now in cancer where you basically have to wait for the cancer to show up 

again. You have clinical trials in process right now on the East 

Coast for a blood test for lung and for breast cancer that is being 

looked at. Has anybody in your agency taken a look at the fact that 

this is not just a product that may be able to detect cancer for 

treatment but maybe one of those huge breakthroughs that cancer 

researchers are looking at to be able to more efficient in their research, much like they do with AIDS? Is anybody considering the 

connection between this blood test may not only be a good treatment but may be an essential part of research to address this 

issue? 

Ms. HAMBURG. Yes, and let me just clarify that actually partly 

stemming from the work in HIV/AIDS, we do use surrogate markers including the kind of markers identified through blood tests in 

our approval process. That is really what accelerated approval is 

all about, is identifying what can serve as surrogate endpoints for 

an early approval followed by additional clinical studies to confirm 

or not confirm the initial promise as indicated in those studies. So 

we take that very seriously. We use it in our decision making, and 

certainly what you were describing would fit within that framework of regulatory—— 

Mr. BILBRAY. Thank you for your courtesy, Mr. Chairman. 

Mr. PITTS. I thank the gentleman and recognize the gentleman 

from Massachusetts, Mr. Markey, for 5 minutes for questioning. 

Mr. MARKEY. Thank you, Mr. Chairman. 

The Web site clinicaltrials.gov was transformed into a mandatory 

registry that I created along with Representative Waxman in the 

2007 FDA amendments. This Web site publishes information about 

the results of clinical trials designed to evaluate medical treatments but several problematic loopholes exist. For example, a drug 

company finds out from a clinical trial that a diabetes drug is not 

only ineffective but also causes severe side effects. As a result, the 

company abandons the drug’s development, never seeks approval 

with the FDA and never publishes the results because there is no 

incentive to do so. Commissioner Hamburg, will the results of this 

trial ever have to be posted on the clinical trials database? 

Ms. HAMBURG. As I understand it, currently, no. That is an important issue that you raise. I think it could be addressed but it 

is not included in—— 

85 

Mr. MARKEY. So if another researcher decided to pursue clinical 

trials of this same drug, they would have no idea about the dangers 

identified from the previous trial and would put more people at 

risk of the same adverse health effects that had already been identified so generally do you agree that it would be a good public 

health measure to ensure that results of all registered trials, regardless if the drug is approved or not, are posted on the database? 

Ms. HAMBURG. I believe that NIH through its rulemaking process 

is currently looking at this question in terms of whether trials for 

drugs that aren’t actually approved could be posted. I think you 

also raise a broader issue that certainly we are talking about with 

industry and others in terms of more transparency and the benefits, the common good of making more information about, you 

know, not just what works but what doesn’t as well. 

Mr. MARKEY. Thank you. Now, some clinical trials that occur entirely overseas can be used to support a drug application with the 

FDA even though they are not subject to the disclosure requirements of the clinical trials database. Do you agree that any clinical 

trial regardless of where it takes place should be subject to the 

same transparency requirements if the trial is used as part of the 

company’s approval application to the FDA? 

Ms. HAMBURG. You know, yes, you know, in general we certainly 

agree that more transparency, more information is beneficial and 

we think that this is a bit of a disconnect and, you know, we would 

be interested in working with you further. 

Mr. MARKEY. So this is something that Ms. Eshoo and I are 

working on, this next subject, which is that the FDA data shows 

that since 2007, 78 percent of PREA’s pediatric study requirements 

were not completed by their due dates, if at all. These are products 

that could benefit children but the studies needed to provide that 

information are not always being completed. Pediatric studies are 

especially challenging and companies may have a perfectly acceptable reason for asking FDA to extend their deadlines, but if the 

company does not meet its pediatric requirements and fails to provide a reasonable justification, what enforcement options does the 

FDA have? 

Ms. HAMBURG. Well, we do, as I was discussing with Congresswoman Eshoo earlier, have, you know, a limited arsenal of tools 

and it really is an area where it is important, number one, to understand the reasons for the delays, and as you note, there are 

some reasons that are understandable, but these are studies that 

are important to get done. We need to support companies in getting 

them done and there should be expectations and accountability on 

the completion of those studies. 

Mr. MARKEY. Yes, it is my understanding that the FDA’s only option for enforcement is misbranding the product if there is an enforcement action that you can take but that is an option very rarely, if ever, taken by the FDA. If the FDA were to deem a lifesaving 

treatment misbranded because the company failed to complete its 

pediatric requirements, children who were being prescribed the 

drug off-label would lose access to it. Adults would also lose access. 

Is that correct? 

Ms. HAMBURG. That is correct, and that is why in some ways— 

I have heard it internally referred to as the nuclear option. 

86 

Mr. MARKEY. So either FDA triggers the nuclear option of misbranding, costing everyone access to that drug, or they can do nothing, and that is very different from the way many other violations 

of the Food, Drug, and Cosmetic Act are handled, which can incur 

civil monetary penalties. Have civil monetary penalties been effective in other areas to ensure compliance? 

Ms. HAMBURG. I think that they have been and they do give 

more flexibility and the ability to target the action to what needs 

to be done in a more effective way. 

Mr. MARKEY. And I see no reason, Ms. Eshoo and I agree on this, 

that companies failing to meet their obligations to children should 

enjoy those special protections. So we would like to work with you 

in giving you the flexibility to impose those penalties. 

And just finally, Ms. Schakowsky and Ms. Baldwin and I introduced a cosmetics bill last Congress. We reintroduced the same cosmetics bill in this Congress, and as you know, most people believe 

that the government makes sure that personal care products like 

shampoo and cosmetics are safe before they are sold. Does the FDA 

have statutory authority to require safety testing of cosmetic ingredients before they go on the market? 

Ms. HAMBURG. We do not do premarket approval for cosmetics 

except in a very limited domain of color additives. 

Mr. MARKEY. And can you require a recall of any product in cosmetics? 

Ms. HAMBURG. If there were serious safety issues raised with 

public health consequences, we would work with the company to 

get them to voluntarily—— 

Mr. MARKEY. But it is voluntary. You don’t have a mandatory 

power. 

So Ms. Schakowsky and Ms. Baldwin and I are very interested 

again in pursuing that legislation and working with Mr. Pallone 

and working with the chairman towards the goal of finding a way 

of giving you the authority that you need to work on these issues. 

So if you would be willing to work with us, we are willing to work 

with you and with Mr. Pallone and others to see if we can do something legislatively in this area. 

Thank you, Mr. Chairman. 

Ms. HAMBURG. Terrific. Thank you. 

Mr. PITTS. The chair thanks the gentleman. That concludes 

round one, and we will go to one follow-up on each side for round 

two. The chair recognizes Dr. Burgess for a follow-up question. 

Mr. BURGESS. Dr. Hamburg, thank you for spending so much 

time with us here this morning. I just wanted to follow up on something that Mr. Ross from Arkansas brought up about the over-thecounter asthma inhalers, and while I recognize the problem actually originated in the EPA, not at the FDA, on the removal of CFCs 

as a propellant, you know, the fact of the matter remains, I spent 

New Year’s Eve driving from pharmacy to pharmacy to make sure 

I had an adequate supply of Primatene because as he correctly 

points out, it is two vials for $32, so it is a fairly reasonable price 

compared to the expensive price of the albuterol, which is a prescription device. 

My understanding is that the over-the-counter iteration that is 

non-CFC is currently in process with the HFA as a propellant and 

87 

that FDA is evaluating that. I would just encourage you to do so 

with all great dispatch. These are things that have been around for 

a long time, and most people with asthma, as I do, experience 

times when the disease is much worse and times when it is not so 

bad, and those times when it is not so bad, I may get quite far 

away from having anything around the house that would be available to help me, and it was always comforting to know at 2 o’clock 

in the morning I could drive to a 24-hour pharmacy and purchase 

a Primatene inhaler. Now the only option is—and I am a doctor, 

I can write my own prescription, but for the vast majority of people, you have to go to the emergency room, likely going to get a 

breathing treatment and a pulse oximeter, maybe a blood gas, and 

you are going to spend $1,500, $2,500 for what could have been 

fixed, as Mr. Ross correctly points out, for a $20 charge at an allnight pharmacy. 

So it is important to get the over-the-counter option back out 

there. Many people use these rescue inhalers not frequently but 

from time to time, and that is the part of the population that really 

would benefit from having these back and available again. Can we 

look to you to help us get those? 

Ms. HAMBURG. We have indicated that, you know, we would welcome an application and we will work to expedite the review. 

Mr. BURGESS. Because the active ingredient is not any different 

than what it has been for the last 100 years, right? And the difference is the propellant, and if it used in the albuterol inhalers, 

it can’t possibly be harmful. I think it is as good as CFC. CFC gets 

you a much better dispersion. The HFA always ends up in the 

oropharynx and you have to relearn how to use it. 

But this is important to people, and every member of this committee, in fact, every Member of Congress is going to be hearing 

about this at some time during the year when their constituents 

run out of their existing supply of CFC inhalers and find that they 

cannot replace them. 

Thank you, Mr. Chairman. 

Mr. PITTS. The chair thanks the gentleman, and Mr. Pallone is 

recognized for 5 minutes for one follow-up. 

Mr. PALLONE. Thank you, Mr. Chairman. 

Dr. Hamburg, some have suggested that FDA is insisting on too 

much clinical trial prior to approval and that it is resulting in an 

export of innovation and jobs abroad, and to help address this situation, some of the members have suggested that FDA’s mission 

statement should be changed to include things like job creation and 

innovation. In fact, there is a bill, the Food and Drug Administration Mission Reform Act, that would accomplish this. 

Now, even assuming there is some truth to these reports, and I 

think that there is important evidence to suggest that there is not, 

revising FDA’s mission statement seems like a drastic measure to 

me, and I just wanted you to comment on the implication of revising FDA’s mission statement to include things like job creation. 

How would FDA even begin to assess whether certain agency actions would create jobs? 

Ms. HAMBURG. Well, I think that it is very, very important that 

FDA as a science-based regulatory agency with a public health mission really focus our efforts on determining the safety, efficacy and 

88 

quality of the products that come before us and that we do our 

work in the context that clearly understands that we need to make 

sure that we are bringing products to people in a timely way that 

they need and count on and that we do need to do everything we 

can to make sure we have the most modern and streamlined approaches and that we work closely with product sponsors in a way 

that is transparent, consistent and predictable to achieve our common goal of making important products available to people. 

I think that our safety and efficacy standards are very important 

to the success of industry as well as to improving and protecting 

the health of the public. 

Mr. PALLONE. But what I am trying to find out is whether you 

would want to revise the FDA’s mission statement to include 

things like job creation. 

Ms. HAMBURG. Well, I was going to get to that and I think it 

would be very hard for us to factor in to this science-based decision 

making the question of how would approving or not approving this 

product impacts jobs and how would approving or not approving a 

product impact jobs of a competitor, and it would get very, very 

complicated, and frankly, I think it would be quite inappropriate 

and would ultimately not serve the American people well or serve 

industry well, and I think it is something that would be extremely 

hard to quantify, and I think that, you know, what is really important is that we make sure that operating within the ecosystem of 

biomedical innovation and product development that we ensure 

that we are doing our job as well as we can, which is to apply 

science-based, data-driven processes to our decision making, do it 

in as modern and streamlined a way as possible, and work as effectively with industry and other stakeholders to deliver the products 

that people need. 

Mr. PALLONE. Thank you. 

Mr. PITTS. The chair thanks the gentleman. That concludes our 

questions for panel one. The chair thanks the panel, specifically Dr. 

Hamburg, for your excellent testimony. It is very important information you have shared with the committee. 

We will now excuse panel one and call panel two to the witness 

table, and while we change panels, we will take a 5-minute recess 

and reconvene at 12:45. 

[Recess.] 

Mr. PITTS. We will ask all of guests and witnesses to please take 

their seats, and would like to ask at this time unanimous consent 

to enter into the record a statement by NCPA, that is community 

pharmacists, and NACDS, National Association of Chain Drug 

Stores, into the record. It has been shared with the other side, so 

without objection, so ordered. 

[The information follows:] 

89 


76491.040

Statement of the National Community Pharmacists Association 

to the United States House of Representatives 

Committee on Energy and Commerce 

Subcommittee on Health Hearing on 

"Reauthorization ofPDUFA: 

What it Means for Jobs, Innovation and Patients" 

February 1,2012 

Dear Subcommittee Chair Pitts, Ranking Member Palione and Members of the Subcommittee: 

NCPA welcomes this opportunity to provide input and suggestions to the Subcommittee as it 

addresses the reauthorization of PDUFA and related issues, The National Community Pharmacists 

Association (NCPA) represents America's community pharmacists, including the owners of more 

than 23,000 community pharmacies, pharmacy franchises and chains. Together. these small 

business entities employ over 300.000 fuli-time employees and dispense nearly halfofthe nation's 

retail prescription medicines. 

Speeificaliy, NCPA would like to provide the following comments and suggestions regarding a 

number of issues that may be considered in tandem with PDUFA including: potential proposals to 

"track and trace" prescription drugs as they move through the supply chain: the lack of 

standardization for Risk Evaluation and Mitigation Strategies (REMS) and Medication Guides; drug 

shortages; the creation of a "transition" class of drugs; and the regulation of internet pharmacies. 

Potential Proposals to Enhance Snpply Chain Security 

NCPA bclieves that the current pharmaceutical supply chain is safe and secure and accordingly 

independent community pharmacies have trust and confidence in their pharmaceutical wholesale 

suppliers. However. NCPA does feel that there are a number of ditTerent approaches or tactics that 

could be employcd to provide further confirmation of integrity such as the development of federal 

lieensure standards for wholesalers that would be administered by the states. and the imposition of 

greater penalties for cargo theft. 

With respect to a potential inclusion of a "traek and trace" system for preseription drugs, NCPA is 

working with a diverse group of stakeholders on a consensus approach that could add an additional 

layer of security to the current pharmaeeutical supply chain. Our view on such a system is that it 

should be: I) used sparingly - for example. only in cases of recalls; 2) allow for human readable 

identifiers on the saleable unit; 3) not be used by manulacturers as a prerequisite for the ability of 

pharmacists to purchase their products, or return recalled or outdated products; and 4) and not 

impose significant burdens and hardships on certain sectors of the supply chain or serve as an 

unfunded mandate at a time when small businesses. such as independent pharmacies. are already 

struggling under a crushing burden of federal and state regulations. 
90 


76491.041

Lack of Standardization for REMS and Medication Guides 

NCPA continues to have concerns with the lack of standardization for Risk Evaluation and 

Mitigation Strategies (REMS), particularly medication guides. The FDA currently requires 

pharmacists to distribute an increasing number of highly variable paper medication guides for 

hundreds of drugs. These typically long, written documents may be of little value to patients, but 

add significant costs and burdens to the health care system. Instead, NCPA urges the FDA to 

transition to a simple, succinct document that would be produced by manufacturers and provided by 

pharmacies to patients. Phannacies could provide this document to patients, either in print or 

electronic form, following face-to-face counseling. Such a simplified document could be an 

effective tool to reinforce proper medication use and improve overall health outcomes. In addition. 

NCPA urges the FDA to standardize the REMS procedures within the prescription filling process. 

Drug Shortages Impact on Independent Community Pharmacies 

NCPA's community pharmacist members and their patients are greatly affected by drug shortage 

issucs. For example, there is currently a serious shortage of some ADHD medications which may 

be due in part to DEA manufacturer allocation issues. 

Nevertheless, community pharmacies often have little notice of shortages from manufacturers and 

NCPA believes that a better process needs to be established to avert shortages. In addition, federal 

reimbursement policies should require that Medicaid and Medicare Part D programs suspend the 

Federal Upper Limits (FULs) or Maximum Allowable Cost (MAC) pricing on these drugs, as 

pharmacy benefit managers (PBMs) are often slow to provide highcr reimbursement for these drugs 

to pharmacies atter a shortage hits the market, and the price to the pharmacist spikes. Pharmacies 

should also be relied upon to compound medications that may be in short supply, as was the case 

during last year's Tamitlu shortage during which the FDA called on pharmacists to compound 

medications to compensate for the shOitage. 

NCPA Support for a "Transition" Class of Medications 

NCPA supports the creation of a "transition" class of medications, which would be dispensed by a 

pharmacist after consultation with the patient. These medications would initially be prescription 

medications that would most likely be transitioned to full OTC status after a period of monitoring 

by a pharmacist. The creation of such a medication class would provide assurances to the 

manufacturer, the FDA, and consumcrs that the product could be used safely and effectively before 

a complete switch to OTC status is made. A transition class would also reduce consumer health 

care costs, increase convenience, and provide a vehicle for post-market supervision, while providing 

a guarantee of consumer protection. Pharmacists should bc fairly compensated for their role in 

providing medications through such a .. transition" class. 

FL'bnwt'\ 1.2012 

Statement of the National Community Pharmacists As~ociation to the United States House of Representatives 

Committee on Energy and Commerce Subcommittee on Health Hearing on 

'"Reauthorization ofPDUFA: \Vhat it Means for Jobs, Innovation and Patients" 
91 


76491.042

NCPA Supports Efforts to Eradicate Rogue Internet Pharmacies hut Cautions Against Overlv 

Broad Definition of "Internet Pharmacy" 

NCPA supports public policy efforts to eradicate rogue internet websites that illegally sell 

prescription drugs, especially controlled substances. However, we oppose broad sweeping attempts 

to classify every brick and mortar pharmacy that maintains an internet site as an internet pharmacy. 

Such approaches are unnecessary because traditional pharmacies are already heavily regulated by 

both federal and state authorities. 

We appreciate the opportunity to submit these comments for the record, and look forward to 

participating in the development of patient-centered PDUFA legislation. 

Fehruary I. 2012 

Statement of the National Community Pharmacists Association to the United States House of Representatives 

Committee on Energy and Commerce Subcommittee on Health Hearing on 

"Reauthorization ofPDUFA: What it Means for Jobs, Innovation and Patients" 
92 


76491.043

NATIONAL ASSOCIATION OF 

CHAIN DRUG STORES 

Statement 

Of 

The National Association of Chain Drug Stores 

For 

U.S. House of Representatives 

Energy and Commerce Committee 

Subcommittee on Health 

Hearing on: 

Reauthorization of PDUF A: 

What It Means for Jobs, Innovation, and 

Patients 

February 1,2012 

10:00 a.m. 

2123 Rayburn House Office Building 

National Association of Chain Drug Stores (NACDS) 

413 North Lee Street 

Alexandria. VA 22314 

703-549-300 I 

www.nacds.org 
93 


76491.044

NACDS Comments to House Energy and Commerce Suhcommittee on Health 

Reauthorization o(F'DUFA: What It MeansjiJrJobs, Innovation, and Patients 

February /, 2012 

Page 2 0(8 

The National Association of Chain Drug Stores (NACDS) thanks the Members of the Subcommittee 

on Health for consideration of OUf statement for the hearing on "Reauthorization of PDUFA: 

What It Means for Jobs, Innovation, and Patients." NACDS and the chain pharmacy industry are 

committed to partnering with policymakers and others to work on viable strategies to address drug 

safety and the appropriate use of prescription medications in order to help promote optimal drug 

therapy treatment and patient health outcomes. 

NACDS represents traditional dnlg stores, supermarkets, and mass merchants with pharmacies 

from regional chains with four stores to national companies. Chains operate more than 40,000 

pharmacies and employ more than 3.5 million employees, including 130,000 pharmacists. They fill 

over 2.6 billion prescriptions annually, which is more than 72 percent of annual prescriptions in the 

United States. The total economic impact of all retail stores with pharmacies transcends their $900 

billion in annual sales. Every $1 spent in these stores creates a ripple effect of $1.81 in other 

industries, for a total economic impact of $1.76 trillion, equal to 12 percent of GDP. For more 

information about NACDS, visit www.NACDS.orf!. 

While we believe that the U.S. supply chain is the safest in the world, we are working with supply 

chain stakeholder coalitions to help enhance safety through additional achievable and feasible means 

for the security and integrity of the U.S. drug distribution supply chain. We also champion etTorts to 

prevent illegitimate Internet drug sellers from targeting U,S. consumers with unsafe medications. To 

that end, we have endorsed federal legislation (S.2002) that will work toward providing consumers 

with a safe and secure means to identify legitimate online pharmacies. We also support providing 

patients with a useful and understandable drug information document (the "one document solution"), 

and providing patients with a safe and legal means for disposal of their unused medications. We 

believe that these are important issues surrounding the use of prescription drugs. 

In addition, we are devoted to important initiatives to improve patients' adherence to their prescribed 

medications. Chain pharmacies and their pharmacists work with their patients daily to provide them 
94 


76491.045

NACDS Comments to llouse Energy and Commerce Subcommittee on Health 

Reauthorization o( PDUFA: What II Means/i)r Jobs. Innovation. and Patients 

FebruGiT I. 2012 

Page 30(8 

with information and counseling on the proper use of their prescription medications and the 

importance of adhering to their prescription drug treatment. 

NACDS and the chain pharmacy industry look forward to working with Members of Congress on 

issues related to prescription drug use. 

NACDS SUPPORTS FDA'S PDUFA GOALS 

We are pleased that FDA has proposed to apply user fees toward efforts to enhance and modernize 

the U.S. drug safety system. To enhance patient safety, FDA plans to devote user fees toward 

reviewing drug applications for look-alike and sound-alike proprietary names and related factors that 

could contribute toward medication errors such as unclear label abbreviations, acronyms, dose 

designations, and error prone label and packaging design. We wholeheartedly support this proposal 

that would reduce the potential for medication errors throughout the healthcare delivery system. 

We are also supportive of FDA's plans to utilize user fees to develop techniques to standardize 

prescription drug Risk Evaluation and Mitigation Strategies (REMS) and better integrate them into 

the existing and evolving healthcare system. The success of any REMS is h'ighly dependent on the 

ability of all relevant stakeholders to provide ample input during the design phase of the program, 

well before implementation. The concerns of phannacies and other healthcare providers must be 

considered in order for REMS to be successful. Since REMS could impact phannacy operations and 

workflow and even a pharmacy's ability to provide the affected medication to a patient, we welcome 

more opportunities to work with FDA to standardize REMS. 

In addition, we strongly encourage FDA's proposal to develop methodologies for assessing whether 

REMS are achieving their goals of mitigating risks and assessing the etTectiveness and impacts of 

REMS on patient acccss and on the healthcare system. We believe that REMS should be subject to 

review by pharmacies and other relevant healthcare providers, such as by a representative panel of 

expert reviewers to include pharmacists who practice in pharmacy settings affected by the REMS. 
95 


76491.046

.l'vACDS Comments to 110u!'iC Energy and Commerce Subcommittee on Health 

Reauthorization o/f'DUFA: What It Means/ilr Johs, Innovation, and Patients 

Fehruary 1, 2012 

Page.:/ 0/8 

Although pharmacies are not directly responsible to FDA for the design, implementation, and 

success of REMS, pharmacies are subject to the elements of REMS in order to meet the needs of 

their patients, 

THE ROLE OF MEDICA TION THERAPY MANA GEMENT (MTM) 

Services provided by community pharmacists improve drug safety. Pharmacists are uniquely 

qualified to provide Medication Therapy Management (MTM) services to patients, which help 

ensure that patients are prescribed thc correct medications and that they arc taking them properly. 

Unfortunately however, MTM services are infrequently compensated, which limits pharmacists' 

ability to provide these services to patients. 

When patients are prescribed the correct medications, they are less likely to experience adverse 

effects, such as allergies and drug interactions. Thus, they are more likely to take their medications 

as directed, that is, to adhere to their therapy. Patient adherence to their medication therapy leaves 

fewer unused medications in medicine cabinets that can be divelied and abused by others. Properly 

reimbursing pharmacists for providing MTM services is a greatly underutilized tool for addressing 

the problems of prescription drug diversion. 

Pharmacist MTM services and the improved medication adherence that can "result also provide the 

dual benefits of improving patient health outcomes and reducing the use of other more costly 

healthcare services. Research has shown that an estimated one-third to one-half of all patients in the 

United States do not take their medication as prescribed. They may fail 10 take their prescription 

medications, take their medication incorreclly, or stop taking their medication altogether. These 

circumstances seriously undermine quality of life and quality of care, patient outcomes and the value 

of health care dollars spent. Poor medication adherence costs the U.S. approximately $290 billion 

annually - 13% of total healthcare expenditures. Community pharmacies and their phannacists are 

uniquely situated to assist patients in complying with their prescribed medication treatment and· 

explaining the benefits of adherence, Programs such as ChccKmeds in North Carolina, a program 

where community pharmacists provided MTM services involving nearly 27,000 seniors in 2008 and 
96 


76491.047

NACDS Comments to House Energy and Commerce Subcommittee on Health 

Reauthorization o( PDUFA: What It Meansfin' Jobs, Innovation, and Patients 

Februmy 1, 2012 

Page 5 0(8 

2009, showed the benefits and savings by avoiding more costly healthcare services such as 

emergency rooms and hospitalizations and prescription drug savings. For every dollar spent in this 

program for pharmacist medication therapy management services, the benefit was $13.55 in savings, 

TARGET ILLEGITIMATE INTERNET DRUG SELLERS WITH THE "CHOKEPOINT" 

APPROACH 

NACDS also believes that addressing the problem of illegitimate Internet drug sellers is an impOltant 

component of drug safety. These illicit online drug sellers have websites that target U.S, consumers 

with ads to sell drugs often without any prescription required. They are almost without exception 

located outside of the U,S, yet have web sites camouflaged to look like legitimate phannacy 

websites, They operate in clear violation of U.S. state and federal laws and regulations that protect 

public health and safety, They sell drugs to consumers without the safety precautions of a legitimate 

prescriber-patient relationship, a valid prescription. and a licensed U,S, pharmacy. 

These illegal Internet sites that profit from these illegitimate activities are often mistakenly referred 

to as Internet "pharmacies," They are not pharmacies; they are illegitimate Internet drug sellers. 

They are not licensed as pharmacies by any U.S,jurisdiction, nor do they comply with any of the 

rigorous state and federal laws governing pharmacy licensure and the practice of pharmacy hy 

pharmacists, Instead, these illegitimate Internet drug sellers are shipping unapproved, counterfeit, 

mislabeled, or adulterated products within or into the country. 

We support targeting illegal Internet drug sellers through the chokepoint approach, rather than 

placing unwan-anted burdens on legitimate, state licensed pharmacies that have associated branded 

Internet websites, Under the chokepoint approach, entities such as domain name registrars that issue 

websites, financial entities that handle payment transactions, Internet Service Providers that show thc 

illegitimate websites on the Internet, and common carriers that provide the mailing services would 

have authority to stop illicit transactions at their point of interaction with thcse bad actors. 
97 


76491.048

NACDS Comrnenls 10 House Energy and Commerce Suhcommittee an Health 

Reauthorization o/PDUFA: Whatlt iIIeans/iJr./obs.lnnovalion. and Palienls 

Februmy I. 2012 

Pa!!.e 6 ol8 

CHAIN PHARMACY ROLE IN SECURING U.S. DRUG SUPPLY CHAIN 

Weare proud of the systems and initiatives that our members have developed with other industry 

stakeholders to improve u.s. drug supply chain security. 

Chain pharmacy has takcn a leadership role to fUl1her ensurc the intcgrity of the products they 

dispense. For example, many pharmacies have made changes in their purchasing practices, such as 

rcquiring their wholesale distributors to purchase prescription drug products directly from 

manufacturers. Chain pharmacy has been engaged with supply chain stakeholder coalitions working 

to enhancc security for many years, and is currently involved with a coalition that includes 

manufacturers and wholesalers seeking feasible and achievable means to enbance supply chain 

security. 

Our industry has also been engaged at the state level to enhance supply chain integrity. We 

supportcd state-level legislation requiring enhanced wholesale distributor licensure requirements and 

chain of custody "pedigrees" for drug distributions outside the recognized and safe "normal 

distribution channel." More than 60% of the states have enacted laws and regulations to strengthen 

the security of the drug distribution supply chain. We have also supp0l1ed increascd fines and 

penalties for violations of these state laws. Our members have seen marked improvements in the 

security of the drug distribution supply chain since the adoption of these initiatives and state laws. 

While there were several incidents of drug countcrfeiting in the early 2000's, we are not aware of 

notices from the FDA of drug counterfeiting in the U.S. normal distribution supply chain since that 

time. It appears that these initiatives and stricter requirements have removed the bad actors from 

operating within the legitimate drug supply chain. 

Chain pharmacy remains committed to working with Congress on the security of the U.S. drug 

distribution supply chain. However. we remain concerned with mandates to track and trace 

prescription drugs due to disruptions, complexities. and the substantial resources that would be 

required. These would occur at a time when the healthcare system is seeking to reduce costs. 

Moreover, with drug manufacturers almost universally applying "line of sight" "two-dimensional bar 

codes" on their products. these concerns would become quite real. Nevel1heless. we remain 
98 


76491.049

NACDS Comrnents to House Energy and Commerce Subcornmittee on Health 

Reauthori=ation olPDUFA: Whal It MeansjiJrJobs, Innovation, and Patients 

February 1,2012 

Page 70lS 

committed to working with Congress and the supply chain stakeholders to nlaintain and enhance 

supply chain security through viable means, 

IMPROVED PA TIENT MEDICATION INFORMATION "ONE DOCUMENT SOLUTION" 

As FDA has recognized, patients typically receive several different types of medication information, 

developed by different sources that may be duplicative, incomplete, or difficult to read and 

understand, Wc agree with FDA that the current patient mcdication information (PM!) is not 

adequate to ensure that patients receive essential information in a clear and easily understandable 

format. Wc are very pleased that FDA is holding public hearings to gather information to assist the 

agency with the adoption of a single PM! document that is standardized with respect to format and 

content, thc "one-document solution," For each medication, patients want a single, useful document, 

designed and writtcn for thcm, that recognizes their information needs, that focuses concisely on 

critical information, and that provides them with clear instructions on wherc to go for further advice 

and instruction, 

Existing requirements for multiple medication infOlmation documents, containing rcdundant or even 

cont1icting information, creates logistical and financial burdens for pharmacics that compromise 

effective patient counseling, It would be far more convcnient, efficicnt, and ultimately more 

effective for pharmacists to counsel patients by providing a single PMI documcnt that could easily 

bc understood and facilitatc a discussion concerning proper use of medication, 

We belicve the best approach to the developmcnt of PMl is manufacturer development with FDA 

approval. Only this approach could absolutely ensure that all PMlmeet FDA standards of accuracy 

and comprehensibility. and that the information is properly balanced to communicate risks and 

benefits, In our view, each FDA-approved drug would eventually have a single, standardized. 

manufacturer-developed, FDA-approved PMI document. 
99 


76491.050

lVACDS Comments to House Energy and Commerce 5'ubcommittee on Health 

Reauthorization of1'DUFA: What It Means/ilr Johs, Innovation, and Patients 

FebruOlY ], 2012 

Page 8or8 

CONCLUSION 

NACDS thanks the Subcommittee for consideration of our comments. We look forward to working 

with policy makers and stakeholders on these important issues. 
100 

Mr. PITTS. I would like to now welcome panel two and thank all 

of you for agreeing to testify before the subcommittee today, and 

I would like to quickly introduce our expert panel. 

Mr. Geno Germano, President and General Manager of Specialty 

Care and Oncology at Pfizer, is our first guest. Dr. David Gollaher, 

President and CEO of California Healthcare Institute. Mr. Richard 

Pops, Chairman and CEO of Alkermes. Mr. Pops is testifying on 

behalf of the Biotechnology Industry Organization. Mr. Allan 

Coukell, Director of Medical Programs for the Pew Health Group; 

Ms. Diane Dorman, Vice President of Public Policy at the National 

Organization of Rare Disorders; Dr. David Wheadon, the Senior 

Vice President for Scientific and Regulatory Affairs at PhRMA; and 

Dr. Daniel Frattarelli, Chair of the American Academy of Pediatrics’ Committee on Drugs. 

So we will go in that order. Again, thank you all for coming. We 

have your prepared statements, and we will ask each of you to 

summarize in 5 minutes your opening statements. 

Mr. Germano, we will begin with you. You are recognized for 5 

minutes. 

STATEMENTS OF GENO GERMANO, PRESIDENT AND GENERAL 

MANAGER, SPECIALTY CARE AND ONCOLOGY, PFIZER, INC.; 

DAVID L. GOLLAHER, PRESIDENT AND CHIEF EXECUTIVE 

OFFICER, CALIFORNIA HEALTHCARE INSTITUTE; RICHARD 

F. POPS, CHAIRMAN AND CHIEF EXECUTIVE OFFICER, 

ALKERMES, ON BEHALF OF BIOTECHNOLOGY INDUSTRY ORGANIZATION; DAVID E. WHEADON, SENIOR VICE PRESIDENT, 

SCIENTIFIC AND REGULATORY AFFAIRS, PHARMACEUTICAL 

RESEARCH AND MANUFACTURERS OF AMERICA; ALLAN 

COUKELL, DIRECTOR OF MEDICAL PROGRAMS, PEW 

HEALTH GROUP, THE PEW CHARITABLE TRUSTS; DIANE 

EDQUIST DORMAN, VICE PRESIDENT, PUBLIC POLICY, NATIONAL ORGANIZATION FOR RARE DISORDERS; AND DANIEL 

A.C. FRATTARELLI, CHAIR OF PEDIATRICS, OAKWOOD HOSPITAL AND MEDICAL CENTER, ON BEHALF OF THE AMERICAN ACADEMY OF PEDIATRICS’ COMMITTEE ON DRUGS 

STATEMENT OF GENO GERMANO 

Mr. GERMANO. Thank you, Chairman Pitts and members of the 

subcommittee. My name is Geno Germano. I am President and 

General Manager of Specialty Care and Oncology at Pfizer. Founded in 1849 in New York City, we have grown to become the world’s 

largest biopharmaceutical company, providing treatments for a 

myriad of diseases that afflict people around the world. I appreciate this opportunity to testify on behalf of Pfizer and our 40,000 

U.S. colleagues to unequivocally support the reauthorization of the 

Prescription Drug User Fee Act. 

Behind the acronym PDUFA is another acronym: R&D, research 

and development. Research and development is the lifeblood of 

Pfizer. It is the lifeblood of our industry and it is the lifeblood of 

great American innovation. Today it takes on average more than 

a billion dollars and 12 to 15 years to research and develop a new 

medicine. Approximately one in 10,000 compounds that enter the 

drug discovery phrase is every approved by the Food and Drug Administration and made available to patients. Our R&D is ultiVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00104 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
101 

mately codified in our patents. Patents represent our license to 

move forward and are a fundamental legal basis for our existence. 

It is important to remember, we file our patents on compounds 

in the very early stages of development, often a decade or more before the review process begins at the FDA. Therefore, by the time 

we had submitted an application to FDA, the patent life is already 

eroded to a meaningful extent, making an effective and efficient 

process with FDA imperative for our firm. 

Biopharmaceutical companies like Pfizer typically have at most 

between 10 and 14 years to recoup our investment before generic 

competition enters the market. However, the public value, the public health value of our investment continues for generations to 

come. 

It is through this foundational work in R&D and manufacturing 

that the biopharmaceutical industry supports more than 3 million 

U.S. jobs and nearly $300 billion in total output to GDP. PDUFA 

will help keep R&D and new medicine introductions in the United 

States. 

The financial commitment and significant time and resources required to develop a drug reflect the uncertainties inherent in our 

business. The scientific uncertainties are ultimately reduced to the 

core question: does the benefit of the drug outweigh the risk? And 

this is a question we and FDA seek to answer, and it will vary depending upon the treatment and the intended patient population. 

Regulatory uncertainties can complicate this dynamic if the review 

process at FDA is ambiguous and inefficient. This is why a strong 

partnership and communication with the FDA are essential. 

As the head of the specialty care business, I am intimately engaged in the development of our medicines. My business focus is 

on developing therapies for complex and rare diseases, many forms 

of cancer, and vaccines for the prevention of life-threatening infections. 

Prevnar 13, a vaccine for the prevention of pneumococcal disease, 

is a great example of an important medical advancement. In December of last year, Prevnar 13 received approval from FDA for 

adults 50 years of age and older under the accelerated review process, a pathway specifically intended to speed new medicines to 

market for significant unmet health needs. Then last Friday, FDA 

approved our new cancer medicine, Enlighta, that we developed for 

patients with advanced renal cell cancer whose disease continues 

to progress after first-lien therapy fails. The development pathway 

for critical medicines and vaccines like these are not cookie cutter 

in nature, and it is essential to have a strong, functional regulatory 

agency for advancements like these to continue. 

In my full statement, I discuss the major provisions of the new 

PDUFA agreement. I would like to highlight one of these, the review enhancements for new molecular entities, or NMEs, which 

will have an immediate impact on Pfizer and medicines in our pipeline. A good example of the benefit of an effective NME review 

process is Xalkori, which was approved by FDA last August. 

Xalkori is an NME and is the first lung cancer drug approved by 

the FDA in more than 6 years. This scientific innovation is also one 

of the first personalized medicines targeting a genetic abnormality 

shared by only 3 to 5 percent of the 200,000 lung cancer patients 

102 

diagnosed in the United States each year. Xalkori was a fast-track 

product that was given priority review by FDA. The goal was to review in 6 months. FDA reviewed it in 4 months. While Xalkori’s 

approval is an example of getting it right, the challenge we have 

is making sure that situations like Xalkori are the rule and not the 

exception. The NME review process enhancements will help 

achieve that goal. These enhancements embody what we consider 

to be the foundation of a successful review: communication and 

transparency. 

The improved process will encourage better issue identification 

and resolution at the fine stages of the review cycle. Further, these 

enhancements will have a direct impact on the dozens of NMEs at 

various stages of development in our pipeline. These are potential 

new treatments and therapeutic areas such as oncology, pain, cardiovascular disease and vaccines. 

The ability of Pfizer to do its job depends on the ability of FDA 

to do its job, and PDUFA provides a framework and resources for 

that to happen. PDUFA is must-pass legislation. It is must-pass for 

Pfizer and the biopharmaceutical industry. It is must-pass for FDA, 

but most importantly, it is must-pass for patients and society as a 

whole. 

Thank you for this opportunity to testify. I look forward to answering any questions you may have and hearing your views. 

[The prepared statement of Mr. Germano follows:] 

103 


76491.051

Testimony of Mr. Geno Germano 

President and General Manager 

Specialty Care and Oncology 

Pfizer Inc. 

Before the House Energy & Commerce Subcommittee on Health 

Reauthorization of the Prescription Drug User Fee Act (PDUFA) 

February 1, 2012 

Chairman Pitts, Chairman Upton, Ranking Member Pallone, Ranking Member 

Waxman and members of the Subcommittee, my name is Geno Germano. I am 

President and General Manager of the Specialty Care and Oncology businesses 

at Pfizer. Founded in 1849 in New York City, we have grown to become the 

world's largest biopharmaceutical company, providing treatments for myriad 

diseases that afflict people around the world. 

I appreciate the opportunity to testify on behalf of Pfizer and our 40,000 U.S. 

based colleagues, to unequivocally support the reauthorization of the 

Prescription Drug User Fee Act (PDUFA). 

Behind the acronym PDUFA is another acronym: R&D. Research and 

Development. R&D is the lifeblood of Pfizer. It is the lifeblood of our industry. 

And it is the lifeblood of great American innovation. 

Today, it takes on average more than $1 billion and 12-15 years to research and 

develop a new medicine. Approximately 1-in-10,000 compounds that enter the 

drug discovery phase is ever approved by the Food and Drug Administration 

(FDA) and made available to patients. 

Our R&D is ultimately codified in our patents. Patents represent our license to 

move forward and are a fundamental legal basis for our existence. 

It is important to remember that we file our patents on compounds in the very 

early stages of development, often a decade or more before the review process 

begins at the FDA. Therefore, by the time we have submitted an application to 

the FDA, the patent life has already eroded to a meaningful extent, making an 

effective and efficient process with the FDA imperative for the firm investing in 

this innovation. 

Pfizer Inc 
104 


76491.052

Biopharmaceutical companies like Pfizer typically have at most between 11-14 

years to recoup our investment in a new compound before generic competition 

enters the market; however, the public health value of our investment continues 

for generations to come. 

It is through this foundational work in R&D and manufacturing that the 

biopharmaceutical industry supports more than three million U.S. jobs, nearly 

$300 billion in total output to GOP. PDUFA will help keep R&D and new 

medicine introductions in the U.S. 

The odds, financial commitment, and significant time and resources reflect the 

uncertainties inherent in our business. The scientific uncertainties are ultimately 

reduced to the core question: 

Does the benefit of the drug outweigh the risk? 

This is a question we and the FDA seek to answer and it will vary depending on 

the treatment and the intended patient population. Regulatory uncertainties can 

complicate this dynamic if the review process at the FDA is ambiguous and 

inefficient. This is why a strong partnership and communication with the FDA are 

essential. 

R&D at Pfizer 

Before discussing the provisions of PDUFA, it's important to provide additional 

background on the R&D process at Pfizer. My business is focused on 

developing and providing therapies of a specialized nature. This means 

treatments for rare diseases, for many forms of cancer, and vaccines that help 

prevent people from getting infectious diseases like pneumonia or meningitiS. 

As the head of a business, I am intimately engaged in the development of our 

medicines pipeline. The business and R&D share the goal of investing in the right 

therapeutic areas. That means making sure the compounds progressing have a 

reasonable chance of making it through the entire development process and 

gaining efficient and successful review by the FDA. We also look beyond that to 

ensure that payers recognize the value of the product. 

One of our main focuses at Pfizer is to always improve the performance of our 

innovative core - the nexus where strong R&D leads to valuable products. Over 

the past year, there has been a steady cadence of progress in our late stage 

pipeline that includes positive clinical data presentations, submission of 

marketing applications, regulatory approvals, and new product launches, as well 

as the emergence of a promising mix of early to mid-stage assets. 

2 Pfizer Inc 
105 


76491.053

We have a number of products that we're very excited about. 

First is Prevnar 13, a vaccine for the prevention of pneumococcal disease which 

is approved for use in children 6 weeks through 5 years old, and in December of 

last year, received approval for adults 50 years of age and older. This new 

approval is very important given that the most common manifestation of the 

disease in adults is pneumococcal pneumonia, which occurs in about 440,000 

Americans 50 and older every year, accounting for about 300,000 

hospitalizations and significant related personal and societal costs. 

FDA approved Prevnar 13 under the agency's accelerated approval pathway, 

which allows for earlier approval of certain drug products to treat serious or lifethreatening disease which may not be adequately addressed by existing drug 

products. The approval of the vaccine was based on its effectiveness in relation 

to a surrogate endpoint that is likely to predict clinical benefit and was granted on 

the condition that a confirmatory clinical trial be conducted to verify the 

anticipated clinical benefit. While that confirmatory study is currently underway, 

today Americans 50 and older have access to an important new option for the 

prevention of a potentially life-threatening disease. 

Second is Xalkori, a New Molecular Entity (NME), which is the first lung cancer 

drug approved by the FDA in more than six years. This scientific innovation is 

also one of the first personalized medicines, targeting a genetic abnormality 

shared by 3% to 5% of the 200,000 lung-cancer patients diagnosed in the U.S. 

each year. 

Xalkori, which was approved last August, was a fast track product and was given 

priority review by the FDA. The goal for priority review is 6 months - FDA 

approved it in 4 months. Xalkori and other NME's are the highest priorities for 

Pfizer and FDA because as new treatments they target unmet medical needs. 

And while Xalkori's approval is an example of getting it right, the challenge we 

have is making sure that situations like Xalkori are the rule, not the exception. 

Third, we recently received European approval for Vyndaqel (Tafamidis) to 

treat TTR-FAP, a rare and irreversible, progressive neurodegenerative disease 

that affects approximately 8,000 patients worldwide. Patients experience 

debilitating symptoms that usually prove fatal within 10 years, and until now 

there has been no treatment option other than liver transplant. This product 

has been submitted to the FDA with a decision expected later this year. 

We are also pleased with the results we have seen with tofacitinib in the phase 3 

rheumatoid arthritis program and have submitted applications for approval to 

regulators in both the U.S. and Europe. This represents just some of the nearterm opportunities in our growing product pipeline. And while I'm encouraged, I 

know we have much more work to do. 

3 Pfizer Inc 
106 


76491.054

In 2011, we made a strategic decision to narrow our therapeutic areas of focus, 

took steps to identify failures earlier in the development cycle, advanced the most 

promising compounds within our pipeline, and continued to invest in our R&D 

network and the capabilities needed to drive biomedical innovation. 

We are allocating the majority of our R&D efforts to the areas that represent the 

intersection between unmet medical needs, our strength in biology and 

chemistry, and the willingness and ability of patients and payors to value our 

innovation. We are focusing on the areas where we believe we have the right 

elements for success -- Neuroscience, Cardiovascular, Oncology, Inflammation 

and Immunology, Vaccines, Pain and Sensory Disorders and Biosimilars. 

In addition, in 2011, we established an enhanced focus on rare diseases; an area 

in which Pfizer has a strong legacy with more than 17 approved orphan 

indications. Rare diseases are among the most serious of all illnesses and 

impact greater than 50 million patients in the U.S. and the EU, yet fewer than 5% 

of the estimated 7,000 rare diseases have approved treatments. We believe that 

patients suffering from a rare disease deserve equal access to an approved 

treatment so we are actively expanding development in this space for conditions 

like sickle cell anemia, hemophilia, cystic fibrosis and muscular dystrophy. 

We are prioritizing the R&D portfolio. We are focusing our internal capabilities in 

the areas where we offer unique value such as clinical trial design and 

overseeing the end-to-end strategy for our clinical assets. We have turned to 

external partners to manage the areas that don't drive competitive value for us 

such as clinical trial implementation. This makes it easier to scale activity up or 

down based on the needs of the portfolio. 

We have made tough but necessary capital allocation decisions regarding our 

global R&D site network. We are laying the foundation for a new MIT-sponsored 

research site in Cambridge, MA, that will focus on cardiovascular, metabolic and 

neuroscience research. By locating in science and technology hubs we have 

better access to a highly skilled talent base that will enrich our capabilities in the 

biologic sciences and increase our opportunities for external partnerships. 

We have invested in new technologies within our focus areas. 

For example, in Oncology we are investing in Antibody-Drug Conjugates (ADC) 

which combine the best features of two proven cancer therapies - antibodies and 

cytotoxic drugs. 

Through our Centers for Therapeutic Innovation we are partnering with 19 

leading academic medical institutions located in Boston, New York, San 

Francisco and San Diego to tap into the research expertise of academics in 

diseases, targets and patient populations to help bridge the gap between early 

scientific discovery and the translation into new medicines. 

4 Pfizer Inc 
107 


76491.055

We are adopting a Precision Medicine approach to research, integrating clinical 

and molecular information to understand the biological basis of disease. This 

leads to better selection of disease targets and the identification of patient 

populations that demonstrate better clinical outcomes. 

We expect that in 5 years most of our Phase 3 clinical trial starts will·reflect a 

Precision Medicine R&D approach. 

Supporting all our actions is a more rigorous governance model across all of 

R&D and the Business Units that has clear metrics and a process for establishing 

that a compound will meet a clear medical need, be valued by payers and 

patients and have a strong rationale that the product would be approved by 

regulators prior to starting a proof of concept study. We revalidate the value 

needs and regulatory rationale at every step of the development path with 

increased rigor prior to starting our final pivotal Phase 3 trials needed for 

regulatory submissions and for an approval decision point. 

I believe that through all the actions we are taking there is a greater sense of 

urgency, accountability and results focused across R&D. 

All of the work that I described above means nothing without an efficient, well 

funded FDA that is able to keep pace with the evolving science needed to review 

drug applications efficiently and effectively. 

Why PDUFA Matters to Pfizer 

So why does PDUFA matter to Pfizer? 

As I mentioned, to develop a single new medicine for patients, Pfizer will invest 

more than $1 billion and more than ten years identifying new molecules, 

establishing tolerability, and confirming safety and effectiveness in large numbers 

of patients. PDUFA is part of the gateway between such R&D and the many 

patients needing these medicines. The performance metrics and process 

requirements within PDUFA help ensure that the FDA is efficient, transparent 

and predictable. 

Each of the PDUFA three main focus areas helps enable Pfizer and FDA to 

improve transparency in the drug approval process. Here is how. 

5 Pfizer Inc 
108 


76491.056

1. Enhancements to the Drug Review Process 

New Molecular Entity (NME) Review Program: PDUFA V will increase 

predictability, transparency, and scientific communication during FDA's review of 

NME's (drugs containing no active molecules previously approved by the FDA in 

any other application) for new applications. 

Under PDUFA V, the NME review program will help identify and resolve issues 

earlier in the review process and thereby shorten the time to a review decision -

potentially providing patients with earlier access to needed treatment. 

Communication during drug development: Interaction between the FDA and 

drug sponsors during drug development is critical, and this program will help 

sponsors and the FDA engage more efficiently and productively. 

At times, such interactions require a formal meeting; at other times, a response 

can be provided without a formal meeting. However, obtaining FDA responses to 

questions outside the formal meeting process has been challenging due to FDA 

staff workload and competing demands. 

The PDUFA V performance goals propose funding an agency communication 

and training staff that will focus on improving communication between the FDA 

and drug sponsors during development. 

BenefiUrisk assessment: When safety issues arise, the confidence of patients 

and the public may be shaken. BenefiURisk assessment measures a drug's 

benefits and risks and then assesses whether the balance of these factors is 

favorable. This analysis is critical to ensure patient confidence in their medicine. 

PDUFA V would facilitate continued development and implementation of a 

structured benefit-risk framework in the drug evaluation process to increase 

transparency and objectivity. 

E-submission and data standards: Pfizer alone sends about 10,000 

submissions a year to the FDA and has been a leader as the industry moves 

toward digitization, which allows FDA reviewers to have an entire product 

submission in electronic form. This new proposal will require that all applications 

be submitted to the FDA in standardized electronic format - bringing still greater 

efficiency and predictability to the review process. Additionally, the FDA would 

begin a public process to standardize clinical data terminology for certain 

therapeutic indications. 

6 Pfizer Inc 
109 


76491.057

2. Modernizing Regulatory Science 

Advances in regulatory science will help make the evaluation and approval 

process more efficient, helping deliver safe and effective new products to 

patients faster and strengthening the ability to monitor product use and 

improve performance, thus enhancing patient outcomes. 

PDUFA V's enhancements will affect Pfizer in each of the regulatory science 

provisions: 

Meta-analysis: Meta-analysis is the technique of pooling data from different 

clinical trials on a particular drug. FDA needs the ability to review and respond 

to meta-analyses, conducted by third parties to determine if they were in fact 

conducted appropriately. There a number of these analyses conducted on 

Pfizer products and it is crucial that we and the FDA have an accurate way to 

interpret the results of them to better inform patients. 

PDUFA V addresses this issue by requiring FDA to develop a scientific 

method to determine how to best use the information from a meta-an.alysis. 

Doing so will help give the FDA the tools it needs to provide appropriate 

guidance on the results of meta-analysis. 

Biomarkers & pharmacogenomics: A biomarker is anything that can be 

measured as an indicator of biological activity, such as a blood pressure count 

or DNA sequence. Pharmacogenomics is the study of how genes affect a 

person's response to drugs. Biomarkers and Pharmacogenomics can be 

predictors of many things, such as the natural course of a tumor, and enable 

doctors to decide which patients are likely to respond to a given drug and at 

what dose. 

PDUFA V will enhance FDA's ability to address the increasing workload of 

applications that involve biomarkers and thereby allow innovative new 

treatments to get to patients sooner. 

Patient-reported outcome tools: Many quality-of-life problems go unnoticed 

as patients don't always tell their doctors how they are feeling. The only real 

way to get the patient's perspective is to ask the patient directly. However, 

FDA staff is already overloaded and timely patient-reported outcome reviews 

are difficult to ensure - sometimes taking months. 

PDUFA V would increase FDA's review capacity, ensuring that agency 

reviewers have access to every tool needed to support claims within a specific 

drug context. 

7 Pfizer Inc 
110 


76491.058

Rare disease drug development: Pfizer has a strong legacy in rare diseases, 

with more than 17 approved orphan indications, and is actively expanding its 

activity in the space. 

PDUFA V will continue to ensure that regulatory evaluations of orphan drugs 

are conducted flexibly to take account of the specific issues facing that 

particular rare disease. The small number of patients suffering from a given 

rare disease often makes it difficult to enroll a sufficient number of patients in a 

clinical trial. The rarity of the condition results in smaller set of data on efficacy 

and safety compared to more common diseases, and often the evidence will 

include case histories, registry data and studies from distant countries. 

But the standards for safety and efficacy should not be lower, so regulatory 

agencies need to have evidence and flexible approaches to assessment that 

take into account the rarity of the condition, the degree of fundamental 

understanding of the natural history of the disease, the limitations in 

identification and diagnosis of patients, and the urgency of patient need. 

PDUFA V will enhance development of new drugs for rare diseases though 

FDA policy development and training of review staff on scientific issues unique 

to rare diseases, and will support outreach to industry, patients, and the 

scientific investigator communities. 

3. Strengthening Post-Market Safety Surveillance 

As part of its mission to protect and promote the public health, the FDA has 

always kept a keen focus on the safety of drugs and other medical pcoducts. 

Once a drug is approved and reaches the marketplace, FDA and drug sponsors 

maintain a system of post-marketing surveillance and risk assessment programs 

to identify adverse events that may not have been detected during the drug 

approval process. 

Under PDUFA V, two safety enhancements are being proposed, both of which 

would affect Pfizer. 

The Sentinel Initiative: FDA's Sentinel Initiative would access national 

electronic data systems to actively monitor medical product safety in real time - a 

development Pfizer supports as a powerful public health resource that may 

greatly improve drug safety reporting. FDA's phased approach to Sentinel 

implementation, emphasizing success over speed, is appropriate. 

8 Pfizer Inc 
111 


76491.059

As Sentinel advances, FDA must ensure it has the financial resources and the IT 

infrastructure to build a distributed system on such a large scale. Also, Sentinel 

governance and operating frameworks must ensure timely and effective 

company access to product safety data and to signal detection and analysis 

methods - both of which will be critical to maintaining company involvement over 

product safety and risk management. It is extremely important that Sentinel not 

be used as a method for comparative effectiveness. 

Standardizing risk evaluation and mitigation strategies (REMS): FDA has 

the authority to require REMS from manufacturers to ensure that the benefits of a 

drug or biological product outweigh its risks over the longer-term. However, 

industry has expressed concerns regarding the ability of REMS programs to 

mitigate risk and the burden REMS places on providers, patients, pharmacists, 

and the healthcare delivery system. 

It is vital that FDA consider REMS' impact on their ability to meet PDUFA review 

performance metrics and expedite patients' access to safe and effective new 

medicines. Pfizer supports PDUFA V's goal of improving REMS approval times 

by providing better clarity during development meetings and holding public 

meetings on how to reduce the burden of implementing REMS. 

The PDFUA V agreement includes an additional 129 full time equivalents (FTE) 

to support additional activities at FDA. The additional FTE is dedicated to 

support the provisions on modernizing regulatory science. We believe the 

current level of FTE dedicated to the review of applications and to perform post 

marketing safety activities can be accomplished with existing resources. 

User fees to fund drug review activities at FDA are approaching 70% of the total 

budget. While Pfizer understands the current economic situation, this level of 

support nonetheless concerns us. It is important Congress and the 

Administration devote additional government resources to supplement the fees 

paid by our industry. 

Reauthorization of the Best Pharmaceuticals for Children Act (BPCA) and 

the Pediatric Research and Equity Act (PREA) 

Pfizer strongly supports the reauthorization of BPCA and PREA. They work 

together by providing biopharmaceutical companies like Pfizer an incentive, six 

months of additional exclusivity, to study our products in the pediatric populations 

and ensuring that drugs are appropriately studied and labeled for pediatric 

populations. While BPCA and PREA are working, Pfizer supports making them 

both permanent in order to provide us with the certainty that is important in the 

R&D and regulatory process. 

9 Pfizer Inc 
112 


76491.060

Supply Chain Safety 

Pfizer has comprehensive systems and processes in place to manage our global 

supply chain, starting with the raw materials we use to manufacture our products 

and ending when consumers receive our products. Our processes help us to 

prevent, detect, and respond to threats so that we protect the quality and safety 

of our products and ensure that our patients are receiving the life-saving and 

sustaining drugs they expect. 

Pfizer recognizes that the Committee may be considering supply chain security 

provisions for inclusion in the PDUFA legislation. A number of proposals 

addressing upstream and downstream drug supply safety as well as a national 

track and trace system are being discussed. As we have put in place strong 

measures to ensure the integrity of our materials and the quality of our suppliers 

and distributors, we look forward to working with members of Congress who have 

put forward proposals to address these issues. 

Conclusion 

PDUFA represents the best kind of collaborative leadership: where government 

and business come together with rigor and excellence to ensure that patients 

have timely access to the critical medicines they and their families deserve. The 

ability of Pfizer to do its job depends on the ability of FDA to do its job, and 

PDUFA provides a framework and resources for that to happen. PDUFA is must 

pass legislation. It is must pass for Pfizer and the biopharmaceutical industry. 

Must pass for FDA. And most importantly it is must pass for patients and society 

as a whole. 

Again, thank you for the opportunity to testify. I look forward to answering any 

questions you may have and hearing your views. 

10 Pfizer Inc 
113 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman, Dr. Gollaher, for 5 minutes for an opening statement. 

STATEMENT OF DAVID L. GOLLAHER 

Mr. GOLLAHER. Thank you, Chairman Pitts and Ranking Member Pallone. My name is David Gollaher, and I am President and 

CEO of the California Healthcare Institute. California has by far 

the largest cluster of innovative research institutions and biotechnology companies in the world. Today there are about 270,000 

jobs directly connected to biomedical R&D in California. 

My purpose today is first to support the reauthorization of 

PDUFA, then to explain why PDUFA is critical to drug innovation, 

and then briefly to review work that CHI, our institute, has been 

conducting with the Boston Consulting Group, BCG, together and 

analyzed data that accurately reflect FDA performance. 

I know there has been a lot of criticism of the FDA, but all of 

us agree that a strong, efficient FDA is important to our industry 

and to patients, an agency that performs well, encourages medical 

innovation and a regulatory system that has clear rules, that operates transparently, builds confidence among investors, and confidence is key because patients need to be confident that their 

drugs meet the highest standards of safety and effectiveness while 

industry needs to be confident that the FDA is abreast of the latest 

science and is applying it reasonably to innovative products. 

The first point I would like to make is about the relationship of 

advanced science to regulation. We live in an unprecedented age of 

biological sciences. After the human genome project was completed 

in 2003, our ability to understand diseases at the level of genes and 

cells is racing ahead. Still, though, if we compare the past several 

years to the period during the 1980s and 1990s when there was so 

many pioneering biotech drugs along with breakthrough drugs for 

HIV/AIDS, we can see that today drug development has lagged. It 

hasn’t kept up with science. 

The reasons for this are complicated. For one thing, our bodies 

are the most complex organisms in nature, and developing drugs 

that have powerful effects on disease without harming healthy cells 

and tissue turns out to be extremely difficult. So difficult, in fact, 

that developing a new medicine now costs well over a billion dollars. 

In trying to become more efficient and reduce development costs, 

the drug industry is searching for the optimum model for R&D but 

the most productive model and scale for biotech research remains 

a quest in progress. 

The problem is that we continue to see high failure rates for 

drugs that enter the regulatory pipeline. Only 5 to 8 percent of new 

molecular entities that start out as drug candidates make it all the 

way to the market. Commissioner Hamburg has pointed out that 

we are investing between industry and academia about $100 billion 

in research today and not getting our fair share of new medicines. 

But this isn’t true across the board. In 2011, the FDA issued a report citing 35 innovative treatments for hepatitis C, prostate cancer, lupus, pneumonia and other serious disorders. This report 

showed how the FDA used expedited approval authority, flexible 

clinical study requirements, and resources collected under PDUFA 

114 

to improve the rate of approvals. Oncology, for instance, emerged 

as a particularly bright spot, and our recent work with BCG found 

that cancer drugs experience rapid review on the order of 10 to 15 

months. But there were other areas—cardiovascular, central nervous system, gastrointestinal—that stretched almost twice as long. 

The point is, there are major differences in timelines depending 

on a drug’s therapeutic area, and in our view, this suggests an opportunity, namely, for the FDA to learn from its own best practices 

and then replicate those practices across the agency. To accomplish 

this, though, will require more data than we have had in the past 

but timely, accurate data would prove equally valuable for internal 

FDA benchmarking and for industry management. 

It is hard to overstate the importance of good data. A time-honored principle of management is that what gets measured gets 

done. Our work with BCG over the past 2 years, mining the agency 

phone data in order to gain a better understanding of how it operates, suggests a few things to us. First, that we meet regularly together and analyze the best possible data and that there is an opportunity to provide longitudinal data over the next PDUFA cycle 

so that 5 years from now FDA, industry and Congress can share 

the understanding of real trends over time. It is ironic that for an 

agency that regulates more than 20 percent of U.S. GDP and relies 

increasingly on industry user fees that there has been so little in 

the way of consistent tracking. 

In addition, better data may help the agency, Congress and industry to develop a better understanding of benefits versus risks. 

Virtually all medicines carry some capacity for harm, and a zerorisk mentality would shut down development of beneficial drugs altogether. But more attention needs to be devoted to how the FDA’s 

policies and operations encourage or discourage investment in different therapeutic areas. In other words, how should we measure 

risk if the agency’s demands for data become so intense that investors avoid that therapeutic area altogether. This is happening 

today in areas like diabetes and obesity. 

I would like to conclude by observing that PDUFA has been a remarkable success. For this legislation to move science forward, it 

needs to remain highly focused on enabling the agency to promote 

innovation, on encouraging it to address areas of inefficiency, on 

balancing its mission to protect public health with the importance 

of attracting robust private sector investment into new drugs and 

biologics. Ultimately, public health and economic competitiveness 

are two sides of the same coin. Without investment, the next generation of breakthroughs will never materialize nor will the jobs to 

manufacture them. Commissioner Hamburg wrote an op-ed last 

year calling FDA America’s innovation agency. I think this is more 

an aspiration than a historical fact, but it is an aspiration that we 

all share, and PDUFA V is an important step toward accomplishing 

it. 

Thank you, and I would be happy to answer any questions. 

[The prepared statement of Mr. Gollaher follows:] 

115 


76491.061

TESTIMONY OF OAVIO L. GOlLAHER, PH.D. 

C" H • CALIFORNIA HEALTH CARE 

INSTITUTE 

PRESIOENT AND CEO, CALIFORNIA HEAlTHCARE INSTITUTE 

HOUSE COMMITIEE ON ENERGY AND COMMERCE, SUBCOMMITIEE ON HEALTH 

HEARING ON "REAUTHORIZATION OF PDUFA: WHAT IT MEANS FOR JOBS, 

INNOVATION, AND PATIENTS" 

FEBRUARY 1, 2012 

Chairmen Upton and Pitts, and Ranking Members Waxman and Pallone, my name is 

David Gollaher and I am the President and CEO of the California Healthcare Institute 

- CHI. I am honored to testify today on behalf of our organization, which represents 

some 300 biopharmaceutlca! and medical technology companies, along with 

California's leading academic medical centers and private research institutions. 

FDA's Prescription Drug User Fee Act (PDUFA) program has special importance to 

California because the biomedical industry is among our state's leading high-tech 

employers, directly accounting for about 270,000 jobs whose salaries average 

$76,000 a year. The purpose of my testimony today is to support the 

reauthorization of PDUFA, to underscore its critical role in drug innovation, and 

briefly to review a project CHI has been pursuing with the Boston Consulting Group 

(BCG) to gather and analyze data that accurately reflect FDA performance. 

While the FDA has frequently been the target of criticism, I want to emphasize that 

CHI and our industry are committed to strengthening the partners hlp with the 

Agency. A strong, efficient FDA is equally important to industry and to the patients 

we serve. We believe that positive policy and operational improvements at the FOAl 

along with constructive legislation, will encourage biopharmaceutical innovation. A 

predictable and transparent regulatory process is an essential component of our 

biomedical innovation ecosystem. Since its inception, PDUFA has been a notable 

success. By working together, Congress, the Agency, industry and other 
116 


76491.062

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb. 1 2012 

Page 2 

stakeholders can maintain the high standards of safety and effectiveness that 

physicians, patients and their families expect while also enhancing the biomedical 

sector's ability to attract the capital essential to secure U.S. global leadership in life 

sciences. 

1. EFFICIENT REGULATION IS ESSENTIAL TO REALIZING THE PROMISE OF ADVANCED SCIENCE 

In an era of increasing global competition, the United States remains the world 

leader in basic biological sciences and in translating laboratory breakthroughs into 

new medicines for patients. Since the mid-twentieth century, America's competitive 

advantage in biomedical innovation has been driven by federal investment in basic 

research, principally through the National Institutes of Health (NIH). In the 1970s, 

NIH funding fueled the discovery of recombinant DNA at the University of California 

- San Francisco. This made possible genetic engineering and led to the creation of a 

whole new industry called biotechnology. More recently, in 2003, scientists at the 

NIH and in the private sector completed the sequencing of the human genome. The 

Human Genome Project took fourteen years and cost more than one billion dollars. 

Yet the pace of scientific advance is so rapid that today you can have your personal 

genome sequenced for about a thousand dollars -- a million-fold drop in price in just 

nine years. Low-cost human genomics has two implications. First, it enables 

scientists to correlate genes with diseases, and we are discovering that a great 

many disorders have a genetic basis. Second, it opens the way to personalized 

medicine, allowing physicians to determine in advance how various medicines may 

affect an individual. There is already a genetic test for women with breast cancer, 

for example, that accurately predicts whether or not a patient will respond to a 

targeted monoclonal antibody therapy. Only patients who test positive for a specific 

genetic mutation are treated with the drug. 

Our expanding ability to understand diseases at the levels of genes and cells means 

that there has never been a time in history when the science of human health has 
117 


76491.063

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb. 1,2012 

Page 3 

been so promising. Still, after a period during the 1980s and 1990s that saw the 

introduction of many breakthrough biotechnology drugs, along with remarkable 

medicines for HIV!AIDS and other infectious diseases, drug development has not 

kept pace with science. The reasons for this are understandable. The human body is 

the most complicated organism in nature, and developing drugs that have powerful 

effects on disease without undue side effects turns out to be extremely difficult. At 

the same time, faced with drug development costs that average well in excess of a 

billion dollars, industry is searching for the optimum model for R&D. The most 

productive organizational model and scale for drug research remains a quest in 

progress. 

Beginning in the early 1980s, much of the work of translating basic scientific 

inventions into commercial products for patients was the province of biotechnology 

startups. Here the classic pattern involved a basic research discovery, say, in a 

university laboratory which the university patented and then licensed the invention 

to a company funded by venture capital. Hundreds of companies began this way, 

creating tens of thousands of jobs. But this model began to run into trouble after 

the dotcom bubble burst in 2000. The global financial crisis beginning in 2008 has 

further pressured venture capital, sharply reducing the reservoir of funds available 

for new firms. In addition, volatility in the financial markets stemming from the 

global contraction and European debt crisis has heightened investors' sensitivity to 

risk. 

Risk is the necessary framework for understanding how the FDA influences drug 

development. Whether from the viewpoint of venture capitalists or drug company 

executives, regulation has always weighed as a key risk factor in decisions about 

capital allocation. In the drug discovery pipeline, Phase I trials are first used to 

evaluate if a new drug is safe, then Phase II trials are done to assess the drug's 

efficacy, and finally Phase III trials are performed in a larger population to confirm 
118 


76491.064

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb. 1,2012 

Page 4 

the safety and efficacy of the drug. Each consecutive phase includes more people to 

refine the results obtained in the previous phase. Since the 1990s, the trend has 

shifted toward a higher and higher failure rate. The odds of drug candidates -- a new 

molecular entity (NME) making it all the way through three phases of clinical trials 

is between five and eight percent. 

Since most new drug candidates fail, in a capital-constrained environment, 

regulatory risk increases exponentially. As Joseph DiMasi at the Tufts Center for the 

Study of Drug Development observed, "Longer development times increase R&D 

costs and shorten the period during which drug companies can earn the returns they 

need to make investments financially viable .... longer development times reduce 

innovation incentives." Significantly, a study by CHI and BCG, Competitiveness and 

Regulation: The FDA and the Future of America's Biomedical Industrv (February 

2011), found that from the time PDUFA was first authorized in 1992 until 2007 there 

were clear improvements in FDA drug review performance. But comparing 

submissions for NMEs from 2003-2007 with 2008, there was a 28 percent increase 

in the number of months to approval (from an average of 14.7 months to 18.9 

months). One result of longer review times at the FDA was a new drug lag, with a 

number of new drugs approved in Europe ahead of the U.S. from 2007-2010. 

A slowdown at the FDA was frustrating to industry because it widened that gap 

between fresh knowledge emerging from the engine of biosciences research (much 

of it funded by government), on the one hand, and the application of this knowledge 

to human health, on the other. Meanwhile, the relationship between industry and 

the Agency was strained by unpredictability, by unexplained regulatory delays, by a 

lack of clear standards for what clinical data would ultimately be sufficient for 

product approval, and by a bureaucracy whose communications were inconsistent. It 

is worth noting that many, if not most, of industry's criticisms focused less on 
119 


76491.065

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb, 1,2012 

Page 5 

matters governed by the Agency's statutory authority than on those that were the 

prerogatives of Agency management. 

2. FDA PERFORMANCE DISPARITIES AMONG THERAPEUTIC AREAS 

In 2011, there is evidence that the FDA began to address drug approval timelines. 

In November 2011, for example, the Agency issued a report, Innovative Drug 

Approvals, citing 35 innovative drugs that represented advances in treatment for 

hepatitis C, late-stage prostate cancer, lupus, drug resistant skin infections, 

pneumonia, and other serious disorders. This report detailed how the FDA used 

expedited approval authorities, flexible clinical trial requirements and resources 

collected under PDUFA to improve the rate of approvals. Earlier, a study from the 

Friends of Cancer Research noted that for oncology over the past decade, most 

innovative medicines were approved in the U.S. in advance of the European Union. 

This is an important finding, and evidently, among therapeutic areas within the FDA, 

oncology is a bright spot. But recent analysis of FDA data by BCG suggests a more 

nuanced picture. The FDA is not a monolith; there are significant deviations in 

average review times, depending on a product's therapeutic area. Oncology and 

anti-infective drugs, for example, experience the fastest reviews, on the order of 10-

15 months. For other categories cardiovascular, central nervous system, gastrointestinal, respiratory, etc. - average review times stretch from 20 to 30 months. As 

a consequence, a drug's therapeutic area influences both the time it spends under 

review and the probability of its being approved first in the U.S. or Europe. 

It is unclear what explains differences in performance from one therapeutic area to 

another. Some fields may be inherently more complicated, with fewer biomarkers or 

with poorly understood mechanisms of action for novel drugs. Alternatively, certain 

therapeutic areas may be understaffed or may reflect differences in managerial 

priorities or effectiveness. Oncology, for example, remains a field in which there are 
120 


76491.066

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb. 1, 2012 

Page 6 

comparatively few effective drugs, while prevalence of cancer and public concern 

runs high. The same may be said of infectious diseases. Unsurprisingly, the Agency 

performs comparatively well in both areas. 

In some ways, variations in FDA performance in different therapeutic areas suggest 

an opportunity. That is, the Agency is in a position to learn from its own best 

practices, and to replicate them across different areas. To accomplish this will 

require more data than we have had in the past; data that would prove equally 

useful for internal FDA benchmarking and for industry management. 

Ideally, recognizing that the FDA must set priorities and that not all disorders pose 

equal threats, one would hope for basic alignment between regulation and public 

health. Yet, to some degree, things have gotten out of balance. Diabetes, obesity, 

and cardiovascular disease exert enormous, and growing, damage on health. 

Unfortunately, though, regulatory pathways in these areas are fraught with 

uncertainty. And the result is that fewer large pharmaceutical manufa'cturers are 

developing products for these indications, while venture funding for startups has all 

but disappeared. Within industry and the venture community alike, the common 

wisdom is that the Agency has, in these areas, tightened its benefit-risk calculation, 

demanding more data over longer periods, thus increasing the cost of clinical trials 

to the breaking point. 

There is broad agreement between industry and the FDA about the importance of 

building a better shared understanding of benefits and risks. Virtually all medicines 

bear some capacity for harm. A zero-risk approach would shut down the 

development of beneficial drugs. In this regard, however, the Agency focuses almost 

exclusively on the direct risks of drugs: side effects, adverse events and so forth. 

These are comparatively discrete and measurable. But indirect risks are both 

difficult to observe and subject to a much longer time horizon. Where are data that 
121 


76491.067

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb. 1 2012 

Page 7 

allow one to calculate the harm to public health if investors avoid an important 

disease because the FDA's demands for data are so extensive and its standards for 

drug approval so uncertain? 

We are encouraged that the Agency has begun to address this challenge. Its report, 

Driving Biomedical Innovation: Initiatives to Improve Products for Patients (October, 

2011), acknowledged that despite more than $95 billion invested into biomedical 

R&D between the NIH and industry, "these investments have not translated into a 

parallel increase in novel products" (p. 3). As Commissioner Margaret Hamburg's 

Innovation Initiative starts to unriddle the reasons for this, we hope that a top 

priority will be a more transparent elaboration of how the Agency manages its 

benefit-risk calculations, including an appreciation of indirect risk. Indeed we also 

acknowledge and laud PDUFA V provisions to enhance benefit-risk assessment as 

well as a concentration on patient-focused drug development. 

3. THE IMPORTANCE OF RELIABLE DATA 

A time-honored prinCiple of management is that what gets measured gets done. We 

have learned a great deal in working over the past two years with BCG and the FDA, 

mining the Agency's data in order to gain a better understanding of how it operates, 

and how its performance metrics have changed over time. So we believe that there 

is great value in (a) regularly gathering and analyzing the best possible data; (b) 

updating performance metrics during the next PDUFA cycle in order to track 

performance consistently and longitudinally; and (c) ensuring that there is 

agreement among the FDA, industry, and congress that the data and how they are 

reported are the most accurate possible measures of agency performance. It seems 

ironic that for an agency that regulates more than 20 percent of American 

production, and depends increaSingly on industry user fees, there has been so little 

in the way of consistent tracking mechanisms. In this vein, we believe all would 
122 


76491.068

California Healthcare Institute (CHI) 

PDUFA Reauthorization 

Feb. 1.2012 

Page 8 

benefit from more granular information from the division review level in order to 

understand where things are working and where they need improvement. 

4. CONCLUSION 

PDUFA V represents the next step in a successful, ongoing partnership between the 

FDA and industry. It is important for the legislation to remain highly focused: to 

support the Agency in its efforts to promote biomedical innovation; to encourage it 

to address areas of inefficiency; to balance its imperative to protect public safety 

with the importance of continuing robust private-sector investment into new drugs 

and biologics. In the long view, public health and the economic health and 

competitiveness of the biomedical industry are two sides of the same coin. Without 

immense investment, the next generation of breakthroughs for our greatest 

healthcare needs will never materialize. Nor will the jobs to produce them. 

Commissioner Hamburg has called the FDA "America's Innovation Agency" (Wall 

Street Journal, August 1, 2011), which might be considered more an aspiration than 

historical fact. But it is an aspiration we share, and believe that PDUFA V will be an 

important step in accomplishing it. 

Thank you again for the opportunity to testify. And I would now be pleased to 

answer any questions you may have. 
123 

Mr. PITTS. The chair thanks the gentleman and recognizes Mr. 

Pops for 5 minutes for an opening statement. 

STATEMENT OF RICHARD F. POPS 

Mr. POPS. Thank you, Chairman Pitts and Ranking Member 

Pallone. I appreciate the opportunity to be here today. I am Richard Pops, Chairman and CEO of Alkermes, and I am here testifying on behalf of the Biotechnology Industry Organization, or BIO. 

I coordinated BIO’s engagement on the PDUFA V discussions with 

FDA, and I have got more than 20 years of experience in managing 

biotechnology companies and successfully developing new therapies 

for patients. So I know firsthand the impact that PDUFA has had 

on patients and on medical innovation. 

BIO, in summary, supports a swift enactment of PDUFA V recommendations that improve this regulatory process and provide patients and doctors with earlier access to breakthrough therapies 

that we focus our lives on developing. So at Alkermes, our company, we are in a very exciting phase of growth with a diversified 

portfolio of commercial products that have already made it through 

the FDA process, so we have had that experience, but also new 

medications in development where we are in the midst of the regulatory process addressing central nervous system disorders such as 

addiction, schizophrenia and depression. 

We began as a raw startup in labs next to MIT up in Massachusetts, and today we employ over 1,200 individuals in Massachusetts, Georgia, Ohio and worldwide, and we operate large manufacturing facilities in both Ohio and in Georgia as well. 

The key to our success and I think the success of the industry 

in general is a reliable and predictable FDA, and the PDUFA program is an incredibly important part of that. 

The PDUFA V recommendations are based on the principles that 

a science-based transparent and well-managed review process that 

appropriately balances benefit and risk can enhance the public 

trust and increase patient access to new medicines. Industry and 

FDA agreed upon a set of enhancements under PDUFA V designed 

to reinforce FDA’s review performance and get back to basics for 

patients. These proposals have also been informed by an unprecedented level of public input, which has further strengthened the 

technical agreement. These enhancement include a new molecular 

entity, or NME, review program that we hope will lead to further 

review cycles and earlier patient access to needed treatments, enhanced communication during drug development, regulatory 

science modernization and robust safety and postmarket surveillance capacities. 

While BIO, of course, supports the entirety of the technology 

agreement, today I would like to focus primarily on the enhanced 

communication in PDUFA V. This initiative is based on the philosophy that timely interactive communication with biotechnology and 

life science companies during drug Venezuela should be a core 

agency activity. While many biotechnology companies operate on 

the cutting edge of biomedical science and develop new therapies, 

science is a collaborative process. It doesn’t occur in a vacuum. And 

it is critical to promote interactive scientist-to-scientist communications between FDA and sponsors. 

124 

In the course of drug development, we often have simple clarifying questions, the responses of which could have a significant impact on the development program but are not extensive enough to 

warrant formal meetings with FDA. To obtain timely responses to 

such questions, we currently often have to engage in lengthy exchange of multiple formal letters with FDA, which is an inefficient 

and cumbersome use of both FDA’s and sponsors’ time. For small 

biotechnology companies reliant on limited venture capital funding 

sources, these delays can create significant impediments to development programs and therefore innovation. 

So as part of the enhanced communication program, FDA will establish best practices for this type of interactive dialog and train 

staff on communication. Independent reports commissioned by FDA 

have demonstrated that enhanced communication during drug development ultimately results in higher quality applications which 

can improve efficiency for FDA reviewers. This proposal was a top 

BIO priority and we are pleased that it was included in the agreement. 

In addition to the enhanced communication features, the PDUFA 

V agreement makes new resources available to modernize regulatory science in the areas of personalized medicine and rare disease drug research. Modern approaches to drug development and 

evaluation will introduce new efficiencies in the drug development 

process and provide FDA with additional tools to evaluate the benefits and the risks of pharmaceutical products. These proposals will 

also integrate more structured and systematic approaches to addressing benefits and risks and allow FDA to conduct outreach to 

patients and hold workshops to better understand patient perspectives on disease severity and unmet medical need. 

BIO looks forward to working with the committee and the FDA 

to implement PDUFA V, and I want to thank you again for having 

us here today. 

[The prepared statement of Mr. Pops follows:] 

125 


76491.069

BIOTECHNOLOGY 

INDUSTRY ORGANIZATION 

TESTIMONY OF RICHARD F. POPS 

CHAIRMAN AND CHIEF EXECUTIVE OFFICER, ALKERMES. 

HOUSE COMMITTEE ON ENERGY & COMMERCE, SUBCOMMITTEE ON HEALTH 

HEARING ON "REAUTHORIZATION OF PDUFA: WHAT IT MEANS FOR JOBS, 

INNOV A TION, AND PATIENTS" 

FEBRUARY 1,2012 

Chairmen Upton and Pitts, and Ranking Members Waxman and Pallone, it is my privilege to 

provide testimony before this Subcommittee today. My name is Richard Pops and I am 

Chairman and CEO of Alkermes. I am here testifying on behalf of the Biotechnology Industry 

Organization where J serve on BIO's Health Section Governing Board and coordinated BlO's 

strategic engagement in the Prescription Drug Uscr Fee Act (PDUFA V) technical discussions 

with FDA. [3]0 represents over I, I 00 members involved in the research and development of 

innovative healthcare, agricultural, industrial, and environmental technologies. 'As an 

entrepreneur with more than twenty years experience managing biotechnology companies and 

successfully developing novel therapies for patients, I would like to speak to the positive impact 

that the PDUFA program has had on patients and medical innovation, and highlight the 

challenges we seek to address under PDUFA V. 

In short, BIO supports quick enactment of the PDUFA V recommendations as we believe they 

can enhance the drug development and review process through increased transparency and 

scientific dialogue, advance regulatory science, and strengthen post-market surveillance. Most 

impOliantly, from the standpoint of young, innovative companies, our hope is that PDUFA V 

will provide patients and doctors with earlier access to breakthrough therapies. 

Page I of 12 
126 


76491.070

I. BIOMEDICAL INNOVATION REQUIRES A RELIABLE, PREDICTABLE, 

SCIENCE-BASED REGULATORY ENVIRONMENT 

At Alkermes, we have a steadfast commitment to develop innovative medicines based on our 

imaginative science and proven technologies. We are inspired by real patient needs as we 

develop products to help patients and physicians better manage diseases. We arc in an exciting 

phase of growth, with our diversified portfolio of commercial products that address central 

nervous system (CNS) disorders such as addiction, schizophrenia and depressio·n. and an exciting 

late-stage pipeline. We began as a raw start up in rented labs next to MIT, and today Alkermes 

employs 1,200 individuals in Massachusetts, Georgia, Ohio and world-wide. 

The U.S. biotechnology industry is poised to be a m~jor driver in an innovation-driven economy. 

Biotechnology offers real solutions to our most pressing health care needs: curing disease, 

reducing costs, increasing quality, and ensuring that people enjoy not only longer lives, but better 

and more productive lives. A key to Alkennes' success and the future of the U.S. biotechnology 

industry is a reliable, predictable, and science-based regulatory environment, and the PDUFA 

program represents an important element of our nation's overall innovation eco-system. A 

fundamental part of biotechnology companies' ability to innovate and raise private investment is 

having an FDA with the resources and infrastructure required to review and approve innovative 

products effectively, consistently, and in a timely manner based on the best available science. 

Since 1992 Congress, FDA, and the biopharmaceutical industry have supported a carefully 

structured user fee program to help fund FDA's human drug review activities. This program has 

contributed to the approval of more than 1,200 new medicines and, initially, reduced review 

times for the newest, most innovative drugs by more than a year. In the past year alone, 

biophannaceutical companies have successfully brought to market remarkable therapies to treat 

Page 2 of 12 
127 


76491.071

hepatitis C, melanoma, lung cancer, lupus, and rare genetic disorders. Last week, aner a decade 

of development, FDA approved an exciting new diabetes drug, which only needs to be 

administered once a week, developed by us and our partners. These advancements in patient 

care represent the leading edge of the next generation of biotechnology innovations. 

But the pace of biotech innovation-and. more specifically, the pace at which new 

pharmaceutical treatments reach patients who need them-is not keeping LIp with our nation's 

health care needs. Developing innovative treatments and cures is a time- and capital-intensive 

endeavor, and the average time between treatment discovery and aV(lilability to sick and suffering 

patients is between 10 to 15 years. That is much 100 long. Additionally, new scientific and 

regulatory complexities in the FDA's drug review process have stressed our ability to speed safe 

and effective new treatments to patients. Unpredictability and inconsistency in the review 

process, suboptimal communication with sponsors, and decreased FDA performance not only 

hinders patient access to new treatments. but also negatively affects the ability ofbiotechnology 

companies to raise funding to support clinical development and ongoing innovation. This 

undermines economic growth in the biotechnology sector as well as biomedical research into key 

public health priorities. 

II. I'])UFA V; GETTING BACK TO BASICS FOR PATIENTS 

Just as we have witnessed a revolution in genomics and our understanding of the molecular and 

biological basis of disease, we also must pursue new regulatory paradigms and modern 

approaches to how we assess the safety and effectiveness of novel therapies. When we began the 

process of organizing for our discussions of I'DUFA Y, we in the industry started with a simple 

Page 3 of 12 
128 


76491.072

set of principles that could provide the foundation for our discussions with FDA and other 

stakeholders. These were that a science-based, transparent, and well-managed review process 

that appropriately balances bene/its and risks can enhance public trust and increase patient 

access to new medicines. 

With these principles in mind, industry and FDA agreed upon a set of enhancements under 

PDUFA V that seek to reinforce FDA's review performance and get back-to-basics for patients. 

These proposals also have been informed by an unprecedented level of public input through 

workshops, meetings, and stakeholder outreach, which fUliher strengthened the technical 

agreement. These enhancements include: 

New Molecular Entity (NME) Review Program: Historically, nearly 80% of all NME 

applications submitted to FDA are ultimately approved, but fewer than half are approved 

on the first submission.' Sponsors and FDA can and must do better for patients. By 

strengthening scientific dialogue and transparency between FDA and Sponsors under the 

proposed review program for novel drugs and biologics, we can minimize the potential 

review issues that can delay patient access to needed treatments. Increased FDA-Sponsor 

scientific dialogue and transparency, such as a mid-cycle communication, exchange of 

discipline review letters and advisory committee information, and a significant new latecycle meeting, will help to identify and resolve issues earlier in the review. This 

represents a significant paradigm shift in FDA's review process while n1aintaining FDA's 

high standards for safety and efficacy. An additional two-month validation period during 

the review period will help to ensure FDA has all the information it needs at the 

Page 4 of 12 
129 


76491.073

beginning of the process to perform a complete review. Finally, a robust third-party 

evaluation will provide data on whether we have been successful in this program of 

leading to fewer review cycles, shorter approval times. and earlier patient access to 

needed treatment. 

Enhanced Communication during Drug Development: To help advance American 

innovation and promote the development of the next generation of modern medicines, 

FDA has also committed to a philosophy under PDUFA V that timely. interactive 

communication with biotechnology and life science companies during drug development 

is a core Agency activity. 

FDA's recent report on driving biomedical innovation highlights that "the private sector 

is the engine of innovation, and much of this innovation begins with sm<lll business."" 

Indeed, many small biotechnology companies operate on (he cutting edge of biomedical 

science to develop new therapies for devastating discases. Yet we must acknowledge that 

the scientific method does not operate in a vacuum. and it is critical to promote 

interactive, scientist-to-scientist communication between FDA and Sponsors. In the 

course of drug development, Sponsors sometimes have simple or clarifying questions, the 

responses to which could have a significant impact on the development program, but 

which are no( extensive enough to warrant formal meetings. To obtain timely responses 

to such questions. Sponsors currently often have to engage in a lengthy exchange of 

multiple formal letters with FDA. which is an inefficient and cumbersome use of both 

FDA's and the Sponsor's time. For small biotechnology companies reliant on limited 

PageS of 12 
130 


76491.074

venture capital, these delays can create significant impediments to development 

programs. 

Additionally, independent reports commissioned by FDA have also demonstrated that 

enhanced communication during drug development ultimately results in higher quality 

applications, which can improve efficiency for FDA reviewers.'" 

BlO fully supports the PDUF A V proposal to promote innovation through enhanced 

communication between FDA and Sponsors during drug development, which will 

establish best practices for this type of interactive dialogue, train staff on communication 

practices, and provide the Agency with additional stafT capacity to respond to sponsor 

inquiries in a timely manner. 

• Modernizing Regulatory Science: Additionally, the PDUFA V agreement makes new 

resources available to modernize regulatory science, for example, in the areas of 

personalized medicine and rare disease drug research. Modern approaches to drug 

development and evaluation, such as through the application of new tools for rare disease 

drug development, flexibility with regard to creative study designs and new endpoints. 

greater utilization of biomarkers and patient reported outcome tools will introduce new 

efficiencies in the drug development enterprise and provide FDA with additional tools to 

evaluate the benefits and risks of phannaceutical products. These proposals will also 

integrate more structured and systematic approaches to assessing benefits and risks of 

Page 6 of 12 
131 


76491.075

therapies, and allow FDA to conduct outreach to patients and hold workshops to 

understand better patient perspectives on disease severity and unmet medical need. 

• Robust Drug Safety and Post-Market Surveillance Capacity: PDUFA V continues 

industry's commitment to a lifecycle approach to product evaluation by strengthening 

FDA's post-market surveillance and benefit/risk management capacity. Earlier 

discussion of risk management strategies, standardized approaches to REMS, and further 

validation of the Sentinel Network will promote patient confidence in drug and biologics. 

Under the PDUFA V agreement, industry has reinforced its commitment to a well-funded drug 

and biologics program that supports sound, science-based regulation consistent with FDA's 

public health mission. However, user fees are intended to support limited FDA activities around 

the drug review process and were never intended to supplant a sound base of appropriations. 

User fees currently account for nearly two-thirds of the cost of human drug review. We urge 

Congress to support FDA's mission and fund the Agency at the Administration's FY 12 

requested levels. 

Additionally, it is critical for PDUFA to be reauthorized well in advance of PDUFA IV's 

expiration in September 2012, to avoid a reduction in force at the FDA. Even the threat of a 

downsizing at the FDA would be devastating to the Agency's public health mission and its 

ability to review new drugs and biologics. 

B[O looks forward to working with Congress and FDA to fully implement these enhancements 

undcr PDUFA V. 

Page 7 of 12 
132 


76491.076

III. PEDIATRIC DRUG DEVELOPMENT 

The Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) 

have been remarkably successful in ensuring that the medications used in children are tested and 

labeled appropriately for their use. BPCA and PREA have generated a wealth of pediatric drug 

information for physicians and parents, contributing to improved health outcomes for pediatric 

patients. Working in tandem, BPCA and PREA have resulted in nearly 425 pediatric labeling 

changes since 1998, according to the FDA. Congress should recognize the success of these 

programs and: 

I. Reauthorize the existing framework and incentive for ongoing pediatric research, and 

2. Make the programs permanent by climinating their sunset provisions. 

The five year sunset periods for BPCA and PREA result in an uncertain regulatory environment 

for pediatric drug development. Since the average pediatric clinical research program spans 6 

years, most clinical programs will span two reauthorization periods in which the ground-rules for 

pediatric research are subject to change. This uncertainty makes it difficult tor companies to 

invest in infrastructure to support development of products for children, and practically 

impossible tor the FDA to issue guidance to promote understanding of the current regulatory 

framework. 

Since their enactment, UPCA and PREA, working together, have been widely acknowledged as 

effective in promoting pediatric drug research. There is no logical reason to continue to allow 

such impOliant legislation to sunset, as the ambiguity associated with this situation has the 

potential for limiting or endangering the pediatric research infrastructure that companies have 

been endeavoring to build and expand. 

Page 8 or 12 
133 


76491.077

IV. REFORM OF ADVISORY COMMITTEE CONFLICT OF INTEREST POLICIES 

As a pre-eminent science-based regulatory agency, it is critical that FDA have access to the most 

knowledgeable and most qualificd scientifIc minds to help inform key public health decisions 

and evaluate the safety and effectiveness of innovative new cures and treatments for patients. 

810 thanks Representative Burgess for his work on this issue and for introducing legislation that 

will enhance FDA's ability to empanel highly-qualified external scientific advisors. while 

maintaining the highest levels of integrity for these proceedings. 

[n recent years, arbitrary limits and unnecessarily restrictive interpretations of conflict of interest 

rules have created barriers that have prevented FDA from consistently recruiting highly qualifIed 

scientific advisors. Consequently, advisory committee vacancies are at an all-time high, the 

quality of the scientific discourse on such panels has suffered. and FDA has at times had to rely 

on scientific advice from panel members lacking relevant expertise. particularly with respect to 

rare diseases and cutting-edge technologies where the pool of available experts can be quite 

small. 

13[0 believes that FDA should have greater tlexibility and discretion to select the most 

appropriate advisors, consistent with the rules that apply to other federal agencies. Such changes 

will help to ensure that FDA decisions arc informed by the best available scientitlc experts and in 

the best interest of patients. 

Page 9 of J2 
134 


76491.078

V. FDA MISSION STATEMENT 

FDA's mission. as amended by tbe Food and Drug Administration Modernization Act of 1997 

and set forth in section 903 of the Federal Food. Drug. and Cosmetic Act (FFDCA). is to 

promote and protect the public health. lIowever. the FDA mission statement docs not reflect the 

Agency's critical role in incorporating modern scientific advances into review practices to ensure 

that innovative treatments and therapies arc made available to the patients who need them. 

The pathway for such long-sought health technology advances as personalized medicine. health 

applications of nanotechnology. and other cutting-edge developments to reach patients and to 

improve healthcare in the United States goes through FDA. The Agency has a critical role in 

t~lcilitating healthcare innovation. but this fact is not formally and fi.)rcefully recognized in 

FDA's legislative mandate. RIO applauds Congressman Mike Rogers for introducing legislation 

and advancing a dialogue on updating the FDA's mission for the 21 st century. 

VI. SUPPLY CHAIN INTEGRITY & ADOPTION OF A NATIONAL 

PHARMACEUTICAL TRACEABIL TY SYSTEM 

Due to the nature of the United States' closed and highly regulated pharmaceutical supply chain. 

American patients have high confidence in the integrity of the drugs and biologics they arc 

prescribed. RIO mcmber companies believe the quality and safety of their products is their 

responsibility to the patients they serve, and is their first priority. BIO supports the initiatives 

that FDA has already implemented to expand the Agency's global presence through foreign 

offices; expand the foreign inspectorate and part of a risk-based inspectional strategy; and 

modernize registration and facility tracking systems and information technology infrastructure. 

Page 10 of 12 
135 


76491.079

This Committee has also been examining granting the Agency several new regulatory authorities 

to further secure the supply chain and BIO looks forward to working with the Committee to 

further strengthen FDA's import programs and oversight. BIO is supportive of well crafted 

proposals to increase penalties for criminal counterfeiters and adulterers. provide FDA with 

authority to detain or destroy known counterfeits at our ports, modernize FDA's facility 

registration and tracking systems, and better leverage the resources of established international 

regulatory authorities through joint inspections. 

In addition to enhancing oversight over the "upstream" supply chain for pharmaceutical 

ingredients, it is critical to make enhancements to the "downstream" domestic supply chain for 

finished pharmaceutical products. BIO supports the establishment of strong, uniform, national 

standards for serialization and tracing systems, rather than relying on the emerging patchwork of 

individual state mandates. In this case, BIO believes that the Congress should enact laws 

governing drug product serialization and traceability systems that regulators can leverage to hold 

supply chain members accountable for ensuring that legitimate product reaches the patient. A 

national system using existing and proven technologies would best protect supply chain integrity 

and patient safety. 

Specifically, this approach would standardize efforts nationwide and provide immediate 

measures to increase supply chain security. Such an approach would enable the identification 

and adoption ora consensus and technology neutral standard for a traceability system achieved 

through a progressive process where each system advancement is predicated upon clearly 

defined triggers and benefits analysis. Such a system should be sutliciently flexible to allow the 

Page 11 of 12 
136 


76491.080

end-state to reflect the realization of the project's goal-facilitating the identification of and 

preventing the introduction of counterfeit, diverted, substandard, adulterated, misbranded or 

expired drugs from the supply chain and improving the efficiency and effectiveness of recalls. 

VII. CONCLUSION 

Thank you for the opportunity to offer BIO's support for the PDUFA V recommendations. We 

believe that these are common sense recommendations that will help advance innovative new 

cures for patients. We call on Congress to fully support FDA's appropriated budget and to pass 

PDUFA V as expeditiously as possible. I would be pleased to answer any questions from the 

committee. 

REFERENCES 

, FY J 0 PDUFA Performance Report, pA, 

h11J2~LL~Yl'('!tiillLgQy{~fownJoads! AboutFDA~~129J!,'j.ManuaL'i.E9rms/~1~j1L'!~rFecRcpoJ:t~/rg:rfbr.!lli!!.~IT1~&Q"Qrts/l:I~ 

.IJIAiUC1V1:C433~.Jllif 

"FDA, Driving Biomedical [nnovation: initiatives/or fmprovinS( Productslor Patients, October 2011, 

http://www.fda"gov!downloads/AboutJ~·DA!Reportsivlanua!sForms/Repoits/lJCM274464.pdf 

iii Booz Allen Hamilton, [ndependent Evaluation o./,FDA ~5' First ()IC{C Review PCfformance - Final Report 

July 2008, http://'vvww.fda.gov/Porlndustrv/UserFces/PrescriptionDrugUserFeducmI27117.htm 

Page 12 of 12 
137 

Mr. PITTS. The chair thanks the gentleman and recognizes Dr. 

Wheadon for 5 minutes for an opening statement. 

STATEMENT OF DAVID E. WHEADON 

Mr. WHEADON. Thank you. Chairman Pitts Ranking Member 

Pallone and members of the subcommittee, good afternoon. I am 

David Wheadon, Senior Vice President of Scientific and Regulatory 

Affairs at the Pharmaceutical Research and Manufacturers of 

America, better known as PhRMA. PhRMA appreciates this opportunity to testify today and share our views on the fifth reauthorization of the Prescription Drug User Fee Act, PDUFA, and the reauthorization of the Best Pharmaceuticals for Children Act, BPCA, 

and the Pediatric Research Equity Act, PREA. 

PhRMA and its member companies, the country’s leading pharmaceutical research and biotechnology companies, strongly support 

the original goals of PDUFA, namely to provide patients with faster access to innovative medicines, to preserve and strengthen 

FDA’s high standards for safety, efficacy and quality, and to advance the scientific basis for the agency’s regulatory oversight. 

PDUFA has advanced public health by accelerating the availability 

of innovative medicines to patients while helping to ensure patient 

safety. 

Furthermore, PDUFA has helped to improve America’s competitiveness around the world. Since the passage of the original Prescription Drug User Fee Act in 1992, the United States has become 

the world leader in bringing new medicines to patients first. Ensuring that the United States maintains a policy and regulatory environment that encourages an efficient, consistent and predictable 

drug review process is key to keeping America competitive in today’s global economy. 

PhRMA strongly endorses the recommendation of PDUFA V performance goals letter, which was created with unprecedented transparency and input from diverse stakeholders. This agreement will 

provide FDA with the resources and the tools required to further 

enhance the timeliness, completeness and efficiency of the drug review process including provisions to advance regulatory science and 

modernize drug development, to improve benefit-risk decision making, and to further strengthen FDA’s focus on patient safety. 

I would like to focus for a moment on one specific provision in 

the PDUFA V agreement. PDUFA V will improve the review process for new molecular entity, NME, drug and biologic applications 

which will be particularly significant for patients because NMEs 

are novel compounds that have the potential to address unmet 

medical needs and advance patient care. Specifically, it is anticipated that earlier and more comprehensive communication between 

the agency and drug sponsors as required in this enhanced review 

program will improve the rate of on-time first-cycle successes. The 

success of the new review program and of the agency’s ability to 

achieve its drug review goals will be independently assessed and 

reported in 2015 and 2017. PDUFA V will continue to provide FDA 

with the resources and tools that are essential to support patient 

safety and promote medical innovation through enhanced timeliness, completeness and efficiency of the drug review process. 

138 

PhRMA encourages Congress to reauthorize PDUFA in a timely 

manner based on the negotiated PDUFA V performance goals and 

to minimize the inclusion of additional provisions that may have 

the unintended consequence of distracting from the act’s original 

intent. 

The Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act have been extraordinarily successful in improving medical care for children by driving research to create innovative medicines for use in pediatric patients. According to the FDA, 

the current pediatric exclusivity program has done more to spur research and generate critical information about the use of medicines 

in pediatric patients than any other government initiative. Ensuring that the pediatric exclusivity incentive is preserved is key to 

continued innovation and improvement in pediatric medical care in 

the face of rising research costs. Since their initial enactment and 

subsequent reauthorizations, BPCA and PREA have been subject to 

a sunset clause under which their provisions expire after 5 years 

unless reauthorized by Congress. To build upon the tremendous 

success of BPCA and PREA in improving medical care for children, 

Congress should permanently reauthorize BPCA and PREA. 

In closing, I would like to use this opportunity to briefly discuss 

the issue of pharmaceutical supply chain integrity. PhRMA supports granting FDA discretion to set routine inspection intervals for 

foreign and domestic facilities according to risk. We support providing FDA with the flexibility to prioritize inspections of foreign 

establishments based on the risk they present and believe relying 

on set criteria such as compliance history, time since last inspection, and volume of type of products produced will enhance the 

FDA’s ability to target its inspection resources efficiently and effectively. A more detailed description of additional recommendations 

on how to strengthen the integrity of the supply chain can be found 

in PhRMA’s written testimony. We look forward to continuing to 

work with this committee, FDA and other stakeholders on these 

important issues. 

Chairman Pitts and members of the subcommittee, thank you for 

the opportunity to testify. I am happy to answer any questions. 

[The prepared statement of Mr. Wheadon follows:] 

139 


76491.081

"Reauthorization ofPDUFA: \Vhat It Means for Jobs, Innovation, and Patients" 

David E. Wheadon, M.D. 

Senior Vice President, Scientific and Regulatory Affairs 

Pharmaceutical Research and Manufacturers of America (PhRMA) 

Summary of Testimony 

The Prescription Drug User Fee Act (PDUFA). PDUFA has been a great success for patients 

since its initial passage in 1992. The PDUFA user fee program has provided FDA with the 

additional staffing and resources it needed to significantly reduce the timeframe for the review of 

new medicines, while protecting public health by assuring the safety of these products. 

The PDUFA-V performance goals letter is the result of extensive negotiations hetween the FDA and 

the innovative biopharmaceutieal industry. FDA's process for negotiating these performance goals 

included unprecedented transparency and input from all stakeholders, including patient advocates, 

healthcare professionals, consumers and academia. 

A number of important new commitments are detailed in the PDUFA-V performance goals letter, 

including provisions to make the regulatory review of new medicines more efficient and timely, to 

advance regulatory science and to modernize drug development. to improve benefit/risk decisionmaking, and to further strengthen FDA's ()CUS on patient safety. PhRMA strongly endorses the 

recommendations of the PDUFA-V performance goals lettcr. 

Since the passage of PDUFA-I in 1992, the U.S. has become the word leader in bringing new 

medicines to paticnts first and PDUFA has helped to improve America's competitiveness around the 

world. The reauthorization of PDUFA is an important factor in ensuring that biopharmaceutical 

companies maintain this level of job creation and economic growth. 

Failure to reauthorize PDUFA in a timely manner would not only have an extraordinarily disruptive 

effect on the FDA and impede patients' access to new and innovative treatments, but such a failure 

would also endanger biopharmaceutical innovation. 

Advancing Pediatric Drug Development. The Bcst Pharmaceuticals for Children Act (BPCA). 

BPCA was established in 1997 as part of FDAMA to provide incentives to encourage manufacturers 

to conduct pediatric studies ofmeclicines with the potential for use in children. The legislation 

grants pharmaceutical companies an additional six-month period of pediatric cxelusivity upon the 

completion and submission of pediatric studies that meet the terms of a written request from FDA. 

The Pediatric Research and Equity Act (PREA) gave FDA the authority to require manufacturers to 

conduct pediatric studies for certain new drugs and biologics approved for use in adults where the 

indication for use in children would be comparable to that for adults and to produce formulations 

appropriate for children, e.g. liquid or chewable tablets. 

BPCA and PREA have been extraordinarily successful in improving medical care for children by 

driving research to create innovative medicines for use in pediatric patients. 

Ensuring that the pediatric exclusivity incentive is preserved is key to continued innovation and 

improvement in pediatric medical care. Since thcir initial enactment and subsequent 

reauthorizations. BPCA and PREA have been subject to a "sunset clause" under which their 

provisions expire after five years unless reauthori~cd by Congress. To build upon the tremendous 

success ofBPCA and PREA in improving medical care for children, Congress should permanently 

reauthorize BPCA and PREA. 

Supply Chain Security. The U.S. ensures drug safety in part by maintaining a closed system for the 

distribution of prescription medicines. Supply chain security is the responsibility of all parties 

involved in the distribution ofmeclicines to patients in the U.S. 

PhRMA supports granting FDA discretion to set routine inspection intervals for foreign and 

domestic facilities according to risk by providing FDA with the flexibility to prioritize inspections of 

foreign establishments based on the risks they present. 
140 


76491.082

TESTIMONY OF DAVID E. WHEADON, M.D. 

SENIOR VICE PRESIDENT, SCIENTIFIC AND REGULATORY AFFAIRS 

PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) 

HOUSE COMMITTEE ON ENERGY AND COMMERCE, SUBCOMMITTEE ON HEALTH 

HEARING ON "REAUTHORIZATION OF PDUFA: WHAT IT MEANS FOR JOBS, 

INNOVATION, AND PATIENTS" 

FEBRUARY 1,2012 

Chairman Pitts, Ranking Member Pallone, Members ofthe Subcommittee, goos afternoon. I am 

David Wheadon, Senior Vice President, Scientific and Regulatory Affairs at the Pharmaceutical 

Research and Manufacturers of America (PhRMA). PhRMA appreciates the opportunity to 

testify today and share our views on the fifth reauthorization of the Prescription Drug User Fee 

Act (PDUFA) and the reauthorization of the Best Pharmaceuticals for Children Act (BPCA) and 

the Pediatric Research Equity Act (PREA). 

Reauthorization of the Prescription Drug User Fee Act (PDUFA-V) 

PDUFA has been a great success for patients - the tens of millions of Americans who rely on 

innovative drugs and biologics to treat disease and to extend and improve the quality ofthcir 

livcs. The PDUFA user fee program has provided the U.S. Food and Drug Administration 

(FDA) with additional starting and resources needed to significantly reduce the timeframe for 

rcview of new medicines, while protecting public health by assuring the safety of these products. 

Furthermore, PDUFA has helped to improve America's competitiveness around the world. 

Since the passage of the original PDUFA in 1992, the U.S. has become the word leader in 

bringing new medicines to patients first. 

Page 11 

Pharmaceutical Research alld Manufacturers of America 

950 F Street. NW • Washington, DC 20004 * (202) 835-3400 
141 


76491.083

The PDUFA-V performance goals letter is the result of extensive negotiations between the FDA 

and the innovative biopharmaceutical industry and is intended to improve FDA's ability to 

conduct thorough and efficient reviews of new medicines for patients. FDA's process for 

negotiating these performance goals included unprecedented transparency and input from all 

stakeholders, including patient advocates, healthcare professionals, consumers and academia. 

PhRMA and its members, the country's leading pharmaceutical research and biotechnology 

companies, strongly support the original goals of PDUFA. namely to provide patients with faster 

access to innovative medicines, to preserve and strengthen FDA's high standards for safety, 

efficacy and quality, and to advance the scientific basis for the Agency's regulatory oversight. 

PhRMA strongly endorses the recommendations of the PDUFA-V performance goals letter. 

This agreement will provide FDA with the resources and tools required to further enhance the 

timeliness, completeness and efficiency of the drug review process. 

The Role ofPDUFA in Encouraging Innovation and Economic Growth 

Ensuring that the U.S. maintains a policy and regulatory environment that encourages an 

efficient, consistent and predictable drug review process is key to keeping America competitive 

in today's global economy. A 2011 report by Baue/le 1 found that the U.S. biopharmaceutical 

industry "is well recognized as a dynamic and innovative business sector generating high quality 

jobs and powering economic output and expOlts for the U.S. economy." According to the report, 

nationwide the sector supported a total of four million jobs in 2009, including 674,192 direct 

I Battelle Technology Partnership Practice, The U.S. Biopharmaceuticals Sector: Economic Contribution of the Nation, July 2011, 

Battelle Memorial Institute, Prepared for the Pharmaceutical Research and Manufacturers of America. 

Page 12 

Pharmaceutical Research and Manufacturers a/America 

950 F Street. NW * Washington. DC 20004 1< (202) f13S~3400 
142 


76491.084

jobs. The total economic output from the sector's direct, indirect and induced impacts was $918 

billion. Because PDUFA has injected greater consistency, transparency and predictability into 

the FDA's drug review process, its reauthorization is an important factor in ensuring that 

biopharmaceutical companies maintain this level of job crcation and economic growth. Failure 

to reauthorize PDUFA in a timely manner would not only have an extraordinarily disruptive 

effect on the Agency and impede patients' access to new and innovative treatments, but such a 

failure would also endanger biopharmaceutical innovation. 

There are a number of important new commitments in the carefully negotiated PDUFA-V 

performance goals letter, including provisions to make the regulatory review of new medicines 

more efficient and timely, to advance rcgulatory science and to modernize drug development, to 

improve bcncllUrisk decision-making, and to further strengthen FDA's focus on patient safety. 

Below I will discuss these significant enhancements contained in the PDUFA-V performance 

goals letter. 

Enhanced NME Review Program 

PDUFA-V will improve the review proccss for new molecular entity (NME) drug and biologic 

applications which will be particularly significant for patients, because NMEs are novel 

compounds that have the potential to address unmet medical needs and advance patient care. 

The enhanced NME review model addresses the increasing complexity ofreviewing new drug 

applications (NDAs) and biologic license applications (BLAs), and provides fOF increased 

communication between FDA and drug sponsors prior to and during the drug review process. A 

Page 13 

Pharmaceutical Research and Manufacturers of America 

950 F Sireet, NW • Washington, DC 200114 • (202) 835-3400 
143 


76491.085

validation period will help FDA plan activities such as inspections and advisory committee 

meetings, and will accommodate iterative interactions between sponsors and the Agency. As a 

result, the NME review program is expected to improve the efficiency of the review process and 

reduce the overall time until new medicines become available to patients. Specifically, it is 

anticipated that earlier and more comprehensive communication between the Agency and drug 

sponsors will improve the rate of "on-time, first-cycle" successes the number of new medicines 

that are fully reviewed and for which definitive regulatory action is taken within the target 

timeframe following initial submission. The success of the new review program and of the 

Agency's ability to achieve its drug review goals will be independently assessed and publicly 

reported in 2015 and 2017. 

Advancements in Regulatory Science 

Several new provisions in the PDUFA-V performance goals letter will afford FDA with 

appropriate staffing and resources to develop, through public input, new tools and methods to 

integrate emerging scientific data and techniques into the drug development and review process. 

These advancements in regulatory science will rely on engagement with industry, academia and 

other stakeholders to identify best practices so the Agency can provide appropriate guidance to 

stakeholders involved in drug development. 

Provisions to enhance FDA's regulatory review capabilities include: 

>- The use of pharmacogenomics and biomarkers to decrease drug development time by helping 

demonstrate therapeutic benefits more rapidly, and identifying patients who are likely to 

benefit from treatment, as well as those at increased risk for scrious adverse events; 

Page 14 

Pharmaceutical Researcil and Manufacturers of America 

950 F Sireet, NW * Washingtoll, DC 20004 * (202) 835-3400 
144 


76491.086

).- Avenues foraccelerating drug development for rare and orphan diseases and provide FDA 

with the necessary regulatory flcxibility to encourage and advance research into novel 

treatments for patients with significant unmct nceds today; 

);. Standards for and validation of patient-reported outcomes and other assessment tools that 

may assist regulators in cvaluating treatment bencfits and potential risks from the patient's 

point of view; and 

);. The evaluation of the use of meta-analyses in regulatory review and decision-making, 

highlighting best practice and potential limitations. 

Systematic Approach to Benefit-Risk Assessment 

A key provision in the PDUFA-V performance goals letter recognizes that the drug review 

process could be improved by a more systcmatic and consistent approach to benefit-risk 

assessment that fairly considers disease severity and unmct medical needs. During PDUFA-V, 

the Agency will implement a structured benefit-risk framework, and hold public meetings to 

assess the application of such frameworks in the regulatory environment. In addition, over the 

course of PDUFA-V the Agency will hold a series of public meetings with the patient advocacy 

community to identify disease states that - from the patient pcrspective have considerable 

unmet needs. Devclopment and implementation of a patient-focused, structured framework for 

evaluating benefits and risks of new treatments will help inform the drug development process as 

well as ensure that regulatory decisions are consistent, appropriately balanced and based on best 

science. 

Page I 5 

Pharmaceutical Research and Manufacturers of America 

9S0 FStreet. NW * Washington. DC }0004 • (202) 835-3400 
145 


76491.087

Modernizing the U.S. Drug Safety System 

Finally, further enhancement and modernization orlhe FDA drug safety system under PDUFA-V 

will ensure that patient safety remains paramount. The PDUF A-V performance goals letter 

provides for a public process to help standardize risk evaluation and mitigation strategies 

(REMS). with the intent to assess and reduce burden on healthcare providers and patients. 

Additionally, FDA will continue to evaluate the feasibility of using the Agency's Sentinel 

Initiative to actively evaluate post-marketing dmg safety issues. 

PDUFA has advanced public health by accelerating the availability of innovative medicines to 

patients while helping to ensure patient safety. The PDUFA program has strengthened the 

scientific basis of FDA's regulatory review process through the development and application of 

new tools, standards and approaches that facilitate assessment of the safety and emcaey of 

innovative drugs and biologics. PDUFA-V will continue to provide FDA with the resources and 

tools that are essential to support patient safety and promote medical innovation through 

enhanced timeliness, completeness and emciency of the drug review process. PhRMA 

encourages Congress to reauthorize PDUFA in a timely manner based on the negotiated 

PDUFA-V performance goals and to minimize the inclusion of additional provisions that may 

have the unintended consequence of distracting from the Act's original intent - to provide 

patients with faster access to innovative medicines, to preserve and strengthen FDA's high 

standards for safety, emeacy and quality, and to advance the scientific basis for the Agency's 

regulatory oversight. 

Page 16 

Pharmaceutical Research and Manufacturers of America 

950 F Street, NW • Washingtoll, DC 20004 * (202) 835-3400 
146 


76491.088

Reauthorization of the Best Pharmaceuticals for Children Act (BPCA) and 

the Pediatric Research and Equity Act (PREA) 

Prior to passage of the pediatric exclusivity provisions in the Food and Drug Modernization Act 

(FDAMA) of 1997, there were significant disincentives for biopharmaceutical companies to 

conduct clinical trials for pediatric use - generally speaking, in patients under the age of 18 - for 

medicines developed primarily for adults. At the same time, there were concerns that many 

FDA-approved drugs had not been clinically tested in children. For example, at that time about 

70 percent of medicines used in children had been dispensed without adequate pediatric dosing 

information.2 

Growing recognition of the need for pediatric-specific information prompted action by Congress 

and the FDA. Congress responded by establishing BPCA to provide incentives to encourage 

manufacturers to conduct pediatric studies of medicines with the potential for usc in children as 

patt of FDAMA. The legislation included a provision that granted pharmaceutical companies an 

additional six-month period of exclusivity, known as pediatric exclusivity, upon the completion 

and submission of pediatric studies that meet the terms ofa written request from FDA. 

In addition to BPCA, PREA gave FDA the authority to require manufacturers to conduct 

pediatric studies for certain new drugs and biologics approved for use in adults where the 

indication for use in children would be comparable to that for adults and produce formulations 

appropriate for children, e.g. liquid or chewable tablets. 

2 u.s. Pediatric Studies Incentive Led to New Labeling for Nearly 100 Drugs, Impact Report, Tufts Center for the Study of Drug 

Development, Vol. 7. No.4, July/August 2005. 

Page 17 

Pharmaceutical Research and lolanufacturers of America 

950 F Street. NW • Washington. DC 20004 • (202) 835-3400 
147 


76491.089

Although FDAMA included a sunset provision effective January 1,2002, Congress subsequently 

reauthorized these provisions in BPCA and PREA in 2002, and again in 2007 as part of the Food 

and Drug Administration Amendments Act (FDAAA). Similarly. there are provisions in the 

Biologics Price Competition and Innovation Act of 2009 (BPCIA) to provide pediatric 

exclusivity for biologics if the sponsor submits pediatric studies in accordance with a written 

request from FDA. BPCA and PREA both sunset on September 30, 2012. unless reauthorized or 

made permanent. 

BPCA and PREA have been extraordinarily successful in improving medical care for children by 

driving research to create innovative medicines for use in pediatric patients. According to the 

FDA. the current pediatric exclusivity program has done more to spur research and generate 

critical information about the use ofmedicincs in pediatric patients than any other government 

initiative.] As of2008. an estimated 50 to 60 percent of prescription drugs used to treat children 

have been studied in some part of the pediatric population.4 Since 1998, BPCA and PREA have 

resulted in 426 pediatric labeling changes.5 and a GAO report released in May 2011 states that 

pediatric studies conducted in the past five years represent 16 different therapeutic areas 

including oncology, endocrinology, hematology. cardiovascular disease. infectious disease and 

neurology. 

A recent issue of NIH MedlinePlus magazine notes the importance of pediatric clinical trials and 

cites several examples of how clinical trial knowledge has improved the lives of children. The 

3 Pediatric Study Costs Increased a-Fold Since 2000 as Complexity Level Grew, Impact Report, Tufts Center for the Study of Drug 

Development. Vol. 9, No.2, March/Apri! 2007. 

4 FDA, "Giving Medication to Children: Q&A With Dianne Murphy, MD," June 2009. 

5 FDA, hUp:IIWWW.fda.gov/downloads/ScienceResearch/SpeciaITopicsIPediatricTherapeuticsResearch/UCM163159.pdf 

Page 18 

Pharmaceutical Research and Manufacturers of America 

950 F Street, NW • Washingtoll, DC 2011114 * (2112) 835-34011 
148 


76491.090

article states that, among other examples of great progress in innovative pediatric drug 

development, "as a result of repeated clinical trials in children with cancer, most children who 

develop leukemia survive" compared to 50 years ago when "acute leukemia was almost 

universally fatal in young children". Additionally, clinical trials in young children "showed that 

surfactant - a substance that keeps air sacs in the lungs inflated - helps premature infants breathe" 

and with this knowledge "the lives of thousands of babies who would otherwise die of 

respiratory failure are saved each year".6 

Permanent Reauthorization of BPCA and PREA is Key to Ensuring Innovation in 

Pediatric Research 

Ensuring that the pediatric exclusivity incentive is preserved is key to continued innovation and 

improvement in pediatric medical care in the face ofrising research costs. Since their initial 

enactment and subsequent reauthorizations, the pediatric exclusivity incentive and PREA have 

been subject to a "sunset clause" under which their provisions expire after five years unless 

reauthorized by Congress. To build upon the tremendous success ofBPCA and PREA in 

improving medical care for children over the past tifteen years, Congress shoula permanently 

reauthorize BPCA and PREA. 

Permanent reauthorization of these provisions would provide greater certainty to companies by 

allowing a more predictable regulatory path and would help spur increased pediatric research. 

Pediatric product development would also benefit from updated regulatory guidance to assist 

both industry and FDA review staff in achieving a common understanding of the requirements 

S NIH Medline Plus, "Developing Safe and Effective Medicines for Children," Winter 2012, < 

http://WININ.fnlm.org/Program_MLP/MLP_intro.html> 

Pharmaceutical Research and Manufacturers of America 

950 F Street, NW * Washington, DC 20004 * (202) 835-3400 

Page 19 
149 


76491.091

under the Federal Food, Drug, and Cosmetic Act (FDCA). Because ofthc five-year 

BPCA/PREA sunset and reauthorization cycle, no such currcnt guidance exists, since every 

reauthorization has brought new changes to the law. Thc lack of current FDA guidance creates 

additional challenges for sponsors involved in pediatric product development to incorporate any 

differences into its plans due to changes in statutory requirements. IfCongrcss were to 

reauthorize BPCA and PREA permanently, it would enable the FDA to publish and maintain upto-date regulatory guidance for companies that seek to develop pediatric treatments. 

Further, making BPCA and PREA permanent would allow sponsors to build upon the existing 

pediatric research infrastructure and expand their capacity to conduct clinical studies. 

Uncertainty about whether incentives will continue could deter this vital investment. A similar 

pediatric inccntive was successfully introduced in the European Union (EU) in 2007, and while 

the regulation is subject to review, the EU's pediatric incentive is permanent. The permanent 

incentive in the EU has enabled the Europcan Medicines Agency (EMA) to publish clear 

guidelines for industry and regulators making the process more efficient, transparent and 

predictable. 

Given the undisputed success ofBPCA and PREA, we urge Congress to permanently reauthorize 

BPCA and PREA in their current forms to allow pediatric research to thrive and create more 

options for our most vulnerable population: children. 

Page 110 

Pharmaceutical Research and Manufacturers of America 

9JII F Street, NW * Washington, DC 211004 * (202) 83J-34011 
150 


76491.092

Maintaining Pharmaceutical Supply Chain Integrity 

In addition to the Subcommittee's focus on the reauthorization ofPDUFA, BPCA, and PREA, 

PhRMA shares the Subcommittee's longstanding interest in helping to assure the safety of the 

U.S. pharmaceutical supply. 

The U.S. ensures drug safety in part by maintaining a closed system for the distribution of 

prescription medicines. In addition to the existing standards that require an NDA or a BLA and 

maintenance of current Good Manufacturing Practice (cGMP). the U.S. closed preseription 

distribution system helps provide assurance regarding the quality, safety and integrity of the 

products lawfully sold in the U.S., and helps minimize the possibility that a consumer receives a 

counterfeit medicine. Even with FDA's comprehensive regulatory system, increasing 

globalization of pharmaceutical supply chains presents challenges that require biopharmaceutical 

companies and the FDA to be more adaptive and flexible in the review and oversight of entities 

located around the world. Relying on risk-based approaches will help achieve these goals. 

Supply chain security is the responsibility of all parties involved in the distribution of medicines 

to patients in the U.S. We appreciate the Subcommittee's long-standing commitment to these 

issues and Congressman Dingell's particular focus on thcse topics. As you know, PhRMA has 

constructively engaged with this Subcommittee, with the full Committee and other stakeholders 

on all aspects of supply chain sccurity, and appreciates the oppOliunity to continue to be part of 

this important dialogue. 

Page III 

Pharmaceutical Research and Mallufacturers of America 

950 F Street, NW • Washington, DC 2011114 • (2112) 835-34011 
151 


76491.093

As part of this discussion, we are pleased to provide the following preliminary commcnts, and 

look forward to an ongoing dialogue on these important issues. 

Enhancements to FDA's Inspection Regime - Adoption of Risk-Based Inspection Inten'als 

PhRMA supports granting FDA discretion to set routine inspection intervals for foreign and 

domestic facilities according to risk. The use of risk-based approaches to regulation, and in 

particular, to cOMP inspections is not a new concept.7 We support providing FDA with the 

flexibility to prioritize inspections of foreign estahlishments based on the risks they present, and 

believe relying on set criteria such as compliance history, time since last inspection, and volume 

and type of products produced, will enhance the FDA's ability to target its inspection resources 

efficiently and effectively. 

Leverage FDA's Inspection Resources by Allowing Use of Foreign Inspection Reports or 

Accredited Third Parties as Appropriate 

In recognition of the fact that the Agency does not have unlimited resources and in order to help 

ensure that foreign inspections occur on a more regular basis. Congress should consider allowing 

FDA to rely on the inspection results of other foreign regulatory bodies with similarly robust 

drug regulatory oversight systems, or to use accredited third parties to conduct certain foreign 

inspections, such as inspections of facilities considered moderate to low risk based on 

appropriate criteria. These inspections would not take the place of FDA inspections, which are a 

necessary and important part of the Agency's mandate; however, they would provide FDA with 

the flexibility to leverage the work of foreign regulatory bodies of similar standing and maximize 

7 See e.g., "FDA Guidance: Risk-Based Method for PrioritiZing GMP Inspections of Pharmaceutical Manufacturing Sites - A Pilot 

Risk Ranking Model." (Sept. 2004). 

Page I 12 

Pharmaceutical Research and Manufacturers of America 

950 F Street, NW * Washingtoll, DC 20004 • (202) 835-3400 
152 


76491.094

its resources, all without foreclosing its ability to inspect any facility. FDA recently 

acknowledged and embraced the concept of relying on "public and private third parties to 

conduct audits and other oversight activities on behalf of FDA:,8 

A risk-based approach to inspections and reliance on third parties inherently contemplate that 

limited sharing of inspection-related information may be a necessary component of these 

proposals. In those circumstances, we must also protect confidential commercial and trade secret 

information, including information relatcd to manufacturing methods and processes. It will be 

critical for FDA to have in place written agreemcnts with relevant foreign governments setting 

out the scope of information that can be shared and obtaining assurances from those foreign 

governments that the pharmaceutical scctor's innovation and ingenuity will be protected from 

public disclosure. Continued innovation of developing and manufacturing tomorrow's new 

medicines depends on this information being adequately protected. 

When considering the issues of supply chain security, another enhancement that could bc 

considered would include requiring all foreign facilities manufacturing prescription drug 

products or components destined for import into the U.S. to register with FDA and list their 

products, to the extent they are not already required to do so undcr current law. By requiring 

such facilities to register, the FDA will be able to establish a single database that will contain 

information on all facilitics that manufacture products or components of products that are sold in 

the U.S. 

8 "Pathway to Global Product Safety and Quality: Special Report," Food and Drug Administration, (July 7, 2011), available at: 

<http://v.Nr.N.fda,gov/AboutFDAlCentersOffices/OC/GlobaIProductPathway/default.htm> , 

Page 113 

Pharmaceutical Research and Manufacturers of America' 

950 F Street, NW * Wasilillgtoll, DC 20004 * (202) 835-3400 
153 


76491.095

Finally, as we consider whether new authorities are needed to help strengthen our existing 

prcscription drug supply chain, we must also consider the appropriateness of including new 

burdens on the import of materials for use in preclinical and clinical investigations. The 

continued, uninterrupted access to preclinical research and clinical trial materials, including 

active pharmaceutical ingredients (APls), is essential to ensure that vital research into innovative, 

life-saving and life-enhancing new treatments is not hindered in any way. Materials and articles 

used in preclinical research activities are not used in the treatment of patients, but instead are 

used in laboratory testing as scientists try to understand the pharmaceutical properties and initial 

safety profile of the test article. Thus, we strongly encourage the inclusion of an exemption for 

APls, investigational drugs and other materials intended for use in preclinical testing and clinical 

trials that comply with FDA's stringent requirements relating to the proper use of investigational 

material, including labeling and import of investigational products and materials for use in 

clinical trials under an Investigational New Drug application (IN D), into any new provisions 

related to securing our pharmaceutical supply chain. 

We commend the Subcommittee for its focus on and commitment to the issue of securing the 

pharmaceutical supply chain. The U.S. system of prescription drug supply chain security today 

is of a very high standard, but even good systems can be improved upon. We look forward to 

continuing to work with the Committee, FDA and othcr stakeholders on these important issues. 

Thank you for the opportunity to testify today and I welcome any questions you may have. 

Page I 14 

Pharmaceutical Research and Manufacturers of America 

950 F Street, NW • Washington, DC 20004 * (202) 835-3400 
154 

Mr. PITTS. The chair thanks the gentleman and recognizes Mr. 

Coukell for 5 minutes for an opening statement. 

STATEMENT OF ALLAN COUKELL 

Mr. COUKELL. Chairman Pitts, Ranking Member Pallone and 

committee members, thank you for the opportunity to be here 

today. 

My name is Allan Coukell. I am the Director of Medical Programs with the Pew Health Group, which seeks to improve the 

health and wellbeing of Americans by supporting policies that foster innovation and reduce risks to consumers. I am here today to 

talk about the safety of the U.S. drug supply. Pew has focused on 

this for the last 4 years as has this committee. 

In recent years, pharmaceutical manufacturing has been transformed. What was once a domestic industry is now global. Forty 

percent of our finished drugs and 80 percent of the active ingredients now originate outside our borders. Much of the supply is purchased in India and China. The number of non-U.S. plants that 

supply the United States has doubled in just the past decade. Yet 

the Food, Drug, and Cosmetic Act remains overwhelmingly domestically focused. This puts consumers at risk and American manufacturers on an uneven playing field. While the leading companies 

are already doing thorough assessments of their supply chains, we 

have to make sure that there is no incentive for the weaker actors 

to gain a competitive advantage by cutting corners. 

Just 4 years ago, hundreds of American patients were sickened 

and some died after they received a blood-thinning drug, heparin, 

that had been adulterated during manufacture in China. This was 

a U.S. company that was reliant on an upstream network of suppliers that it didn’t know and couldn’t control. Since that tragedy, 

this committee has held nine hearings and heard from more than 

60 witnesses. You have conducted a careful and thorough investigation that has identified serious gaps in the system. We don’t know 

who adulterated that heparin from China but we certainly know 

how to reduce the risk that someone else will adulterate some 

other imported drug in the future. 

Congress needs to act to protect Americans. We need a system 

that reduces risks, that rewards companies that have proper quality systems in place, promotes an even playing field, and uses taxpayer dollars efficiently. Pew’s ‘‘After Heparin’’ report identifies the 

risks and suggests some pragmatic solutions. Let me make three 

key points. 

First, inspections. Not that far from here is one of the U.S.’s largest pharmaceutical manufacturing facilities. It is a Mylan facility 

in West Virginia that employs a lot of people, and like any other 

domestic manufacturing facility, it can expect an FDA inspection 

about every 2 years. That company’s competitors in India and 

China also making drugs for the U.S. market face nowhere near 

that level of scrutiny. A plant outside the United States knows that 

FDA may visit only once before the product is first approved and 

then may never return, and that reduces the incentive to make ongoing investments in quality. The FDA should inspect plants both 

domestic and overseas based on risk, and no company should go 

uninspected for more than 4 years. We support the call by Mylan 

155 

and others in industry for a level playing field to ensure safety regardless of where the drugs come from. 

Inspections are one part of the solution. Let me talk for a moment about supplier quality. Pfizer, represented here today on this 

panel, has invested heavily in supply chain integrity from production and ingredient sourcing to distribution security. Let me quote 

from previous testimony by Pfizer. They said ‘‘Companies in emerging markets are operating in a developing regulatory environment 

with a novice inspector. Many have rudimentary quality systems, 

or none at all. Before a U.S. pharmaceutical firm can considering 

sourcing from these suppliers, it is imperative that the firm work 

with suppliers to upgrade their quality systems and standards.’’ 

The Pew report outlines well-documented cases of suppliers concealing the actual sources of drug ingredients, in some cases bringing in chemical materials that were not intended for pharmaceutical use. We call for modernizing current regulations to ensure 

that every company has appropriate measures in place to ensure 

quality standards at their suppliers. 

And finally, we need to make sure that the FDA has the tools 

that are appropriate for today’s global paradigm. For example, companies with high quality systems and an established track record 

shouldn’t face delays at the border. Companies that don’t have 

those things should face heightened scrutiny. We need to make 

sure that the FDA has the clear authority at the border to refuse 

products when the plant that made them has denied an FDA inspection. 

The proposed generic user fee agreement will provide FDA with 

new resources for increased inspections of overseas generic manufacturing. It is an important step, and the PDUFA reauthorization 

is the opportunity to bring the FDA into the 21st century to give 

Americans a greater assurance of safety. 

Let me conclude with something that we heard often over the 

course of our research. If there are feasible practical steps that we 

don’t take, it is not a question of if there is another tragedy, it is 

a question of when. 

Thank you, and I welcome any questions. 

[The prepared statement of Mr. Coukell follows:] 

156 


76491.096

ONE PAGE SUMMARY 

Testimony before the 

House Committee on Energy and Commerce, Subcommittee on Health 

United States House of Representatives 

February L 2012 

Allan Coukel!, Director, Medical Programs, Pew Health Group, The Pew Charitable Trusts 

The safety of the U.S. pharmaceutical supply system, a focus for Pew for the past four years, has also 

been a matter of sustained interest to this Committee. Nevertheless, many Americans would be surprised 

by the rapid and profound changes in how our prescription drugs are made - and the new risks that brings. 

Today, 40% of all finished phannaceuticals, and 80% of the active ingredients and bulk chemicals in U.S. 

drugs, are now sourced by industry Irom foreign countries. 

Despite this shift, FDA oversight of manufacturing is overwhelmingly domestically-focused. This puts 

consumers at risk and American manufacturers on an uneven playing field. While the best companies are 

already doing thorough assessments of their supply chains, we must make sure there is no incentive for 

the weaker actors to gain a competitive advantage by cutting corners. 

Pew has been working to identify the risks to the drug supply and advance pragmatic solutions. In July of 

20 II, we released a report entitled "After Heparin: Protecting Consumers trom the Risks of Substandard 

and Counterfeit Drugs." The report was informed by a two-day conference we hosted in March 2011 that 

included representatives of brand and generic pharmaceutical manufacturers, active drug ingredient 

makers, major and secondary pharmaceutical wholesalers, chain and independent pharmacies, consumer 

and health professional organi7.ations, the U.S. Food and Drug Administration (FDA), state regulators and 

independent supply chain experts. 

One of the most striking outcomes of this conference was the amount of consensus among stakeholders 

about risks and the need to address them. The stakeholders all acknowledged the geographic disparities in 

FDA oversight of drug manufacturing. In addition, Pew's research underscored again and again how 

important it is that companies know their suppliers and have systems in place to ensure the production 

quality throughout their supply chains. Finally, fDA needs regulatory systems that are appropriate for 

today's global paradigm. For example, we should ensure that companies with high-quality systems in 

place don't face delays at the border. We also need to ensure that the FDA has the clear authority to 

refuse products when the plant that made them has denied an FDA inspection. 

The authorization of the Prescription Drug User Fec Act (PDUFA) and other user fce programs this year 

offers an opportunity for Congress to tackle the risks of the global supply chain. Numerous stakeholders 

agree on the path forward here. They also agree that without action, we will face another disa,ter. Now is 

the time for this Committee to Act on what it has learned over the past four years. 
157 


76491.097

Testimony before tbe 

House Committee on Energy and Commerce, Subcommittee on Healtb 

United States House ofRcpresentatives 

February 1,2012 

Allan Coukell, Director of Medical Programs, Pcw Health Group, The Pew Charitable Trusts 

Chairman Pitts, Ranking Member Pallone and members of the Health Subcommittee, thank you for 

the opportunity to submit testimony about the essential steps Congress must take to protect 

Americans and ensure the integrity of our drug supply. 

Based on research and critical analysis, the Pew Health Group seeks to improve the health and wellbeing of all Americans by reducing unnecessary risks to the safety of medical and other consumer 

products and supporting medical innovation. Pew applies a rigorous. analytical approach to improve 

public policy, inform the public and stimulate civic life. 

The safety of the U.S. phatmaceutical supply system, a focus lor Pew for the past four years, has also 

been a matter of sustained interest to this Committee. Nevertheless, many Americans would be 

surprised by the rapid and profound changes in how our prescription drugs are made and the new 

risks that brings. Today, 40 percent of all finished pharmaceuticals,! and 80 percent of the active 

ingredients and bulk chemicals in U.S. drugs, are now sourced by industry from fOfeign 

countries.' Up to half are purchased from plants in India and China.' The number or non-U.S. plants 

we depend on has doubled in just the past decade. 4 

Despite this shift, FDA oversight of manufacturing is overwhelmingly domestically-focused. This 

puts consumers at risk and American manufacturers on an uneven playing lield. While leading 

companies are already doing thorough assessments of their supply chains, we must make sure there is 

no incentive for the weaker actors to gain a competitive advantage by cutting corners. 
158 


76491.098

In 2008, hundreds of American patients were sickened, and some died, after they received a blood 

thinning drug, heparin, that had been adulterated during the manufacturing process in China. 

Since that time, this committee has held nine hcarings and heard from more than 60 witnesses, in this 

Congress and those prior. You have conducted a careful and thorough investigation that has 

identified serious gaps in the system. We do not know who intentionally adulterated Chinese made 

heparin in 2008 but we certainly know how to make it much less likely that that kind of adu Iteration 

can happen again. Congrcss needs to act now to protect American consumers. 

An ideal system will reduce risks, reward companies with good quality systems, promote an even 

playing field and use taxpayer dollars efficiently. 

Pew has been working to identity the risks to the drug supply and advance pragmatic solutions. In 

July 01'2011, we released a rcpOIi entitled "After Heparin: Protecting Consumers from the Risks of 

Substandard and Counterfeit Drugs:'; The repOl1, which underwent extensive external review, was 

based upon information from regulatory and public documents, peer-reviewed journal articles and 

interviews with dozens of supply chain experts from numerous perspectives. It was informed by a 

two-day conference we hosted in March 20 II that included representatives of brand and generic 

phannaceutical manufacturers, active drug ingredient makers, major and secondary pharmaccutical 

wholesalers, chain and independent pharmacies, consumer and health professional organizations, the 

U.S. Food and Drug Administration (FDA), state regulators and independent supply chain experts. 

One of the most striking outcomes of this conference was the amount of consensus among 

stakeholders about risks and the need to address thcm. Leaders within industry that adhere to high 

standards of quality managcment and supply chain oversight understandably want all makers of 

drugs to be held to maintain and ensure drug quality. 

Stakeholders at the Pew meeting acknowledged the geographic disparities in FDA oversight of drug 

manufacturing. Not far from here is a pharmaccuticalmanufacturing plant in West Virginia, operated 

by Mylan, the largest U.S. producer of generic drug products. Like every other domestic facility, it 

faces FDA inspections at least every two years. But as Heather Bresch, the company's president has 

noted, her competitors in China receive nowhere near this level of scrutiny. She has written that: 

"Every consumer should have the peace of mind in knowing that every prescription 

2 
159 


76491.099

purchased in the U.S. is held to the same standard of quality regardless ofwhether the 

product or its ingredients originated in the U.S. or outside its borders.,,6 

While FDA inspections alone arc not enough to ensure quality, the expectation of inspection is a 

critical driver of quality compliance by makers of drugs and their ingredients. A plant outside the 

U.S. knows FDA may visit only once, before the product is first approved, and then never return. 

That reduces the incentive to make ongoing investments in quality. The FDA should inspect plants, 

both domestic and overseas, bascd on risk, which will permit the Agency to make much more 

efficient use of its limited resources. However, no plant should go indefinitely without an inspection. 

A minimum frequency of 4 or 5 years should thus also be established. 

Second, Pew's research underscored again and again how important it is that companies know their 

suppliers and have systems in place to ensure the production quality throughout their supply chains. 

Pfizer, who joins us on this witness panel, has invested heavily in supply chain integrity, creating 

overarching systems that cover all company functions from production and ingredient sourcing to 

distribution security. Pfizer has said in testimony: 

"Companies in emerging markets are operating in a developing regulatory environment with 

a novice inspectorate. Many have rudimentary quality systems or none at all. Before a US 

pharmaceutical linn can consider sourcing from these suppliers, it is imperative that the firm 

works with the suppliers to upgrade their quality systems and standards. To accomplish this, 

Pfizer and other companies have taken steps to Educate, Evaluate and for lack of a better 

word, Enforce appropriate quality standards.', 7 

Pew SUppOlts updating current regulations to ensure all companies implement quality systems to 

manage their supply cilains. These systems should include robust supplier assessment. Companies 

that do not adequately monitor and control suppliers may not only be ignorant of quality problems, 

they may be deliberately deceived. There have been well-documented cases of suppliers concealing 

the actual source of drug ingredients, in some cases bringing in chemical materials ~that were not 

intended for pharmaceutical use. 

Martin VanTrieste, Vice President for Quality at Amgen and a founder of an industry phannaceutical 

quality consortium called Rx-360 has said: 

3 
160 


76491.100

"'Rx-360 members recognize that we are responsible for our suppliers and supply chains and 

have a responsibility to tackle head-on the challenges associated with a global supply 

chain."g 

Finally, we need to ensure FDA regulatOlY systems are appropriatc for (oday's global paradigm. We 

should ensure that companies with high-quality systems in place don't face delays at the border. We 

need a system that benefits those companies and allows FDA to focus resources on finns that can't 

show a record of inspections or compliance with best practices. Indced, FDA has conducted pilot 

programs in this area, and is also implementing a new risk-based screening system for imports to 

increase the efficiency of targeting. We also need to ensure that the FDA has the clear authority to 

refuse products when the plant that made them has denied an FDA inspection. 

This year's authorization of the Prescription Drug User Fee Act (PDUFA) and other user fee 

programs offers an opportunity for Congress to tackle the risks of the global supply chain. We are 

greatly encouraged that the Generic Drug User Fee agreement, which will providc the FDA with new 

resources to conduct increased inspections of overseas gencric manufacturing facilities - reaching 

parity with US inspections within t1ve years. The additional changes to bring the FDCA into the 21 51 

Century are feasible, practical and germane to the user fce rencwal. 

Numerous stakeholders agree on the path forward. They also agree that without action, we will face 

another disastcr like that of the adulterated heparin four years ago. We havc heard over and over the 

mantra, "it is not if, but when." Now is the time for this Committee to act on what it has learned over 

the past four years. 

Thank you, and I welcome your questions. 

1 Hamburg, Margaret. Commissioner, U.S. Food and Drug Administration. Testimony before the House Committee 

on Energy and Commerce, Subcommittee on Oversight and Investigations. April 13, 2011. 

http://republicans.energycommerce.house.gov/Media/fi Ie /H ea rings/Overs ight/041311/Ha m bu rg. pd f. Accessed 

April 27, 201l. 

1 U.S. Government Accountability Office (March 1998). Food and Drug Administration: Improvements Needed in 

the Foreign Drug Inspection Program (Publication No. GAO/HEHS-98-21). 

4 
161 


76491.101

, NSD Bio Group. Potential Health & Safety Impacts from Pharmaceuticals and Supplements Containing Chinese· 

Sourced Raw Ingredients. Prepared for the United States China Economic and Security Review Commission. April 

2010. 

4 Woodcock, Janet. Director, Center for Drug Evaluation and Research, Food and Drug Administration. "The FDA's 

Response to Biogenerics, QA and Globalization." Unbranding Medicines: The Politics, Promise, and Challenge of 

Generic Drugs. Harvard Interfaculty Initiative on Medications and Society. December 12, 2008 

5 Pew Health Group. "After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs." 

(2011) http://www.prescriptionproject.orgiafter heparin report 

6 Bresch, Heather. President, Mylan Inc. Submission to Docket No. FDA·201O·N·0381 Re: Generic Drug User Fee, 

FDA Request for Comments. October 17, 2010 

7 Migliaccio, Gerry, Vice President, Quality, Pfizer Inc. "Restoring FDA's Ability to Keep America's Families Safe". 

Testimony before the Senate Health, Education, Labor, and Pensions Committee, April 24, 2008. 

B VanTrieste, Martin. "Securing the Pharmaceutical Supply Chain". Testimony before the Senate Health, Education, 

Labor, and Pensions Committee. Wednesday, September 14, 2011 
162 

Mr. PITTS. The chair thanks the gentleman and recognizes Ms. 

Dorman for 5 minutes for an opening statement. 

STATEMENT OF DIANE EDQUIST DORMAN 

Ms. DORMAN. Thank you, Mr. Chairman. Thank you, Ranking 

Member Pallone. Thank you for the opportunity to testify before 

you today. I am Diane Dorman, Vice President for Public Policy for 

NORD, the National Organization for Rare Disorders. 

Since 1983, NORD has served as a leading voice and advocate for 

the approximately 30 million men, women and children with rare 

diseases in the United States. NORD’s mission is to foster a social, 

political and financial culture of innovation that supports the basic 

and translational research necessary to develop new diagnostic 

tests and therapies for all rare disorders. This requires a regulatory environment that encourages the development and timely 

approval of new, safe and effective treatments for rare disorders. 

Reauthorizing PDUFA presents an opportunity for Congress to 

achieve that goal. Greater clarity and predictability for the review 

of novel therapies for rare disorders can be achieved by allocating 

some of the PDUFA resources to support the enhancement of regulatory science. Of special significance in the draft agreement is the 

rare disease initiative that will enhance development of drugs and 

biologics for the treatment of rare conditions. We support these efforts and look forward to the opportunity to work with the agency 

and with Congress to guarantee the success of this initiative. 

The rare disease community was heartened recently when the 

drug approval summary for 2011 was announced. Of the 35 innovative drugs approved in 2011, ten were orphan drugs. We hope and 

expect that further investment in orphan products will lead to continued development of therapies that address the unmet medical 

needs of patients. We are encouraged that the Orphan Drug Act 

has brought about such successful innovation in the market for 

rare disease therapies. 

The reality is that we have barely started the journey. There is 

still approximately 6,800 rare diseases that lack an FDA-approved 

therapy. The reauthorization of PDUFA offers hope that we may 

build on previous successes by strengthening the review process 

still further and by creating an environment that encourages innovation and investment. We believe that the rare disease program 

will enhance the regulatory science needed to accelerate development of new therapies. This initiative allocates a small fraction of 

user fees to support the existing rare disease program and CDER. 

The agreement completes the current staffing and implementation 

plan and establishes a rare disease liaison within the Center for 

Biologics. 

Last October, NORD released a landmark study that looked at 

all drugs for diseases other than cancer approved as orphans since 

1983 to identify whether and when FDA exercised flexibility in the 

review process. Of the 135 drug approvals studied, NORD concluded that the FDA demonstrated flexibility in the review of effectiveness data on orphan drug therapies for two out of every three 

orphan drugs approved. FDA clearly has demonstrated in its actions on orphan products over the past three decades that it recognizes the importance of therapies for people with rare disorders. 

163 

NORD believes it would be helpful for such flexibility to be recognized in a formal FDA policy and for officials to incorporate flexibility in a systematic way in their evaluations of each new therapy. 

While the statutory standard for safety and efficacy should be 

the same for all medical products, enhancement of the rare disease 

program will allow FDA to provide greater clarity in how it applies 

the standards for safety and effectiveness to orphan products. A 

formal policy setting forth the agency’s view of flexibility in conducting orphan product review is likely to provide more certainty 

to innovators seeking to develop rare disease therapies. Further, 

we would like to see the proposed public meeting and staff training 

implementation dates moved forward to occur no later than 2013. 

PDUFA V will provide FDA with the resources needed to maintain a strong professional staff that is necessary for the development of clear guidelines and the expedited review of innovative 

therapies. 

In addition to the rare disease program, there are two other policy considerations that we feel are worthy of your consideration: 

current conflict-of-interest provisions and patient participation in 

risk assessment. First, during FDAAA negotiations, NORD argued 

that because patient populations are very small and the number of 

researchers who study a particular rare disease is limited, identifying experts not financially conflicted to sit on an advisory committee would be difficult, if not impossible. Those concerns were realized in 2008 when it took the FDA nearly 6 months to identify 

an expert to review a life-saving therapy to treat infantile spasms. 

While conflict-of-interest considerations are clearly necessary, our 

view is that the existing provisions in the Federal Advisory Committee Act and the Ethics in Government Act of 1978 are adequate 

to safeguard against conflicts of interest. A separate standard is 

not needed. 

Second, NORD, working with like-minded patient organizations, 

has developed a proposal submitted to the FDA to allow the patient 

community to communicate on a more frequent and periodic basis 

with medical reviewers and other relevant FDA staff to make risk 

tolerance and other decisions. We advocate that more systematic 

processes be established at FDA to enable contributions from the 

patient community at the time that critical decisions on risk tolerance are being made. We do not seek to create a burdensome or 

time-consuming process; rather, we want to be sure that patients 

have the opportunity to share their views. 

In closing, I want to thank the committee again for giving NORD 

the opportunity to testify today regarding the reauthorization of 

PDUFA. The rare disease community believes that engaging Congress and FDA officials in the process has and will continue to lead 

to practical, detailed improvements to the regulatory process that 

will accelerate the development of orphan products from concept to 

access. 

Thank you very much. 

[The prepared statement of Ms. Dorman follows:] 

164 


76491.102

Testimony of Diane Edquist Dorman 

Vice President, Public Policy 

National Organization for Rare Disorders (NORD) 

Before the 

United States House of Representatives 

Committee on Energy and Commerce 

Subcommittee on Health 

February 1,2012 

Mr. Chairman, ranking member Pallone, distinguished members of the Subcommittee, I want to 

thank you for the opportunity to testify before you today. I am Diane Dorman, Vice President 

for Public Policy ofthe National Organization for Rare Disorders, or NORD. 

Since 1983, the National Organization for Rare Disorders has served as the leading voice and 

advocate for the approximately 30 million men, women and children with rare diseases in the 

United States. NORD is a '501(c)(3)' nonprofit federation of voluntary health organizations 

dedicated to helping Americans with rare 'orphan' diseases and assisting the organizations that 

serve them. NORD is committed to the identification, treatment, and cure of'rare disorders 

through programs of education. advocacy. research. and service. 

NORD's mission is to foster a social, political. and financial culture of innovation that supports 

the basic and translational research necessary to develop new diagnostic tests and therapies for 

all rare disorders. This requires a regulatory environment that encourages the development of 

and timely approval of new safe and effective treatments for rare disorders. 

To that end, reauthorizing the Prescription Drug User Fee Act (PDUFA) presents an opportunity 

for Congress to achieve that goal. In particular, some of the resources generated by the user fee 

program should be allocated to support the enhancement of regulatory science, to create greater 

clarity and predictibility for the review of novel therapies for rare disorders, and to empower 

patients to fully participate in the regulatory decision-making process where questions of benefitrisk assessment arise. 

Of special significance in the draft agreement is the rare disease initiative that will enhance the 

development of drugs and biologics for the treatment ofrare conditions. NORD supports these 

1 
165 


76491.103

efforts and looks forward to the opportunity to work with the Agency and Congress to guarantee 

the success of this initiative. 

RARE DISEASE PROGRAM INITIATIVE 

The Food & Drug Administration (FDA) has facilitated a series of open meetings for patient 

stakeholders. providing a forum for input from patients and consumers regarding the human drug 

and biologic review programs. NORD has been active participant in this process. voicing the 

concerns and priorities of patients with rare diseases. 

Mr. Chairman. everyone within the rare disease community was heartened recently when the 

drug approvals summary for FY2011 was announced. Of the 35 innovative drugs approved by 

the FDA in FY20 II. 10 were orphan drugs that treat rare diseases with few or no treatment 

options I. We hope and expect that further investment in orphan products will lead to continued 

development of therapies that address thc unmet medical needs of patients with rare diseases. 

We are encouraged that the Orphan Drug Act has brought about such successfu I innovation in 

the market for rare disease therapies. The reality is that we have barely started on the journey. 

There are still approximately 6.800 rare diseases that lack an FDA approved therapy. The 

reauthorization of PDUFA offers hope that we may build on previous successes by strengthening 

the review process still further and by creating an environment that encourages innovation and 

investment. 

Particularly. we believe that the Rare Disease Program Initiative in the agreed upon PDUFA 

reauthorization performance goals will enhance the regulatory science needed to accelerate 

development of new therapies that treat rare diseases. This initiative allocates a small fraction of 

user fees for the expansion of the existing Rare Disease Program in the FDA's Center for Drug 

Evaluation and Research (COER). In brief, the agreement completes the current staffing and 

implementation plan for the COER Rare Disease Program in the Office of New Drugs. and 

establishes a rare disease liaison within the Office of the Center Director of the Center for 

Biologics Evaluation and Research (CBER). The patient community supports this initiative. 

A key ingredient to successful innovation is how FDA vicws drugs for rare diseases. Last 

October, NORD released a landmark study that looked at all drugs for diseases other than cancer 

approved as orphans since 1983 to identify whether and when FDA exercised flexibility in the 

review process. Of the 135 drug approvals studied. NORD concluded that the FDA 

demonstrated flexibility in the review of effectiveness data on orphan drug therapies for two of 

every three orphan drugs approved. FDA clearly has demonstrated in its actions on orphan 

products over the past three decades that it recognizes the importance of therapies for people 

1 See report, "FY2011lnnovative Drug Approvals," US FDA, 

http://www.fda.gov!AboutFDA!ReportsManualsForms!Reports!ucm276385.htm. 

2 
166 


76491.104

with rare disorders. (Several examples of flexibility in orphan product review are included in 

Appendix A). 

NORD believes it would be helpful for such tlexibility and importance to be recognized in a 

formal FDA policy, and for FDA officials to incorporate tlexibility in a systematic way in their 

evaluations of each new therapy in development and under FDA review for Americans with any 

rare disease. 

While NORD believes that the statutory standard for safely and efficacy should be the same for 

medical products for both rare disorders and prevalent diseases, enhancement of the Rare 

Disease Program will allow FDA to provide greater clarity in how it applies thC'standards for 

safety and effectiveness to orphan products. A formal policy setting forth the agency's view of 

flexibility in conducting orphan product review is likely to provide more certainty to innovators 

seeking to develop orphan products. 

Missing in the draft agreement is increased coordination between CDER and CBER and two other 

key FDA Centers. Although the regulatory schemes differ between CDER, CBER, CDRH and 

CFSAN, there are underlying themes of cOlllmonality geographically dispersed small patient 

populations and, of course, the challenges of trial design. Because humanitarian use devices and 

med ical foods for inborn errors of metabolism and other rare conditions arc equally critical to rare 

disease patients, increased collaboration and education of reviewers in CDER and CBER with CDRH 

and CFSAN is strongly supported by NORD. 

Further, we would like to see the proposed public meeting and staff training implementation dates in 

the PDUFA reauthorization performance goals moved forward, to occur no latcr than the end ofFY 

2013. 

Additionally, we think that the American public is served well by a strong FDA that continues to 

review safe and etTective therapies and approve them lor marketing in the United States first, 

faster than in Europe, (as dcmonstrated by a recent study of new oncology therapy approvals at 

the FDA and the European EMA\ Likewise, our own analysis comparing orpkan drug 

approvals over the last decade indicates that a total of 106 more orphan products have been 

brought to market in the United States compared to the European Union, (see Appendix B). 

PDlJFA V will provide FDA with the resources needed to maintain a strong professional staff 

that is necessary for the development of clear guidances and the expedited review of innovative 

drugs. 

ADVISORY COMMITTEES AND CONFLICT OF INTEREST 

During FDAAA negotiations, NORD argued that because patient populations are very smail, and 

the number of researchers who study a patiieular rare disease is limited, identifying experts not 

2 This study, by Friends of Cancer Research, indicates that a sizeable majority of new cancer therapies approved for 

marketing by both the US FDA and European EMA from 2003-2010 were approved by FDA first. 

3 
167 


76491.105

financially conflicted to sit on an Advisory Committee would be difficult, if not impossible. 

Those concerns were realized in 2008 when it took the FDA nearly six months to identify an 

expert to review a life-saving therapy to treat infantile spasms3 

To address those concerns, NORD has joined forces with over 50 organizations who are deeply 

concerned about the current conflicts-of-interest statutory provisions and their impact on the 

appointment of experts, particularly researchers and patients, as Special Government Employees 

on FDA Advisory Committees and as otherwise needed. As a group, the organizations promote 

efforts to bring bctter treatments and cures to those struggling with diseases. Many of these 

conditions have no adequate treatments and, therefore. it is imperative that we challenge hurdles 

that impede the quality and efficiency of the treatment development process. 

It is our belief that protections must be in place when persons are appointed to positions where 

their own financial interests might influence their service to the federal government. However, it 

is also our strong belief that the currcnt conflict-of-interest statutes that apply to the FDA have 

resulted in a system that is out of balance to the point that conflict avoidance is the primary 

driver of who serves on Advisory Committees, regardless of the extent of the con1lict, the 

uniqueness of their expertise, or the government's need for their services. 

As you know, FDA SGE's are subject to an additional layer of statutory conflict-of-interest 

provisions beyond those that already govern SGE's for all other departments and agencies in the 

executive branch. Specifically, under current law, the FDA must analyze potential committee 

members pursuant to Section 712 of the Food, Drug, & Cosmetic Act (FDCA), in addition to the 

government-wide provisions found in the Federal Advisory Committee Act and the Ethics in 

Government Act of 1978. This additional FDA-specific provision appears to drive the FDA to 

look only for individuals to serve as SGE's who have virtually no financial ties to any issue that 

might be addressed by a given Advisory Committee. 

While that may sound wise at first glance, in fact those with expertise in a given area often have 

foreseeable and unavoidable ties to the community as a result of their expertise. Yet, under the 

current structure, the FDA is not allowing those individuals to serve as SGE's, despite the fact 

that by doing so the FDA is being deprived of expertise by those who are best qualified. 

Accordingly, we support any effort to eliminate the additional conflicts of interest restrictions 

that apply only to the FDA'. 

Our view is that the existing provisions in the Federal Advisory Committee Act and the Ethics in 

Government Act of 1978 are adequate to safeguard against conflicts of interest, while still 

'The details of this delay are outlined in an article appearing in Pink Sheet Daily, August 27, 2008. See references. 

lillJ?ii:~)YJlf££:ill!l\!lh.!ilitJ!Q:>i!:J!hl.fu£ki!J:ill:!D'!:QliJill!=QITiQD='lll!'!!iU<=W":Allii:sm!ill:~}:£l!0;J!i5ill While FOCA 

do..::s give the fDA authority to Issue \vai\"ers conflicts of inter~st (with an annuall~ap on the number) it fr~quently 

selects lor SGE service those \vho need no waivers. o11cn meaning they have little direct invo!vement in an issue or a field. 

4 
168 


76491.106

allowing those with the necessary expertise and perspective to serve on these very important 

committees. In fact, the specific standard for SGE's found in 18 U.S.C. 208(b)(3) recognizes 

that potential SGE's may have conflicts-of-interest, but allows for their service nevertheless 

when the need for their services outweighs the potential for a conflict-of-interest created by the 

financial interest involved. 

That standard is clear, reasonable, and balanced and appropriately recognizes that some potential 

SGE's may come to the FDA with ties to the cOlllmunity that may pose some conflict-of-interest, 

but that the primary issue must be the government's need for their services. The main goal of 

these committees, after all, is to help the FDA to make the best decisions possible. The FDA can 

only do that if it has the best, most well-informed researchers. clinicians, and patients advising it. 

RISK TOLERANCE IN THE PATIENT COMMUNITY 

Early this year, NORD convened a meeting of/ike-minded members of the patient community to 

discuss the willingness or reluctance of patients and their families to tolerate a greater degree of 

risk in the use oftherapies to treat chronic and rare conditions. Our goal was to develop a 

proposal to be submitted to the FDA as to how the patient community can communicate on a 

more frequent and pcriodic basis with medical reviewers and other relevant FDA staff as they are 

making risk tolerance and other decisions regarding specific product applications or making 

policy decisions. 

The 32 organizations who signed the letter submitted to CDER on September 27, 2011 5

, are in 

full agreement that it is essential that patients have the 0ppoltunity to provide such input to 

product and policy decisions made by the FDA. patticularly with regard to risk tolerance 

associated with the use of specific products. Mechanisms currently exist for patients and other 

external audiences to provide input to the FDA e.g., at the public sessions of advisory 

committees - but the input does not necessarily occur at the time that risk tolerance and other 

critical issues are being deliberated, and docs not necessarily represent a broad spectrum of 

patient views. 

As the FDA commits to a more patient-centric posture, and as patients themselves become more 

knowledgeable and sophisticated about diseases and their treatmcnt options. we advocate that 

more systematic processes be established at FDA to enable contributions from the patient 

community at the time that critical decisions on risk tolerance are being madc, and from a 

representative sample of patient views. 

We believe the process should be well-defined and well-understood within the r.eview divisions, 

and provide a universally applied opportunity for patients to make such input. We are conscious 

that FDA reviewers and other relevant FDA staff have many demands on their time, but strongly 

5 A copy of the letter may be found on NORD's website: 

http://www.rarediseases.org/docs/policy/MullinRiskToleranceletter .. pdf 

5 
169 


76491.107

believe that a new process for input will improve product analysis and approval and access to 

necessary treatments in a timely manner. 

We recognize that risk tolerancc and other critical decisions are made at many points during the 

regulatory life cycle of a product - trom initial clinical trials through marketing.- However, at 

some points of the review process when risk assessments are made, patient contributions would 

be of value to the FDA decision-makers. 

We also rccognize that continuous interaction with the patient community is not feasible. At the 

same time, the patient community believes that specific milestone events should be designated at 

the times at which FDA, as a matter of policy, seeks formal input from the patient community. 

We do not seek to crcate a burdensome or time-consuming process. Rather, we want to be sure 

that paticnts across the country, whether they belong to a patient organization or not, have the 

opportunity to share their views with the FDA. 

Our hope and expectation is that the kinds of infomlation that patients and patient organizations 

can share with the FDA will contribute toward its decision-making in assessing the benefit-risk 

equation of new products as well as the amount of risk paticnts at various stages of their 

condition are willing to take. the quality-of-life challenges they face, the ways they receive 

information about the proper use of their therapies, how often they see and receive information 

from their physicians. and other information that FDA medical reviewers and other relevant FDA 

staff may benefit from knowing directly from patients. 

CLOSING 

In closing, I want to thank the Subcommittee again for giving NORD thc opportunity to testify 

today regarding the reauthorization of the Prescription Drug User Fee Act. The rare disease 

community believes that engaging Congress and FDA officials in thc process has, and will 

continue to lead to practical, detailed improvements to the regulatory process that will accelerate 

the development of orphan products- from concept to access. 

Thank you. 

Respectfully Submitted, 

Diane Edquist Donnan, Vice President 

National Organization for Rare Disorders 

1779 Massachusetts Avenue, NW. Suite 500 

Washington DC, 20036 

Office: (202) 588-5700 

ddorman(iiJrarediseases.org 

\,ww.rarediscascs.org 

6 
170 


76491.108

References 

I) Samantha A. Roberts, Jeff D. Allen, and Ellen V. Sigal. "Despite Criticism of the FDA 

Review Process, New Cancer Drugs Reach Patients Sooner in the United States Than in 

Europe." Health Affairs. July, 2011, 30: 1375-1381. 

2) Frank. 1. Sasinowski, "Quantum of Effectiveness Evidence in FDA's Approval of Orphan Drugs: 

Cataloguing FDA's Flexibility in Regulating Therapies for Persons with Rare Disorders:' II Oct. 

2011. Accessed 30 Jan. 2012. 

«htlp:llwww.rarediseases.org/docs/policv/NORDstudv()jTDAapprovulof(Jrphandrug.,.pdf» 

3) Kate Rawson and Michael McCaughan. "The Longest Review: Inside Ovation's Wait for 

Sabril." The Pink Sheel Daily. 27 Aug. 2008. Print. 

Appendix A 

Selected CDER Rare Disease Product Approvals from 2007 to 2012 

I. Voraxaze (glucapidase) - New Biologic 

On January 17,2012 FDA approved Voraxaze (glucarpidase) to treat patients with toxic levels of 

methotrexate in their blood due to kidney failure. 

Methotrexate is a commonly used cancer chemotherapy drug normally eliminated from the body 

by the kidneys. However, patients receiving high doses of methotrexate may develop kidney 

failure. Voraxaze is an enzyme that rapidly reduces methotrexate levels by breaking this 

chemotherapy drug down to smaller, inactive components that can be eliminated from the body 

by the liver. Voraxaze is administered as a single injection directly into a patient's vein 

(intravenously). Prior to approval ofVoraxaze, there were no effective therapies for treatment of 

toxic methotrexate levels in patients with renal failure. 

The effectiveness ofVoraxaze was established in 22 patients from a single clinical study, in 

which all patients received Voraxaze treatment (open-label. single-ann trial). Patients ranged in 

age from 5 to 84 years, and the most coml11on cancers being treated were a form of bone cancer 

(osteogenic sarcoma) and blood cancers (leukemia and lymphoma). The treatment was 

considered successful if the methotrexate level fell below a critical level within 15 minutes and 

stayed below the critical level for eight days. Ten of the 22 patients achieved this standard. 

Although not all patients experienced this result, Voraxaze reduced methotrexate levels by more 

than 95 percent in all patients. 

Voraxaze was given a priority review by FDA. which is a shortened review time of6 months for 

drugs that may offer major advances in treatment or that provide a treatment when no adequate 

therapy exists, instead of the standard review time of 10 months for other drugs, FDA exercised 

regulatory flexibility in evaluating efficacy based on rapid and sustained clearance oftoxie 

methotrexate blood levels, a novel endpoint for drug approval. The use of this endpoint in a 

selected patient population allowed efficacy to be demonstrated in a single arm study. 

7 
171 


76491.109

2. Erwinaze (asparaginase) - New Biologic 

On November 18,2011 FDA approved Erwinaze (asparaginase) to treat patients with a form of 

blood cancer. acute lymphoblastic leukemia (ALL). Erwinaze is a component of multi-agent 

chemotherapeutic regimens for the treatment of ALL. 

ALL is a malignancy arising in the bone marrow. and most commonly affects children. 

Epidemiologic data from 2004-2008 show that the median age at diagnosis for ALL was 13 

years of age, and 60% of newly diagnosed patients are under age 20. 

The efTectiveness of Erwinaze was established in one trial in 58 patients, in which all patients 

received Erwinaze treatment (open-label, single-arm trial). All patients were enrolled in NCIsponsored cooperative group trials conducted by the Children's Oncology Group. Patients in the 

study ranged in age from 2 to 18 years (median 10 years). The main outcome measure in the 

trial was the level of asparaginase activity in serum, an accepted surrogate measure for clinical 

benefit, which supported a full approval for Erwinaze. 

3. Zclboraf (vemurafcnib) - New Molecular Entity (NME) 

On August 17,20 II FDA approved Zelboraf (vemurafenib) to treat patients with metastatic 

melanoma that has a specific abnormality of a gene know as BRAF. It also required 

coordination with CDRH on the simultaneous approval ora diagnostic tcst for the gene 

abnormality, which was the first-ever approval by FDA of a drug + a "companion diagnostic". 

Zelborafs effectiveness and safety were established in one Phase 3 randomized. open-label (not 

blinded to treatment) trial and one Phase 2 open-label, single-arm trial. In the Phase 3 trial, 

patients were randomized to Zelboraf or treatment with the chemotherapeutic agent dacarbazinc. 

The results showed an increase in median overall survival (OS) and progression-free survival in 

patients treated with Zelborafvs. dacarbazine. and an overall response rate of 48% in the 

Zelboraf group vs. 6% in the dacarbazine group. 

Due to the results of these studies showing a significant benefit in overall survival in patients 

with melanoma with the BRAF mutation. Zelborafwas given a priority review: In addition, 

because of the paucity of effective therapies for patients with this disease, this application was 

given an expedited review and approved by FDA more than 2 months ahead of the PDUFA 

priority rev iew goal date. 

This application is also notable in that FDA became aware of preliminary results in the sponsor's 

Phase 2 study as well as published results of the Phase I study with Zelborafthat showed 

impressive objective response rates of>50% in this patient population. In published literature 

reports of patients with metastatic melanoma treated with a variety of chemotherapy agents, 

objective response rates ranged from II % to 24%. Given these notewOlihy rcsults with 

Zelboraf, FDA proactively communicated with the applicant to modify the statistical plan for the 

Phase 3 trial, adapting the impressive observed activity of Zelboraf in the Phase I and 2 studies. 

With this adaptation, the applicant was able to successfully conduct the analysis early in a 

planned manner with the timely adaptation of the clinical trial. 

8 
172 


76491.110

4. Carbaglu (carglumic acid) - New Molecular Entity (NME) 

On March 18,20 I 0 FDA approved Carbaglu (carglumic acid) for the treatment of NAGS 

deficiency, a rare, serious inherited disorder. Less than 20 patients in the US are known to have 

NAGS deticiency. 

NAGS deficiency is onc ofa group of diseases known as urea cycle disorders. Urea cycle 

disorders most commonly present in infancy and early childhood. The urea cycle is responsible 

for removing ammonia from the blood stream. Ammonia is toxic, and high levels in the blood 

can cause brain damage and death .. NAGS is a required cofactor which combines with an 

enzyme in the first step in the urea cycle, and a deticiency in NAGS results in severe impairment 

in the urea cycle. Carbaglu is a closely related drug to the naturally occurring NAGS, and acts as 

a replacement for the deficient cofactor. 

Carbaglu's effectiveness and safety were dcmonstrated in a retrospective case series in which the 

clinical course of23 patients with NAGS deficiency who were treated with Carbaglu for a 

median of 8 years (range 0.6 months to 21 years) was evaluated. Patients included in the 

analysis started Carbaglu treatment at ages ranging trom less than 1 year to 13 years. This 

retrospective analysis was unblinded and had no concurrent control group, so no meaningful 

statistical analysis could be performed. The results showed stable or favorable neurological 

outcomes in most patients over time, which was notable when compared to historical 

descriptions of the clinical course of the disease ("historical control"). In 13 of the 23 patients, 

laboratory data on blood ammonia levels was available. which showed decreases in ammonia 

levels in both short-term (1 day) and long-term (median 6 years) follow-up. 

Carbaglu was given a priority review of 6 months. Although non-specific treatments for urea 

cycles have been available for many years in the US, prior to the approval of Carbaglu, no 

targeted and specific treatment was approved for NAGS deficiency. Carbaglu represented an 

advance in treatment for NAGS ddiciency patients. 

5. Arcalyst (rilonaccpt) - New Biologic 

On February 27, 2008 FDA approved Arcalyst (rilonacept) for the treatment of cryopryinassociated periodic syndromes (CAPS). a group of rare inheritcd disorders affecting 

approximately 200-300 patients in the US. 

CAPS is a deficiency in a protein "cryopyrin", which is part of the innate immune response. 

Deticiency in cryopyrin results the body's over-production of another protein, IL-I, which leads 

to the development of recurrent rashes, fever and chills, joint pain and other symptoms. In 

scvere forms. it can lead severe organ damage, sllch as deafness, protein aecumu lation in vital 

organs, joint and bone deformities, and nervolls system impairment. Depending on disease type, 

CAPS can manifest in neonates, children or adults. Arcalyst is a protein product, which was 

developed to interfere with IL-1. and hence, to decrease the signs and symptoms of the disease. 

Arcalysfs safety and effectivencss profiles were described in one randomized, double-blind, 

placebo-controlled trial in 47 patients. The effectiveness of Arcalyst was evaluated using a daily 

symptom qucstionnaire, which was a novel endpoint developed for this study with the drug 

developer and FDA working in collaboration. 

9 
173 


76491.111

Arcalyst was given a priority review. Prior to the approval of Arcalyst, there were no targeted 

products approved for the treatment of CAPS, and Arcalyst represented an advance in the 

treatment of this disorder. 

6. Soliris (eculizumab) - New Biologic 

On March 16,2007, FDA approved Soliris (eculizumab) for the treatment of paroxysmal 

nocturnal hemoglobinuria (PNH), a rare, serious, acquired disorder estimated to affect several 

thousand people (or fewer) in the US. 

PNH is a deficiency in a blood component "terminal complement inhibitor", which results in an 

over-activation of other proteins in the complement system. This over-activation leads to the 

breaking apart of red blood cells in the blood stream (hemolysis). Hemolysis can lead to blood 

clots, abdominal pain and other signs and symptoms. The formation of blood clots is the most 

serious manifestation of the disease and can lead to death and severe complications, such as 

stroke or liver failurc. Soliris is a monoclonal antibody, which was developed to specifically 

target the over-activation of one protein in the complement system (C5). Sol iris' mechanism of 

action is intended to result in less hemolysis and longer red blood cell survivaL 

Soliris' safety and effectiveness were demonstrated in one randomized, double-blind. placebocontrolled trial in 87 patients, with supporting evidence provided by a second, open-label study 

in which 97 patients all received treatment with Soliris. Soliris' effectiveness was assessed in the 

first study by changes in laboratory values, including stabilization in measures of red blood cells 

(e.g .. hemoglobin) and whether blood transfusion could be avoided. These endpoints were 

significantly improved with treatment with Soliris. 

Sol iris was given a priority review. Prior to the approval of Soliris, there were no targeted 

products approved for the treatment of PNH, and Soliris represents an advance in the treatment 

of this disorder. 

10 
174 


76491.112

Appendix B 

Year EU Orphan US Orphan 

Marketing Drug 

Authoriziations Approvals 

2001 8 6 

2002 7 14 

2003 4 12 

2004 6 13 

2005 3 20 

2006 8 23 

2007 15 16 

2008 6 14 

2009 8 20 

2010 4 15 

2011 4 26 

TOTAL 73 179 

These data taken from publically available database access, FDA & EMA, 27 Jan. 2012. 

11 
175 

Mr. PITTS. The chair thanks the gentlelady and recognizes Dr. 

Frattarelli for 5 minutes for an opening statement. 

STATEMENT OF DANIEL A.C. FRATTARELLI 

Mr. FRATTARELLI. Thank you. Mr. Chairman, members of the 

subcommittee, my name is Dr. Daniel Frattarelli. I am a practicing 

pediatrician and Chair of Pediatrics at Oakwood Hospital in beautiful Dearborn, Michigan. I am here today representing the American Academy of Pediatrics in my official capacity as Chair of the 

AAP’s Committee on Drugs. 

The testimony I give you today is supported and endorsed by the 

Elizabeth Glazer Pediatric AIDS Foundation, and I am here today 

to discuss the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, and I would like to begin just by amplifying something that Dr. Wheadon said. When we are looking at 

BPCA and PREA, we can really say unequivocally that these two 

laws have added more pediatric-specific information to the labels of 

drugs and biologics than we have been able to in the 70 years prior 

to their enactment, and it is vitally important for infants, children 

and adolescents that these laws be reauthorized. 

I wish to extend the academy’s sincerest thanks to Representative Anna Eshoo for her longstanding support and for championing 

these important laws for children, and although not the subject of 

today’s hearing, the academy also wishes to acknowledge and 

thank Representatives Mike Rogers and Ed Markey, who together 

authored the Pediatric Medical Device Safety and Improvement Act 

of 2007. 

Now, as a pediatrician, I see firsthand the need for all children 

to have medicines that are studied for their use, and thankfully, we 

have gone from a time back when I trained when about 80 percent 

of the drugs that we used didn’t have any specific pediatric labeling, to today, where that number is down to about 50 percent, and 

this success is a direct result of BPCA and PREA. Since 1997, 426 

labels have been updated with new pediatric information, and in 

many cases, studies have altered the dosages or formulation we 

give our patients, and in others, drugs that were previously 

thought to be safe or effective in children have proved not to be. 

The 2007 reauthorization led to several improvements in the 

function of these laws. All BPCA and PREA studies now result in 

label changes, and the number of times companies have declined 

BPCA studies has gone down tremendously while the number of 

products studied under BPCA and PREA has gone up, and the consistency and quality of pediatric studies has improved significantly, 

largely through the hard work of the FDA’s internal pediatric review committee. 

Based on what we have learned about these laws since 1997, the 

academy offers five recommendations for improvements to BPCA 

and PREA in 2012. The first of these is to do pediatric study plans 

earlier. Now, PREA is a premarket requirement for safety and effectiveness. However, the law does not require the submission of a 

plan for pediatric studies until a company submits its drug application to the FDA. Submission of this plan so late in the process can 

lead to insufficient planning and potentially avoidable delays in 

getting important pediatric data. The AAP therefore recommends 

176 

amending PREA to require the submission of a pediatric study plan 

by the end of phase II. 

The second recommendation is to improve accountability. We 

heard this already also that 78 percent of PREA studies due after 

September 27, 2007, are currently late or were completed late. 

While many of these studies might be delayed for good reason such 

as difficulty recruiting patients, FDA’s publicly available data do 

not distinguish between the reasonable and the unreasonable 

delays. We feel the FDA should have the authority to grant extensions when there is a good cause, but in cases where there isn’t a 

good cause, FDA should have added enforcement tools comparable 

to those it has for postmarketing commitments involving adults. 

Third recommendation is to promote studies in younger age 

groups. Now, the neonatologists, the people who take care of babies 

from birth to age one month, report that almost 90 percent of the 

drugs that they use routinely have never been labeled for this population, and neonatal drug research faces some unique hurdles. 

The AAP believes that the FDA should be required to ensure that 

BPCA and PREA written requests includes neonates whenever possible, and if they are not, explain the rationale why. PREA should 

be triggered when a company decides to expand to a new age group 

so that pediatricians will have data for an age group that is as 

young as the FDA determines necessary. The GAO also identified 

a lack of neonatal expertise at the FDA, and we feel that a dedicated neonatologists added at FDA would assist in reviewing divisions in thinking through these neonatal drug studies. 

Fourth recommendation is to increase transparency. As we 

learned in the 2007 amendments, increased transparency benefits 

policymakers and researchers. Building on this, the AAP also recommends that new written requests under BPCA be made public 

at the time they are accepted or declined. 

And our fifth recommendation is to make PREA permanent. We 

call upon Congress to make PREA permanent in 2012. The FDA 

currently has permanent authority to ensure the safety and efficacy of drugs used in adults, and children deserve the same. As 

part of this legislation, Congress should also reauthorize the important program at the National Institutes of Health to fund the study 

of older drugs no longer subject to BPCA and PREA. 

I would like to thank the committee again for allowing me the 

opportunity to share with you the strong support of the American 

Academy of Pediatrics for the reauthorization of BPCA and PREA, 

and would be happy to answer any questions that you have. 

[The prepared statement of Mr. Frattarelli follows:] 

177 


76491.113

Testimony of 

Daniel A.C. Frattarelli MD FAAP 

On behalf of the 

American Academy of Pediatrics 

Before the 

Energy and Commerce Committee 

Health Subcommittee 

February 1, 2012 

American Academy 

of Pediatrics 

j)FDlCATED TO HEALTH OF ,\LL CHIL])REN" 

American Academy of Pediatrics • Department of Federal Affairs 

601 13th Street NW, Suite 400 North • Washington, DC 20005 

Tel: 800.336.5475 • E-mail: kids1st@aap.org 
178 


76491.114

Daniel A.C. Frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

Mr. Chairman, members of the subcommittee, I am Daniel Frattarelli MD FAAP, a practicing 

pediatrician and Chair of Pediatrics at Oakwood Hospital and Medical Center in Dearborn, MI. 

am here today representing the American Academy of Pediatrics (AAP) in my official capacity as 

chair of the AAP Committee on Drugs. The AAP is a non-profit professional organization of 

62,000 primary care pediatricians, pediatric medical subspecialists, and pediatric surgical 

specialists dedicated to the health, safety, and well-being of infants, children, adolescents, and 

young adults. As a pediatrician, I see first-hand the need for all children to have medicines that 

are studied for their use and are in dosage forms that are made for their size and stages of 

development. 

The testimony I give today is supported and endorsed by the Elizabeth Glaser Pediatric AIDS 

Foundation. More than two decades ago, Elizabeth Glaser began lobbying the halls of Congress 

to call for more research for drugs to treat HIV/AIDS in children. The Elizabeth Glaser Pediatric 

AIDS Foundation carries on her work today, advocating for children in the U.S. and around the 

world to have access to the best prevention and care that science and medicine have to offer. 

THE ACCOMPLISHMENTS OF BPCA AND PREA 

I am here today on behalf of the AAP to discuss the Best Pharmaceuticals for Children Act 

(BPCA) and the Pediatric Research Equity Act (PREA), which represent critical public policy 

successes for children. I thank this subcommittee and full committee for its strong support of 

these programs throughout the years. I begin my testimony today by saying enthuSiastically 

and without reservation that through BPCA and PREA we have gained more useful information 

on drugs and biologics used in children than we had in the seventy years prior to their 

enactment. 

I wish to extend the Academy's sincerest thanks to Representative Anna Eshoo for her longstanding support and for championing these important laws for children. Although not the 

subject of today's hearing the Academy also wishes to acknowledge and thank Representatives 

Mike Rogers and Ed Markey who authored the Pediatric Medical Device Safety and 

Improvement Act of 2007. The Academy sees these three laws as a complementary package of 

vital pediatric drug and device laws and all three should be reauthorized together this year. We 

also recognize Senators Jack Reed and Patty Murray for their outstanding leadership in 

championing these laws in the Senate. 

BPCA and PREA have advanced medical therapies for infants, children, and adolescents by 

generating substantial new information on the safety and efficacy of pediatric pharmaceuticals 

where previously there was little. It is vitally important for these pediatric subpopulations that 

these laws be reauthorized. 

Page 2 of 9 
179 


76491.115

Daniel A.C. FraUarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

In a 1977 landmark statement, the AAP's Committee on Drugs, which I now have the privilege 

of chairing, said that it is unethical to adhere to a system which forces physicians to use 

therapeutic agents in an uncontrolled experimental situation virtually every time they prescribe 

for children. The Committee also said that it is not only ethical, but also imperative that new 

drugs to be used in children be studied in children under controlled circumstances so the 

benefits of therapeutic advances will become available to all who need them. 

In the time since that statement was published, we have gone from a situation where about 

eighty percent of time, the drugs we were using in children did not have FDA-approved 

pediatric labeling to today where that number is down to about fifty percent. That success is a 

direct result of BPCA and PREA. However, because half of drugs used in children still lack 

pediatric labeling, off-label use remains an unfortunate but necessary practice. As Congress 

considers legislation related to prescription drugs, such as drug shortages, the Academy asks 

policymakers to ensure that off-label uses of therapeutic agents be part of the discussion since 

it is the standard of care for our patient population. 

BPCA and PREA work together as an effective two-pronged approach to generate pediatric 

studies. BPCA provides a voluntary incentive to drug manufacturers of an additional six months 

of marketing exclusivity for conducting pediatric studies of drugs that the FDA determines may 

be useful to children. PREA provides FDA the authority to require pediatric studies of drugs 

when their use in children is for the same indication as for adults. 

BPCA was first enacted in 1997 and later reauthorized by Congress in 2002. PREA was passed in 

2003 and reauthorized together with BPCA for the first time in 2007, creating a unified 

approach to pediatric drug testing and labeling at the FDA. In 2010, Congress extended BPCA to 

biologics for the first time. Since 1997,426 drug labels have been updated with pediatric 

information including 147 under BPCA, 181 under PREA, 50 under both BPCA and PREA, and 48 

under the precursor to PREA, the Pediatric Rule. 

As a clinician, I cannot overstate the importance of what we've learned through the pediatric 

studies generated by these laws. Pediatric studies conducted under BPCA and'PREA challenged 

what was previously thought about therapeutics in children. In many cases, studies and 

resultant labeling altered the dosages we give our patients. In others, drugs previously thought 

to be safe and effective in children proved not to be. And, pediatric studies have led to more 

effective formulations that are more palatable for children. To put it simply, the more we learn, 

the more we realize what we didn't know. 

Page 3 of 9 
180 


76491.116

Daniel A.C. Frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

CHANGES TO BPCA AND PREA IN 2007 MAKING AN IMPORTANT IMPACT 

In 2007, BPCA and PREA were reauthorized for the first time together. Congress took advantage 

of that historic opportunity and created the most integrated, well-coordinated system at FDA to 

pursue pediatric safety and efficacy labeling that we have seen to date. 

In 2007, the AAP argued that every drug label should reflect when a pediatric study was done 

(either through BPCA or PREA) and the results of the study, whether the results are positive, 

negative, or inconclusive. Prior to 2007, there were studies in which families chose to enroll 

their children for which resultant data does not appear in a products label. I am proud to 

report that based on data from the Government Accountability Office (GAO), all pediatric 

studies completed under BPCA and PREA from 2007 until 2010 resulted in labeling changes that 

included important pediatric information. 

Since the 2007 reauthorization, the number of drugs and biologics studied in children rose 

dramatically: 130 products between 2007 and 2010, compared with 250 products between 

1997 and 2007. The incentive under BPCA is well-targeted and is increasingly more popular 

over time. According to GAO, the number of declined pediatric studies under BPCA fell from 

19% between 2002 and 2005 to 5% between 2007 and 2010. Drugs and biological products 

studied under BPCA and PREA represent a wide range of diseases in children, including those 

that are common or life-threatening such as cancer, HIV/AIDS, diabetes, allergy and asthma. 

The 2007 reauthorization of PREA established the Pediatric Review Committee (PeRC), an 

internal FDA committee that is providing assistance in the review of pediatric study results and 

increasing the consistency and quality of such reviews across the agency. The PeRC has played 

a vital role in helping to better integrate BPCA and PREA and pediatrics generally within FDA 

and should continue to be supported and strengthened. 

BUILDING ON WHAT WE'VE LEARNED FOR FUTURE IMPROVEMENTS 

With each reauthorization of BPCA and PREA, we have learned how truly essential it is for 

children that these laws exist and evolve. Congress has made changes to these programs that 

have monumentally improved how they function. Based on what we've learned about these 

laws since 1997, the Academy offers several recommendations for improvements to BPCA and 

PREA in 2012. 

Page 4 of 9 
181 


76491.117

Remove barriers to earlier pediatric studies 

Daniel A.C. Frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

PREA is a premarket requirement for safety and effectiveness. However, the law does not 

require the submission of a plan for pediatric studies until the time a company.submits its 

application or supplement, which is at the end of the adult drug development process. The 

precursor to PREA, the Pediatric Rule, required that drug companies discuss and plan for 

pediatric studies no later than the end of phase 2. The laws of the European Union require the 

submission of a pediatric investigational plan at end of phase 1. It is important to remember 

that under PREA, failure to submit a pediatric plan at the time of the submission of a drug 

application cannot delay the approval of the drug in adults. 

Submission of a pediatric plan so late in the process can lead to insufficient and inappropriate 

study plans and delays of important pediatric data. Pediatricians and families will get better 

quality pediatric data if discussions with FDA's PeRC happen earlier in the drug development 

process. And, by giving companies more time to work with FDA on a realistic pediatric plan, we 

will reduce the need to rely on deferrals, too many of which are well past their agreed-upon 

due date. 

In the PREA retrospective review required by Congress in the 2007 reauthorization, FDA found 

that with 17 review divisions within the Center for Drug Evaluation and Research (CDER) and 

few or no pediatricians in some divisions, "approaches in the implementation of PREA, 

including the level of detail in reviewing pediatric protocol plans, were quite variable." FDA said 

that many of the pediatric postmarketing requirements listed in the approval letters were 

described in general terms in "one to three sentences". 

FDA found that in cases where PREA studies did not demonstrate efficacy, it is possible that the 

process could have benefitted from a more detailed pediatric plan being submitted by the 

applicant before approval. FDA went on to say, "where there was evidence of specific 

discussion and documentation of the studies needed to fulfill PREA requirements before 

commencement and/or submission of the studies, the PREA assessments generally were of 

higher quality." 

AAP recommends amending PREA to require the submission of a proposed pediatric study plan 

at the end of phase 2 that includes a description of the study objectives, age groups, study 

design, relevant endpoints, statistical approach, and timeline for expected completion of the 

study. Within a reasonable timeframe, the PeRC should approve or reject the proposed 

pediatric study plan. 

Page 5 of 9 
182 


76491.118

Improve accountability 

Daniel A.C. Frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

Based on the data available today from FDA, within CDER, 78% of PREA studies that were due 

after September 27,2007 are still pending today or were completed after their agreed-upon 

due date. Within CBER, 54% of PREA studies that were due after September 27, 2007 are still 

pending today or were completed after their agreed-upon due date, including several 

childhood and flu vaccines. These numbers only include studies that were deferred after 

September 27,2007 and do not include studies that were deferred prior to 2007. 

Under current law, FDA is prohibited from delaying the approval of a drug or biologic in adults 

even if the applicant or sponsor has failed to comply with its PREA requirement. AAP supports 

the principle that adults should not be denied access to effective therapies while studies in 

children are underway. However, it cannot be the case that delays in studies become 

permanent once a drug is approved for marketing. Once a product is approved, FDA treats 

PREA requirements as post-marketing requirements. PREA prohibits FDA from using any 

existing enforcement mechanisms under section 303 of Federal Food, Drug and Cosmetic Act 

even though those enforcement mechanisms explicitly pertain to post-marketing requirements 

that involve adult populations. While we hope enforcement action would never have to be 

taken, FDA should have enforcement tools for children comparable to those for post-market 

requirements in adults to ensure that pediatric data is gathered as soon as possible. Congress 

may also want to consider whether the benefits of BPCA's market exclusivity remain available 

for companies who are ignore their PREA requirements or have not worked with FDA to 

establish a new completion date and other necessary amendments for their studies. 

There are reasons why pediatric studies might take longer than anticipated. For instance, 

companies may encounter problems with patient enrollment. However, FDA currently does not 

distinguish between delays that are for good, justifiable cause and those that are not. The AAP 

recommends giving FDA the authority to grant deferral extensions when there is good cause. 

Promote studies in younger age groups 

Premature babies and babies born with congenital or genetic conditions routinely require 

numerous drugs and other medical interventions to survive their first days, weeks and months. 

AAP's neonatologists report that almost 90% of the agents that are routinely administered to 

neonates (babies from birth to age 1 month) have never been adequately studied for safety, 

dosing, or efficacy in this unique population. As such, these tiny children, remain second-class 

citizens when it comes to drug safety and efficacy information. While neonatal drug research 

faces many barriers that are scientific and ethical, GAO and other experts have identified that 

greater neonatology expertise at the FDA would aid drug development for this population. AAP 

recommends that a dedicated neonatologist be added to FDA's Office of Pediatric Therapeutics. 

AAP also believes that FDA should be required to ensure that BPCA written requests include 

Page 6 019 
183 


76491.119

Daniel A.C..frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

neonates wherever possible and if they are not included, the written request should include a 

statement describing the rationale why. Lastly, PREA requirements are triggered when an 

applicant submits an application for a new active ingredient, new indication, new dosage form, 

new dosing regimen, or new route of administration. We believe new age group should be 

added to this list so that pediatriCians would have data for as young an age group as the FDA 

determines necessary. 

Increase transparency 

As we learned in the 2007 amendments, increased transparency benefits policymakers, 

families, researchers and other stakeholders. Currently, pediatric researchers cannot access 

information on what drugs are currently being studied under BPCA and cannot access written 

requests and the corresponding medical, statistical, and clinical pharmacology reviews for drug 

studies completed under BPCA prior to 2007. In some cases prior to 2007 where a company 

was awarded 6 months of exclusivity for conducting pediatric studies, the labeling does not 

reflect the results of those studies. The reviews of those studies should be made available to 

the public just like they have been for studies conducted after 2007. 

AAP also recommends that BPCA written requests be made public at the time they are 

accepted or declined rather than at the time exclusivity is granted. At present, BPCA study 

requests that are declined by drug companies are never made public. Declined BPCA study 

requests represent an important gap in pediatric data and companies should have the 

opportunity to state their reasons for declining the study request. 

Make PREA permanent 

The AAP commends the House of Representatives for making PREA permanent as part of the 

FDA reform bill it passed in 2007 and we call upon Congress to make PREA permanent in 2012. 

The FDA currently has the permanent authority to ensure the safety of drugs used in adults. 

Children deserve the same. Congress need not debate every few years whether we should 

continue to require safety and efficacy information on drugs used in children. It is useful, 

however, to reevaluate the exclusivity program periodically to ensure that the incentive offered 

achieves its desired goal despite changes in the dynamic pharmaceuticals market. Congress 

should have the opportunity through a 5-year sunset to analyze whether BPCA continues to 

strike the right balance between achieving critical pediatric information and providing an 

appropriate incentive to maintain the number and quality of pediatriC studies for on-patent 

drugs. 

Page 7 019 
184 


76491.120

Continue promising pediatric study program at NICHD 

Daniel A.C. Frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

BPCA and PREA work well for new drugs and other on-patent drugs for which additional market 

exclusivity provides an incentive. However, some of the most commonly-used drugs in children 

are off-patent and beyond the traditional reach of these programs. To address this need, BPCA 

tasked the National Institute for Child Health and Human Development (NICHD) and the 

National Institutes of Health (NIH) with creating a priority list of pediatric therapeutic needs in 

off-patent products and conducting those needed studies. NICHD's program has grown into a 

promising effort to increase pediatric labeling, with more than a dozen clinical trials completed 

or ongoing and dozens more awaiting funding to initiate the trials. AAP recommends that 

NICHD's program continue and be reauthorized without changes at its fiscal year 2008 

authorized level of $200 million. 

By contrast, the Foundation for the National Institutes of Health (FNIH) which is given authority 

to collect donations from pharmaceutical companies to fund declined BPCA studies has 

collected no such donations to enable it to complete any BPCA studies in the history of its 

involvement with BPCA studies. Therefore, its mandate to conduct pediatric studies of onpatent drugs only serves as a barrier to NICHD conducting those studies and, as such, should be 

eliminated. However, the Academy recommends retaining the legal authority of FNIH to 

maintain an emphasis on children and raise money for important pediatric needs, such as 

training pediatric clinical investigators, building pediatric research networks, and studying 

pediatric disease mechanisms. 

CHILDHOOD CANCER AND OTHER RARE DISEASES 

Experts in pediatric oncology have suggested that PREA would better serve the needs of 

children with cancer if it was allowed to require the study of a drug in children even if it is 

intended to treat a cancer-like lung cancer-that does not occur in children. The AAP believes 

this idea has merit and deserves serious consideration by Congress. 

The AAP also underscores the importance of the Orphan Drug Act in stimulating drug 

development for populations with rare diseases, half of which are children. Families with 

children facing these devastating diseases require the special consideration the Orphan Drug 

Act, BPCA and PREA provide. 

Page 8 of9 
185 


76491.121

CONCLUSION 

Daniel A.C. Frattarelli, MD FAAP 

American Academy of Pediatrics 

Energy and Commerce Health Subcommittee 

February 1, 2012 

I would like to thank the subcommittee again for allowing me the opportunity to share with you 

the strong support of the American Academy of Pediatrics for reauthorization of BPCA and 

PREA. For the health and well-being of all children, we urge their renewal, as well as the 

renewal of the Pediatric Medical Device Safety and Improvement Act, as part of the package of 

FDA bills under consideration by the subcommittee. 

I would be happy to answer any question you may have. 

Page 9 of 9 
186 

Mr. PITTS. The chair thanks the gentleman, and I will now begin 

questioning and recognize myself for 5 minutes for that purpose. 

Mr. Germano, will you explain how the PDUFA agreement will 

help improve predictability and transparency of the drug review 

process, why this is important to American patients and jobs? 

Mr. GERMANO. I think that the measure that I spoke of in my 

testimony was a measure that is particularly important. The 

PDUFA provisions allow for a review process that has a number 

of important enhancements. Most notably, as the number of interactions that now would be mandatory for communication and 

transparency between the agency and the sponsor companies, I 

think very often issues that arise during the review process are not 

clearly understood or not consistently understood between the 

agency and the sponsor company, and I think that this enhanced 

level of communication and transparency is likely to result in a 

greater level of understanding and issue resolution and consistency 

in the review process leading to, you know, review times that likely 

could be shortened, and, you know, a clarity on expectations between the two parties. If we can get through the process more efficiently, we can bring new products to the market more quickly and 

benefit patients, and it is good all around for the FDA, for the company and for physicians and patients who need our medicines. 

Mr. PITTS. Thank you. 

I will just down the line. Dr. Gollaher, in your testimony you 

make a connection between differences in FDA review times across 

therapeutic areas and how that affects development decisions by 

investors and companies, and can you speak to that issue a little 

further? You also mentioned the adage that you can’t manage what 

you don’t measure, and PDUFA has long required the agency to report on numerous performance measurements. You suggest that 

performance would benefit from some more granular reporting at 

the review division level. Can you elaborate on that? 

Mr. GOLLAHER. Sure. I think those two are related. Investors in 

large companies like Pfizer but even more venture capitalists who 

are looking at funding new ventures consider the time to market 

for their inventions, for their investments, and as we have seen, for 

example, in diabetes and in cardiovascular, venture investment has 

almost completely dried up because the time for review and the 

cost of clinical studies is so great. So the FDA exists in an ecosystem. It exists in a market in which it sends signals about its 

standards, about times and so forth, and those signals are extraordinarily important for the amount of investment that flows into 

new inventions and innovative products. 

On the data question, you know, we just heard the Commissioner 

talking about moving to electronic submissions and basically taking 

the FDA from the analog era that it has inhabited to the digital 

age, and that is really important, but at bottom, FDA is really a 

data management agency. I mean, it collects data from industry, it 

analyzes the data and makes decisions. The opportunity for a better assessment of some of the metrics that people have been talking about, for example, transparency, communication and so forth, 

and how the agency is performing against those can be measured 

and I think should be part of the ongoing assessment of agency 

performance. 

187 

Mr. PITTS. Thank you. 

Mr. Germano, you had mentioned in your testimony that one of 

your vaccines got approved through the accelerated approval pathway. Can you give us background on the importance of the accelerated approval pathway, why it is important to get the vaccine to 

patients as soon as possible? 

Mr. GERMANO. Yes. Just last December, our vaccine Prevnar 13 

was approved for prevention of pneumococcal disease in individuals 

50 years of age and older under this accelerated review process, 

and the accelerated review process is a measure that the FDA can 

use when they deem a medicine or, in this case, a vaccine to be appropriate to satisfy a significant unmet medical need for a serious 

disease or a serious condition, and in this case, just to give you 

some understanding of the seriousness of pneumococcal disease, 

pneumococcal pneumonia accounts for over 300,000 hospitalizations 

a year in the United States and over 25,000 deaths, so it is a very 

significant disease state and a high burden of both disease and 

high burden of cost for society. So the FDA utilized the accelerated 

review process to review and approve this medicine and now really 

that there is only one other hurdle to get through to bring this vaccine to patients or to society really and that is a CDC recommendation for usage, and we are hopeful that we will get a CDC recommendation later this month when their advisory council on immunization practices meets, and then we will be able to bring the 

vaccine to the American public. 

Mr. PITTS. Thank you. 

I think we are going to have to do a second round. My time is 

up. I will recognize the ranking member, Mr. Pallone, for 5 minutes 

for questions. 

Mr. PALLONE. Thank you, Mr. Chairman. 

I wanted to ask this question, I guess of Mr. Germano and I 

guess Mr. Pops and Dr. Wheadon, the three of you could answer. 

We heard from Dr. Hamburg this morning that the FDA rarely, if 

ever, meets the waiver caps related to the number of persons with 

a conflict of interest that can serve on an FDA advisory panel. At 

the same time, we know there are concerns from the public about 

FDA panelists having conflicts of interest related to the issues they 

are reviewing. About 3 weeks ago, the Wall Street Journal published an article highlighting the conflict of interest three panelists 

had one panel had in relation to a product they were reviewing. 

You know, I know it is a concern, I mean, we are concerned because we want to have the best experts possible on the panels but 

we need to help the FDA get such experts and get them in a timely 

manner. 

But I am having difficulty seeing how removing the waiver caps 

will solve anything when FDA is not meeting these caps, and my 

question is, given that the waiver caps are not routinely reached, 

can you explain how removing the caps would improve the current 

situation, if you believe it would, and are there any other fixes you 

would suggest in addition to or instead of removing the waiver 

caps? Let us start with Mr. Germano. 

Mr. GERMANO. OK. I will start. And I think this is a particularly 

important area for Pfizer. As I mentioned in my testimony, we are 

focused on bringing new medicines in the rare disease and orphan 

188 

disease area, and this is an area where oftentimes there are a 

small number of highly expert opinion leaders and physicians. 

Mr. PALLONE. I don’t have a lot of time, so what do you think? 

I mean, should we be removing them? 

Mr. GERMANO. Well, I think that we—you know, our view is that 

there is a need to improve the process of the advisory committees, 

particularly in areas where there is a paucity of experts, and I 

don’t know if it is additional waivers or better utilization of the 

waivers that exist. I am not familiar enough with the issues, but 

there is a need for improvement. 

Mr. PALLONE. Would either of the other two of you like to answer? 

Mr. POPS. Just being directly responsive to your question, I don’t 

think removal of the waivers does a whole lot for the reasons you 

cited. I think FDA has different standards than other agencies of 

the government with respect to conflict. My own view is that I 

think they are too restrictive. And coming at it from the innovators’ 

point of view, the most important thing for us when we convene a 

panel is that the people sitting at the panel are expert in the disease because they are the best suited to make the decision between 

risk and benefit that are so critical for patients. 

Mr. PALLONE. OK. Dr. Wheadon? 

Mr. WHEADON. Thank you, Representative Pallone. I think in addition to what Mr. Pops just added—— 

Mr. PITTS. Is your mic on? 

Mr. WHEADON. I think it is. Can you hear me? 

Mr. PALLONE. Yes, I can hear you. Maybe talk closer to it. 

Mr. WHEADON. I think it is also important for us to consider 

broadening the question and looking at it from perhaps a different 

perspective from just waiver caps, and that might be recognizing 

that both FDA and industry have a vested interest in working with 

the best expertise. Should there be a penalty for FDA because industry has engaged that expertise and helping it develop its plan 

for investigation and research and vice versa, should industry not 

be allowed to engage that expertise because FDA may be planning 

to use that individual in an advisory committee. And in the case 

of rare diseases, it is even more of a particular issue because there 

could be so few experts for both industry and FDA to engage. 

Mr. PALLONE. All right. Thanks. 

Let me get a second question in here. We talked about how in 

today’s world drug manufacturing is a global affair and outsourcing 

is common, and robust supply chain management is best practice 

for industry including supplier qualification and assessment. So I 

wanted to ask Mr. Germano again, Pfizer has underscored in previous testimony the importance of ensuring the quality of suppliers, 

particularly those in emerging economies. Can you tell me what 

Pfizer is doing to ensure supplier quality? Do you believe that 

every company knows their suppliers and knows the quality system 

in place? 

Mr. GERMANO. Well, I mean, you know, product supply quality 

is the highest interest to Pfizer and I think that we have put a 

number of important measures in place to ensure the integrity of 

our supply, and you know, some of those measures include risk assessments of potential suppliers, you know, contractual measures 

189 

to ensure the effectiveness and quality of those suppliers. We go 

into some of the suppliers and work with them to upgrade their 

systems. We have audits on a routine basis. So we employ quite an 

array of measures to ensure the quality and integrity of our suppliers. 

Mr. PALLONE. I was going to ask Mr. Coukell but I guess I am 

out of time, Mr. Chairman. Thanks. 

Mr. PITTS. The chair thanks the gentleman and recognizes Dr. 

Burgess for 5 minutes for questioning. 

Mr. BURGESS. Thank you, Mr. Chairman. 

Ms. Dorman, let us stay on the issue of the conflicts because you 

referenced that in your prepared testimony, and I do believe it is 

extremely important. In fact, when this reauthorization occurred in 

2007, I was way down at the kids’ table on the minority side and 

wasn’t really able to make the point as effectively as it needed to 

be made, but we have got vacancies on the advisory panels. Now, 

we have got waivers that can be applied and there are caps on the 

waivers. Do you think the system itself creates an environment 

where otherwise qualified people say you know what, I don’t need 

that, I’m not going to go through that. So have we created a hostile 

environment to the researchers and the people who might be 

knowledgeable about these products because of the restrictions 

placed on the advisory panels in the 2007 reauthorization? 

Ms. DORMAN. I don’t know if I would say that there is a hostile 

environment per se but some of the restrictions, especially related 

to, you know, their finances and their investments and things like 

that, could be a deterrent to some people to expose themselves to 

that type of level of scrutiny. I will say, there is something that 

really does need to be done. A colleague of mine is president of the 

Friedrich’s Ataxia Research Association, and he was asked by the 

FDA to apply to sit on an advisory committee, and he was turned 

down because of perceived conflicts, and this is a man whose child 

died of Friedrich’s ataxia, so there are real concerns that really 

need to be looked at, and we feel as if it should be—FDA should 

not held to an even higher standard than all other federal agencies. 

Mr. BURGESS. Well, as I recall, during the discussion, the reference to the Institute of Medicine said no more than 40 percent 

of the advisory panel should be made up of people who potentially 

had a conflict, and I thought that was an OK number. That means 

you still have—as you correctly alluded to, the universe of people 

who have an understanding of the diseases and the treatments proposed is vanishingly small with some of these, and if you exclude 

even one individual, that may be a significant percentage of the 

population, the scientific population that actually understands the 

studies at hand. 

Ms. DORMAN. That is correct. I mean, the patient population— 

the rare disease community is very, very small. Patient organizations work with researchers. They work with companies to encourage the development of these orphan products. So yes, in the rare 

disease community, basically everyone is pretty conflicted. 

Mr. BURGESS. Well, are all conflicts equal? In the real world, are 

all conflicts equal? 

Ms. DORMAN. No, I don’t think so. 

Mr. BURGESS. Yes, I don’t either. 

190 

Let me ask you this. Do you think we have actually—that the advisory conflict policy has hindered bringing new products to market? 

Ms. DORMAN. No. It may have delayed like in the case of Savril 

but I don’t think it has, in my opinion. 

Mr. BURGESS. In my opinion, hindered and delayed would be 

identical, but I will accept your answer. 

Well, would you support loosening some of these restrictions? 

Ms. DORMAN. Excuse me? 

Mr. BURGESS. Would you support the loosening of some of these 

restrictions that were placed in the 2007 reauthorization? 

Ms. DORMAN. Yes, we would. 

Mr. BURGESS. In the interest of full disclosure, I have a bill out 

there, 3206, which attempts to undo some of these restrictions. 

Have you had an opportunity to look at that legislation? 

Ms. DORMAN. Yes, I have, and I have spoken with your staff. 

Mr. BURGESS. And Dr. Hamburg implied that she didn’t need a 

legislative fix, but in your estimation, would a legislative fix expedite the solution to this problem in your world? 

Ms. DORMAN. That has been our position, yes. 

Mr. BURGESS. And no great surprise, my position too. 

Dr. Wheadon, let me ask you a question. Dr. Hamburg referenced coming into the electronic age for some of the applications 

for the premarket approval process, and I guess I am surprised 

that that is not farther along. Do you have a sense as to what is 

the volume of new product applications, new drug applications that 

are sitting on paper applications in boxes in the basement of someone’s warehouse? 

Mr. WHEADON. Well, I think we may be talking about two different things. Most sponsors, if not all, certainly the member companies that we represent now submit what is called an electronic 

document. So everything is electronic. It is no longer boxes in U– 

Haul trucks as it used to be 20 years ago. 

I think what Dr. Hamburg was referring to and what we reference in the PDUFA agreement is an attempt to have more of a 

common template such that that electronic data is collected in a 

common format regardless of who the sponsor may be. The ultimate benefit of that is, when the agency needs to look across products, across sponsors, the data is collected in a similar way. It is 

much easier to collate, much easier to do analyses and come to 

some robust conclusions. Right now, it is all over the place and it 

makes it much more difficult for the agency to do that type of analysis. So I don’t think Dr. Hamburg was intending to imply that 

they are still collecting data on a paper format. That is not the 

case. It is just doing it more physically such that the agency can 

carry out its job much more effectively. 

Mr. BURGESS. Thank you. 

Thank you, Mr. Chairman. I will yield back the time. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

ranking member emeritus, Mr. Dingell, for 5 minutes for questions. 

Mr. DINGELL. Mr. Chairman, I thank you for your courtesy. 

First, welcome to Dr. Daniel Frattarelli. He is a constituent of 

mine from Oakwood Hospital and from Dearborn Medical Center in 

191 

Dearborn, Michigan, my hometown. Doctor, it is a pleasure to welcome you. Thank you for being here. 

Mr. FRATTARELLI. Thank you. 

Mr. DINGELL. As members of the committee well know, I have 

long believed that the FDA does not have the people, the funding 

or the authorities it needs to properly oversee an increasingly global drug supply chain. That has been supported by testimony and 

evidence submitted in hearings before this committee for a number 

of years. So in support of that posture, I would like to direct my 

questions to you, Mr. Germano of Pfizer, and please answer to the 

following questions yes or no. Do you agree that both FDA and industry have a responsibility to ensure the security of our drug supply chain? Yes or no. 

Mr. GERMANO. Yes. 

Mr. DINGELL. Do you agree that the knowledge of your suppliers 

is important? Yes or no. 

Mr. GERMANO. I am sorry. The knowledge about suppliers? 

Mr. DINGELL. Yes, your knowledge and experience with them as 

to their behavior and the quality of the goods that they are delivering you. Yes or no. 

Mr. GERMANO. Yes. 

Mr. DINGELL. Thank you. There are no traps here. 

Mr. GERMANO. I just want to make sure I understand the question. 

Mr. DINGELL. Just give the answers and you will be satisfied and 

so will I. 

Mr. GERMANO. OK. 

Mr. DINGELL. Does Pfizer have systems in place so that they can 

know and understand their suppliers and monitor the manufacturing quality of these suppliers? Yes or no. 

Mr. GERMANO. Yes. 

Mr. DINGELL. Should all companies making drugs in the United 

States know their suppliers and have quality systems in place 

there to assure that they are getting safe supplies from their suppliers? Yes or no. 

Mr. GERMANO. Yes. 

Mr. DINGELL. Now, I must assume, however, though, that there 

would be some instances where additional help would be needed by 

American suppliers, i.e., in the heparin case where raw materials 

or components for the heparin were clearly not safe and the result 

was American manufacturers were put at risk. Should FDA have 

additional authorities to provide that kind of support for American 

manufacturers? Yes or no. 

Mr. GERMANO. Yes. 

Mr. DINGELL. No traps here. I want you to be comfortable. 

Should the companies be using risk analysis to target safety 

risks? Yes or no. 

Mr. GERMANO. Yes. 

Mr. DINGELL. And that is not a standalone basis. Obviously they 

would have to use other things. 

Now, these are for Dr. Wheadon of PhRMA. Doctor, I want you 

to be comfortable with these, and I am not trying to lay any traps 

for anybody here. I want to focus on inspections. Do you agree that 

requiring FDA to conduct comparable inspections of domestic and 

192 

foreign drug facilities is important to ensuring a level playing field 

for our drug manufacturers? Yes or no. 

Mr. WHEADON. Certainly, the answer is yes based on—— 

Mr. DINGELL. Sorry? 

Mr. WHEADON. I am sorry. Certainly, the answer is yes based on 

the ability to assess risk. 

Mr. DINGELL. Good. I have very limited time, Doctor, and I beg 

your cooperation here. 

Mr. WHEADON. I understand. 

Mr. DINGELL. Do you agree that conducting comparable inspections of domestic and foreign facilities is important to public 

health? Yes or no. 

Mr. WHEADON. That is a yes. 

Mr. DINGELL. And of course, it is important to the fairness with 

which we treat our manufacturers. Is that not so? 

Mr. WHEADON. I think it is important to be fair across the board. 

Mr. DINGELL. Now, do you agree that FDA needs adequate resources to conduct comparable inspections of domestic and foreign 

drug manufacturers? Yes or no. 

Mr. WHEADON. I believe the agency should have adequate resources. 

Mr. DINGELL. Now, if FDA does not treat manufacturers alike, 

it is very liable to be unfair to U.S. manufacturers because of its 

inability to impose equal burdens upon both domestic and foreign 

manufacturers who are outside of our borders and outside the capabilities of FDA to reach them. Isn’t that so? 

Mr. WHEADON. I think FDA has ability to impact foreign manufacturers if they are importing drugs into the United States. 

Mr. DINGELL. But you would advocate that FDA do have such 

authority? 

Mr. WHEADON. I think FDA has that ability to impact those 

manufacturers—— 

Mr. DINGELL. Please answer my question. 

Mr. WHEADON. And they should, yes, sir. 

Mr. DINGELL. OK. Does the prescription drug user fee agreement 

currently provide resources for preapproval inspection? Yes or no. 

Mr. WHEADON. Yes, it does. 

Mr. DINGELL. Does the prescription drug user fee agreement currently provide resources for any inspections beyond the preapproval 

inspection? Yes or no. 

Mr. WHEADON. That is a qualified yes, it does. 

Mr. DINGELL. Qualified? But it should be ‘‘yes’’, shouldn’t it? Because FDA should have that authority, should they not? 

Mr. WHEADON. FDA has the ability to inspect facilities with resources—— 

Mr. DINGELL. That is one of the questions we are going to be 

going into, Doctor. 

The generic drug user fee agreement provides additional resources for FDA to conduct GMP inspections of both domestic and 

foreign drug facilities. Would you support providing similar resources to FDA for inspections of facilities manufacturing innovator 

drugs? Yes or no. 

Mr. WHEADON. No. 

193 

Mr. DINGELL. Do you agree that a risk-based inspection schedule 

for domestic and foreign drugs facilities based, for example, on 

compliance history, time since last inspection, volume and type of 

product would allow the FDA to better target the use of their resources? Yes or no. 

Mr. WHEADON. Yes. 

Mr. DINGELL. One obstacle to ensuring comparable inspections of 

domestic and foreign facilities is the lack of complete and adequate 

information that FDA has on drug manufacturing establishments. 

Do you support requiring domestic and foreign drug manufacturing 

facilities to register with FDA to provide a unique facility identifier 

and to list their products? Yes or no. 

Mr. WHEADON. I think that is one I would have to come back to 

you with further comment on. I am not prepared to give a specific 

yes or no on that one. 

Mr. DINGELL. Very good. One question then. Why is it that 

PhRMA does not support additional resources for GMP inspections? 

Mr. WHEADON. Well, this is more than a yes or no, right? 

Mr. DINGELL. It is a fairly simple question. I know you have a 

fairly easy to understand answer. 

Mr. WHEADON. Right. So as you correctly point out, Representative Dingell, the PDUFA fees that the innovative industry presently pays goes towards preapproval inspections. When an inspector goes into a facility, be it domestic or foreign, they don’t only 

look at the product that is under consideration for approval, they 

look at the system of that manufacturing establishment. So a GMP 

inspection is carried out in the context of preapproval inspections. 

Mr. DINGELL. Am I somewhat dense in not understanding why 

we would want to see to it that FDA has the authority that it 

needs to carry out its responsibilities in the best way possible? 

Mr. WHEADON. We certainly agree that FDA should have the resources to carry out their responsibilities very efficiently. 

Mr. DINGELL. I note, Mr. Chairman, I have exceeded my time by 

3 minutes and 5 seconds. You have my thanks and my apologies. 

Mr. PITTS. The chair thanks the gentleman and yields to the gentleman from Illinois, Mr. Shimkus, for 5 minutes for questions. 

Mr. SHIMKUS. Thank you, Mr. Chairman, and I apologize for 

missing the first part. I have a lot of questions about nuclear waste 

I could offer to you, but it is good to be here on the health panel. 

I would also like to go to Ms. Dorman, and can you just elaborate 

on how the FDA’s risk-based, current risk-based analysis is affecting patients? 

Ms. DORMAN. Well, it is the feeling of many patient organizations 

that the FDA has become far more risk averse than it should be, 

and so we want some way that patients can communicate directly 

with the reviewers. We have had conversations with the FDA leadership but the reviewers actually looking at the data don’t normally 

hear from the patients or their families. 

Mr. SHIMKUS. And what would the patients and the families tell 

them if they were listening? 

Ms. DORMAN. It depends on the disease, I suppose, or the condition, but just let them know what their quality of life is, to know 

more about the disease, what the risks of the disease are, what the 

progression of the disease is. I think those are some of the things 

194 

that the reviewers would like to hear, and I would like to point out 

to the committee that Mr. Shimkus was the sponsor of the rare diseases back in 2002. Thank you. 

Mr. SHIMKUS. No, thank you, and that is not why I went to you 

but I appreciate that. 

So I think you kind of answered this. How would you improve 

that risk-based system? What would you want us to do in a public 

policy arena to try to fix that? 

Ms. DORMAN. What we have proposed directly with the FDA, we 

are working internally with the officials there, what we have proposed, which isn’t really written in stone, would allow patients in 

an unburdensome way, maybe through a portal there on their Web 

site that would communicate some of those things. We don’t want 

it to be a burdensome process for the agency at all. But to empower 

patients in some way, shape or form to feel as if they have more 

control over approval of a product. 

Mr. SHIMKUS. And technologically, that shouldn’t be real difficult, should it? 

Ms. DORMAN. I am a real techno dweeb but I would say it is 

probably not all that difficult to do. 

Mr. SHIMKUS. I would also agree with you. 

Let me stay with you and ask about the FDA’s vacancies on their 

advisory committees. Do you know how many there are, and what 

does that mean in this discussion that we are having? 

Ms. DORMAN. I really don’t know what the numbers might be. 

Mr. SHIMKUS. And what is the problem with vacancies? 

Ms. DORMAN. Well, the problem is that it can delay consideration 

of products if they are unable to find someone who is expert, especially in the rare disease world where, you know, there are not of 

people expert in their conditions. Usually the patients know more 

about their conditions than their doctors do, so—— 

Mr. SHIMKUS. Say that again. I mean, just reiterate that point. 

Ms. DORMAN. I am speaking just from NORD’s perspective. I 

mean, many patients have more knowledge about their condition, 

about the progression of their disease than some of the physicians 

do. So it is very important to have their input, and they are anxious to do so. 

Mr. SHIMKUS. And I would agree with you there. I mean, they 

are anxious because either they are suffering themselves or having 

the life experience. They are also very passionate to try to make 

the system better for the future, and by being involved in the process, helpful. That gives them a role in this that they would like to 

be involved in. 

Ms. DORMAN. Yes, and it is helping our organizations understand 

the regulatory process more. So many of them are focused entirely 

on research at NIH and know very little about the FDA process. 

But on March 1, they are having a one-day advocacy meeting with 

patient organizations and over 180 organizations have signed on, 

so they will give them an opportunity to learn about the FDA and 

the FDA to learn about their conditions. 

Mr. SHIMKUS. Great. Thank you. 

And just briefly, Mr. Gollaher, I have been very concerned about 

capital research fleeing the United States because of the FDA’s 

slowness. We have also heard a lot of testimony about venture capVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00198 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
195 

italism. Is that true, if we have research and development, venture 

capital moving overseas? Where are they going and what does this 

mean for U.S. jobs? 

Mr. GOLLAHER. To some degree, and this is less true in the drug 

industry than the medical device industry, there has been a shift 

of first in human trials and of middle-stage and late-stage research 

to Europe and the device field has a faster and more user-friendly 

regulatory system. And we have certainly seen in California, we 

have seen across the country that most venture capitalists will not 

look at a business plan for a device company that doesn’t have a 

European strategy. That is a tremendous change in the last 10 

years. 

Mr. SHIMKUS. And that would really affect jobs and the economy. 

I mean, if they get the approval in Europe, they are most likely 

going to start there. 

Mr. GOLLAHER. Well, no, that is right, and there are also a number of sequelae. So for example, if you introduce a product in Germany before here, the doctors learn to use it. Some of the factors 

that are involved in early-stage manufacturing may go there as 

well. And you also teach your competition how to make the product. So it is a real issue. 

Mr. SHIMKUS. Thank you very much. I yield back my time, Mr. 

Chairman. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from California, Mr. Waxman, for 5 minutes for questions. 

Mr. WAXMAN. Thank you, Mr. Chairman. 

Dr. Frattarelli, in your testimony you provide compelling evidence of the benefits to children that the Best Pharmaceuticals for 

Children Act provides. As you know, because of studies conducted 

in response to BPCA and the Pediatric Research Equity Act, we 

learned invaluable information about the use of drugs in children. 

However, despite how well it has worked, you point out that the 

AAP believes that Congress should not remove the BPCA 5-year 

sunset provision because it provides Congress the opportunity to 

assess whether the BPCA continues to strike the right balance between achieving critical pediatric information and providing an appropriate incentive. Can you briefly expand on your testimony regarding why Congress should retain that 5-year sunset provision? 

Mr. FRATTARELLI. Sure. One of the big issues here is that it is 

kind of a moving target that we are talking about. The cost that 

this is going to incur by varying the period of exclusivity these 

drugs obtain will change over time, and that cost is going to be 

borne by a lot of groups, private insurance companies and the government as well. So there is a financial side to this, but the other 

part is, every 5 years having the opportunity to look at these again, 

revise them, gives us some real benefits. If we go through, you 

know, what happened last time we went and reauthorized these, 

we had some changes made so that, for example, now all the information that we get from these studies results in a label change and 

the information is more publicly available. Those are two real 

meaningful and important things to have, and they came about because we had this opportunity to reevaluate. 

196 

Mr. WAXMAN. That is a very good argument. The other, of course, 

is that when we have a 6-month exclusivity, that is a lot of money, 

and that cost, as you point out, is being carried by the people who 

pay for these drugs, whether it is government, insurance or private 

individuals. If you have a 6-month exclusivity, especially if it is a 

drug like Lipitor where the annual sales are over $5 billion, that 

just can be a huge cost that is being passed on to others. 

And so we need to maintain a balance between providing adequate incentives for developing new indications for pediatric populations and not unduly burdening patients and payers with high 

drug costs for any longer than is necessary. 

During the 2007 reauthorization, we put forward a proposal to 

trim that 6 months of exclusivity for drugs with very high profit 

margins, so-called blockbuster drugs. I thought that made sense, 

but we didn’t prevail in including it. I agree, it is critical to retain 

that sunset provision so we have an opportunity to evaluate these 

questions, both the balance and the research questions as well. 

Ms. Dorman, we have heard concerns from several parties about 

the development of drugs for rare diseases. I talked in my opening 

statement about a proposal under consideration that would make 

changes to FDA’s fast-track approval system for orphan drug, the 

ULTRA Act. Specifically, it would require the FDA to use whatever 

data was available to evaluate and approve surrogate endpoints for 

review of these drugs and would prevent FDA from requiring additional clinical data even when FDA considers such additional data 

necessary to enable it to make an approval decision based on that 

endpoint. That is a concern to me. My understanding is that under 

current law, FDA has a great deal of discretion to identify and require appropriate scientific evidence. 

NORD recently did a study looking at whether FDA is flexible 

in its requirements for the approval of orphan drugs. Can you describe the conclusions of this study in more detail? What is NORD’s 

view on the need for legislative changes to FDA’s fast-track approval program for orphan drugs, specifically on the ULTRA Act? 

Ms. DORMAN. We feel as if ULTRA would require the FDA to rely 

on surrogate endpoints based on little or no clinical evidence, and 

it could expose patients to unnecessary risk and in our opinion 

would lower the approval standards of the FDA, and that is our 

concern. That study is really a landmark study. Of the 130, you 

know, products that were reviewed by a former chair, many of 

them, 90 of the 135, were approved based on administrative flexibility or case-by-case flexibility, and I think the example that Dr. 

Hamburg gave this morning in her testimony regarding the new 

therapy for cystic fibrosis, it was approved in 3 months, so they do 

use that flexibility when something that important comes forward. 

Mr. WAXMAN. Well, we all want these drugs on the market as 

fast as possible but I would be concerned about any proposal to remove FDA’s ability to require clinical data when FDA thinks it is 

essential to assure that these drugs are safe and effective, so I certainly agree with the position NORD has been taking. 

Ms. DORMAN. Thank you. 

Mr. WAXMAN. Thank you, Mr. Chairman. 

197 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from New Jersey, Mr. Lance, for 5 minutes for questions. 

Mr. LANCE. Thank you, Mr. Chairman. 

To Mr. Germano, very nice to see you again. In your testimony, 

you noted that Pfizer’s enhanced focus on rare diseases, specifically 

allocating the majority of your research and development efforts to 

the areas that represent the intersection between unmet medical 

needs and your strength in biology and chemistry, given that, could 

you comment on how the enhancements in regulatory science contained in the goals letter will support the development of products 

for rare diseases? 

Mr. GERMANO. Yes, I think that there are a number of elements 

of the proposed PDUFA V that will help in the advancement and 

review and development of medicines for rare diseases. I think the 

NME review process that I spoke of before will help bring, you 

know, clarity to the review process, which I think will be helpful. 

I think that some of the provisions in the, you know, enhancements 

in regulatory science, you know, specifically for rare diseases, biomarker identification and, you know, other measures that are in 

the PDUFA V I think are all intended to elevate the capability of 

the FDA and the potential for better transparency and problem 

solving and decision making between the company and the FDA. 

Mr. LANCE. Thank you. Are there any other changes that you 

could see that would incentivize innovative biopharmaceutical companies into developing more products for unmet needs? 

Mr. GERMANO. Well, I think overall, you know, confidence in the 

development pathway is a very big part of providing an incentive 

for a company to take on a project in the development of a new molecular entity in particular. So some of these provisions relate directly to improving confidence in the pathway and agreements that 

exist between the agency and the sponsor company. Beyond that, 

I think, you know, intellectual property and exclusivity assurance 

will give greater confidence to the sponsor to make the investments 

necessary to bring these kinds of medicines forward. 

Mr. LANCE. Thank you very much. 

To Mr. Pops, I think it is critical that we ensure a consistent and 

transparent evaluation of benefit-risk during FDA’s review of new 

drugs. Unfortunately, from my perspective, this evaluation has on 

occasion kept life-improving, life-saving drugs from patients, and in 

your opinion, what do we need to do in order to rebalance the analysis? 

Mr. POPS. The was one of the real questions that was brought 

up during the PDUFA V technical negotiations, and I think that 

what we—— 

Mr. LANCE. Which I know you were involved. 

Mr. POPS. Is that in PDUFA V, and I think the Commissioner 

mentioned earlier, there is this patient-centric and more formalized 

risk-benefit evaluation that we are seeking to implement through 

PDUFA V. I think we have a long way to go but I think the agency 

has an interest in bringing more rigor and formalization to the 

risk-benefit analysis. 

Mr. LANCE. Thank you. 

198 

Is there anyone else on the panel who would like to comment on 

that? Very good. Thank you very much. 

I yield back the balance of my time, Mr. Chairman. 

Mr. PITTS. The chair thanks the gentleman and recognizes the 

gentleman from New York, Mr. Towns, for 5 minutes for questions. 

Mr. TOWNS. Thank you very much, Mr. Chairman. 

Let me begin by thanking you, Ms. Dorman, for working with my 

staff and Mr. Stearns on ULTRA. This bill is still a work in 

progress, and we look forward to receiving NORD’s recommendations for changes to the text as your group has promised my staff 

within the next few weeks. We look forward to continued work with 

you on that. 

Let me go to you, Mr. Germano. Last year, the FDA approved a 

Pfizer drug under priority review in 4 months. In your experience, 

is this common for orphan drug review, and what made this one 

so exceptional? 

Mr. GERMANO. This was—I think you are referring to our drug 

crizotinib, and the brand name is Xalkori. It is a drug for—— 

Mr. TOWNS. That is correct. 

Mr. GERMANO [continuing]. A specific subset of patients with 

non-small-cell lung cancer, and in this case, there is a genetic 

marker to identify patients who are most likely to respond to the 

medication. So we were able to—once the identification of the genetic marker occurred, we were able to work with our partners at 

Abbott Laboratories to develop a companion diagnostic and complete a clinical trial that demonstrated, you know, fairly clearly the 

benefit-risk profile of this medicine for this particular patient population. So it is a great example of the benefit of personalized medicine or precision medicine approach to drug development. You 

know, the more we are able to do this, you know, the more efficient 

the development process is, the more efficient the review process 

is and the more quickly we can get new medicines to patients. 

So, you know, I can’t say it is commonplace. I think we are all 

working harder and harder to find, you know, genetic markers and 

biomarkers of activity, whether it is efficacy or safety signals that 

we are after to help bring more clarity to the benefit-risk profile 

of our medicines and make it easier for us to develop them and for 

the agency to review them. 

Mr. TOWNS. Let me just say that I really appreciate Pfizer’s 

strong commitment to finding treatments for rare diseases. To the 

best of your knowledge, have any of Pfizer’s recently offered drug 

approvals been approved under the accelerated approval pathway 

at FDA? 

Mr. GERMANO. Well, this one that we are speaking of, crizotinib, 

was approved under the accelerated review process. 

Mr. TOWNS. Any others? 

Mr. GERMANO. We have another drug for a rare disease, a rare 

polyneuropathy that we have recently filed with the FDA and we 

are seeking accelerated review of that product as well. 

Mr. TOWNS. Do you have any ideas or suggestions as to how we 

might be able to improve the accelerated approval process? Do you 

have any ideas or suggestions that you might want to offer? 

Mr. GERMANO. Well, I think that some of the provisions of 

PDUFA V are likely to be helpful. Again, I think the greater 

199 

amount of required interaction between the agency and the sponsor, the focus that the agency will put on, you know, risk-benefit 

framework, biomarker understanding and, you know, rare and orphan disease issues that are components of the PDUFA V should 

be helpful in improving our ability to bring these kinds of medicines to the market. 

Mr. TOWNS. I want to go to a very quick yes or no question. I 

am very committed to supporting the FDA in their timely approval 

of safe, effective treatment options, particularly for rare diseases. 

For this reason, I am proud to be working with my colleague from 

Florida, Congressman Stearns, on an initiative that I hope will encourage the development of innovative, safe drugs in this space. 

The goal is to improve access to the FDA’s existing accelerated approval pathway for drugs designed to treat patient with life-threatening rare diseases, and this would be a yes or no. Let me ask you, 

Mr. Germano, and of course Mr. Pops and Ms. Dorman, do you support this goal? 

Mr. GERMANO. To—— 

Mr. TOWNS. Do you support the goal? 

Mr. GERMANO. I am sorry? 

Mr. TOWNS. Congressman Stearns and I are working on this initiative that I hope will encourage the development of innovative, 

safe drugs in this space. The goal is to improve access to FDA’s existing accelerated approval pathways for drugs designated to treat 

patients with life-threatening rare diseases. Do you support that? 

Mr. GERMANO. Yes, I would support that. 

Mr. TOWNS. OK. Ms. Dorman? 

Ms. DORMAN. Yes. 

Mr. TOWNS. Thank you very much, and I would note, Mr. Chairman, I don’t have anything to yield back, but I yield back. 

Mr. PITTS. The chair thanks the gentleman and recognizes Mr. 

Guthrie for 5 minutes for questions. 

Mr. GUTHRIE. I think the previous two kind of went down the 

path I was going to go with Ms. Dorman. I think that we do need 

to make sure that we have a good accelerated program for people 

with risk, and I have a friend caught up in another situation, and 

the argument, I always say this. I have bad allergies. I don’t want 

something put out to keep me from sniffling that is going to have 

adverse effects to me. But when you have a friend who has Lou 

Gehrig’s disease, or ALS, and there is some opportunities for them 

to go forward, as long as the patient knows the risk and what could 

be there, I think that we should have a process for them to go forward. So I agree with Mr. Stearns and Mr. Towns and I would like 

to work with you on that because I think that is important to do. 

On the venture capital, which is more medical devices, I gather, 

a lot of times they are encouraged to go to Europe just because 

they get approved. If they get approved in the home country where 

they manufacture, they also get—I think China recognizes it. So 

the President talked about manufacturing, which is my background, we are in a situation where we have American manufacturers having to locate in Europe because of our regulatory process, 

which we are not comparing to a country that doesn’t have substantial safety concerns. I mean, we are talking about the EuroVerDate Aug 31 2005 10:01 Nov 29, 2012 Jkt 037690 PO 00000 Frm 00203 Fmt 6633 Sfmt 6633 F:\112-11~1\112-11~1 WAYNE
200 

pean Union that we are not competitive with in our approval process. 

But I want to get to Mr. Coukell. On this panel, a lot of people 

say ‘‘as a doctor.’’ I don’t get to say that, but as a quality control 

engineer—that was my background before in manufacturing—Pew 

has done some research on drug pedigree, and just if you can talk 

about that and particularly I would like the safety of the supply 

chain, particularly foreign supply chains dealing with third parties 

or foreign regulators. I mean, if you could talk about what your research has been in the drug pedigree world? 

Mr. COUKELL. Thank you for that question, sir. It is an area that 

I didn’t touch on my testimony, but we looked at as drugs move 

from the manufacturer through distributors to the pharmacy and 

ultimately to the patients, what is the pedigree system or the absence of. So if I could share one short story. A couple of years ago, 

there was a tractor-trailer load of insulin that was stolen in North 

Carolina and disappeared for a while. Insulin is a drug that should 

be refrigerated. And then it showed up back in pharmacies of a 

major chain grocery store in a couple of different States. And between there is passed through a couple of different wholesalers. 

And so the question is, is there a system by which the pharmacy 

at the end use could have recognized that as stolen product, flagged 

it, do we have a system that lets you track the product through the 

system, do we have a unique serial number on the drugs, and the 

answer is we don’t have that. California has law which is scheduled to come into effect in 2015. Our view is that a national standard would be much more preferable. 

Mr. GUTHRIE. What about your looking into ingredients, foreign 

ingredients and the integrity and dealing with foreign regulators or 

third parties? I think you looked into that in your report as well. 

And what are solutions? I mean, you said unique serial numbers. 

Are there other things like working with foreign regulators or 

third-party groups? 

Mr. COUKELL. So let me make two points that I think are important. One is, a manufacturer absolutely has to have confidence that 

they know who is in their upstream supply chain and that they 

know what quality standards are in place and that there isn’t a 

risk of sub standard product coming in through the backdoor and 

making its way into the supply chain. 

Mr. GUTHRIE. Did you find that manufacturers didn’t know that 

or didn’t have systems in place for that? 

Mr. COUKELL. We absolutely found a whole spectrum, and there 

are great manufacturers in every country, but there are also risks. 

In our report, there is a photograph from a manufacturing facility 

in China with a whole wall of 50-gallon drums stacked up about 

one deep, and the inspectors went in there and said, you know, 

what is behind those drums; well, nothing. So they climbed over 

and found behind the drums a whole warehouse full of uncertified 

active pharmaceutical ingredient that was destined for, in that 

case, a European supply chain. So it does occur. 

On the question of foreign regulators, I think we acknowledged 

that the FDA is moving in the right direction on this, which is no 

one country can inspect the whole world, and so we have to deploy 

201 

limited resources in a rational way. We do duplicate inspections 

and rely on other trusted regulators wherever possible. 

Mr. GUTHRIE. In automotive manufacturer, you actually hire people to come in and certify and audit your plant, and Ford or GM 

or Chrysler would accept that. Using third-party auditors that are 

reputable, that you can—the trick to it was or the issue was that 

you actually paid them to come to your plant to certify you to 

Ford’s standard, but they had a reputation to uphold as well, and 

so—— 

Mr. COUKELL. Absolutely, and I think Congress did some of that 

for food in the Food Safety Modernization Act a couple of years ago. 

You know, one of the real leaders in industry on quality, a vice 

president of quality for one of the big companies has said every 

supplier and sub-supplier should be audited by somebody, but at 

the same time, if there is one company that is making, you know, 

an inactive ingredient like talc or something for tablets and they 

are supplying 30 companies, you don’t need 30 audits. 

Mr. GUTHRIE. Right. Common sense. 

Thanks. I yield back. 

Mr. PITTS. The chair thanks the gentleman. 

That concludes the questioning, and I would like to thank the 

witnesses and members for participating in today’s hearing. We 

have had a lot of very important information come before the committee, and I remind members that they have 10 business days to 

submit questions for the record. I will ask the witnesses to please 

respond promptly to those questions. Members should submit their 

questions by the close of business on Wednesday, February 15th. 

With that, without objection, the subcommittee is adjourned. 

[Whereupon, at 2:25 p.m., the subcommittee was adjourned.] 

[Material submitted for inclusion in the record follows:] 

202 


76491.122

Opening Statement of the Honorable Marsha Blackburn 

Subcommittee on Health 

Reauthorization of PDUFA: What It Means for Jobs, Innovation, and Patients 

February 1, 2012 

Thank you, Mr. Chairman. 

Today marks an important step towards ensuring the current drug user fee 

program is working as effectively as possible and if not, what changes can be 

brought about for the FDA to meet its commitment to the drug industry and to our 

nation's public health needs. 

It is important for this committee to use the PDUF A opportunity to examine 

and improve the FDA regulatory process. 

The need for these reforms is two-fold. 

First, we must ensure that the companies that invest many years and billions 

of dollars in bringing life saving products to patients are being provided with both 

transparency and consistency throughout the FDA review process. . 

Second, we must ensure the regulatory processes at FDA are conducted with 

certainty and predictability, thus promoting investments in U.S. based innovations 

which in turn grow the American economy and help get our constituents back to 

work. 

Far too many jobs have moved overseas because of overregulation. The 

number one priority at the FDA and all Federal agencies needs to be fostering an 

environment that promotes US based job creation. 

I look forward to working to ensure this is in fact the case. 
203 


76491.123

//'~ DEPARTMENT OF HEALTH &. HUMAN SERVICES 

"'::) 

The Honorable Joseph R. Pitts 

Chaim1an 

Subcommittee on Health 

Committee on Energy and Commerce 

House of Representatives 

Washington, D.C. 20515-6115 

Dear Mr. Chairman: 

Food and Drug Administration 

Silver Spring, MO 20993 

SEP 10 2012 

Thank you for providing the opportunity for the Food and Drug Administration (FDA or 

the Agency) to testify at the February 1.2012. hearing before the Subcommittee on 

Health. Committee on Energy and Commerce, entitIed "Reauthorization ofPDUFA: 

What it Means for Jobs, Innovation, and Patients." This letter provides responses for the 

record to questions posed by certain Members of the Committee, which we received on 

March 9. 2012. 

If you have further questions. please let us know. 

cc: The Honorable Frank Pallone, Jr. 

Ranking Member 

Sincerely. 

] '1 tc .r..-<tfZ'",- {rv ....... Jeanne Ireland 

Associate Commissioner 

for Legislation 
204 


76491.124

Page 2 - The Honorable Joseph R. Pitts 

We have restated each Member's questions below in bold, followed by FDA's responses. 

The Honorable Joseph R. Pitts 

1. The Committee recognizes that FDA's publication orthe July 5, 20ll, draft NDI 

guidance was required by law. However it appears that this draft guidance is 

inconsistent with the new dietary ingredient notification provisions oHhe 

Dietary Supplement Health and Education Act of 1994 (DSHEA). We note that, 

in response to your July 5, 2011, NOI draft guidance, many stakeholders 

submitted comments that called on the Agency to withdraw the guidance and 

work with them to cOllie lip with an approach that is consistent with the 

underlying statute. Would you assure the Committee that FDA will not in allY 

way seek to enforce the requirements ofthc draft NOI guidance document until 

it is finalized? 

We appreciate and share your concern that the New Dietary Inf,'Tedient (NO!) guidance 

be consistent with OSHEA. FDA welcomes comments from all parties on the draft 

guidance and takes seriously the concerns that have been raised. We are currently 

reviewing comments on the draft guidance and will consider all points of view before 

issuing a final guidance. We have also met with industry groups over the past fcw 

months in order to bettcr understand the issues of concern to them. 

We do not regard the draft guidance as establishing or signaling a new enforcement 

posture on the part of FDA. Guidance documents are not enforceable rules or 

requirements, and they do not establish or modify the legal basis for enforcement actions. 

They only indicate FDA's current thinking on the subject, and they are intended to 

provide information and tools to help industry meet the existing statutory obligation to 

ensure that dietary supplements containing NDIs are safe. 

2. In order for FDA reviewers to make informed decisions regarding a produet's 

safety and efficacy, it is critical these reviewers are weU versed in the latest 

science and clinical practice of their respective disease areas. Unfortunately, we 

have heard reports of cases where reviewers, while experienced, and eompetent 

in other fields, do not possess the adequate expertise in the clinical area of 

concern to make these judgments. Please inform the Committee of any efforts to 

ensure that review staff are up to date in the science and clinical practice of their 

disease areas of focus. 

It is critical that our reviewers are up to date in their respective disease areas. For 

example, as part of training and continued education, FDA's Center for Drug Evaluation 

and Research (COER) has developed key competencics for all disciplines. CDER 

scientific disciplines must have the ability to use and apply an understanding of the basic 

science, methods, processes, and procedures in medical and review disciplines related to 

the drug review process. They are required to use and apply related knowledge in basic 

science of clinical practice, clinical phannacology, chemistry, biochemistry, 
205 


76491.125

Page 3 The Honorable Joseph R. Pitts 

phamlaco]ogy/toxico]ogy, biocquivakm:e, and statistics. They must comprehend and 

evaluate the application of pertinent concepts and knowledge from other disciplines in the 

review process related to product development. 

CDER offers continuous education (CE) opportunities for staff to stay abreast ofclinical 

science through training, CE credit, and professional deVelopment. FDA staff 

consistently seek opportunities to enhance mathematical, scientific, technicaL or 

professional expertise. Examples of intemal training programs includc ongoing biweekly 

CDER Seminars, biwcekly CDER Scientific Rounds, quarierly Office of New Drugs 

(OND) Clinical Reviewer Education Program lectures, ongoing OND Phamlacology 

Toxicology scientific lectures, selected lectures in the FDA Scientific Professional 

Development series, and ongoing suhspecialty training for current clinical topics within 

review divisions. Externally, review staff attend annual professional subspecialty 

conferences and are members of professional societies that also provide additional 

specialized learning in their respective fields. Many clinical rcview staff also continue to 

participate in patient clinical care through professional development time pennitted 

through the Agency. 

The Center for Devices and Radiological Health (CDRH) has implemented two new 

training programs designed to improve the consistcncy of medical device reviews by 

enhancing the skills of those reviewing premarket applications. The Reviewer 

Certification Program, which began as a pilot in April 2010 with participants from 

CDRH's Division of Anesthesia, General Hospital, and Infection Control and Dental 

Devices, launched in September 2011 and includes all new device reviewers. The 

program includes up to 18 months oftraining aimed at complementing the skills and 

knowledge that new reviewers bring to CDRH from fields such as biomedical 

engineering and health care. Rcviewers in the program will complete online training 

modules, instructor-lcd courses, and obtain practical experience in the medieal device 

review process. Courses include medical devices, food and drug law and regulatory 

requirements, the CDRH review process, device design, and the impact of human factors. 

CDRH has also developed a pilot Experiential Learning Program (ELP) for premarket 

reviewers. The program will include visits to academic institutions, manufacturers, 

research organizations, and health carc facilities and is intended to give reviewers a better 

understanding of how medical devices are designed, manufactured and used. The 

program will also help new mcdical device reviewcrs understand the challenges of 

technology development and the impact of medical devices on patient care. The ELP 

was announced to CDRH staffon April 26, 2012, and orientation for the pilot participants 

was held on May 1 and is being followed by sessions, prior to each site visit, to prepare 

staff and supervisors with goals and objectives for that visit. Enhancing stafftraining is 

one of the 25 action items listed in FDA's Plan of Action for Implementation of 51 O(k) 

and Science Recommendations to increase the predictability and transparency of 

regulatory pathways and to strengthen the 51 O(k) proccss. The 51 O(k) process is the most 

common pathway to market for medical devices. 
206 


76491.126

Page 4 - The Honorable Joseph R. Pitts 

FDA's Center tl)r Biologics Evaluation and Research (CBER) also offers CE 

opportunities for staff to stay abreast of clinical science through training, CE credit, and 

professional devclopment. CBER staff consistcntly seek opportunities to enhance 

mathematicaL scientific, technical. or professional expertise. Examples of internal 

training programs include CBER Case Seminar, Bone Seminar Series, Division of Viral 

Produets Seminar Series, Clinical Trials Seminar, Office of Biostatistics and 

Epidemiology Seminar Series, Articular Cartilage Seminar Series, Introductory to 

Genetic Epidemiology Lecture Series. and CBER Health lnfonnation Serics. There is 

also ongoing subspecialty training fOT current clinical topics within review divisions. 

Extemally, review staff attend annual professional subspecialty conferences and are 

members of professional societies that also provide additional specialized learning in 

their respective fields. Many clinical review staff also continue to participate in patient 

clinical care through professional development time pennitted through the Agency, In 

addition, the Agency has scientific reviewers of regulatory applications, including some 

physicians, who have active laboratory research programs that keep them current with the 

latest scientific advanccs. 

3. With respect to tobacco, FDA is now starting to impose fines for retailers that 

fail tobacco inspections, but they are imposing multiple fines and alleging 

multiple violations for a siugle inspection. That seems to be contrary to the 

provisions of tlte law establishing the Center for Tobacco Products, whiclt 

specifically states that retailers must be informed of all previous violations 

before being charged witlt another violation, Can you explain how FDA 

imposing multiple fines for a single inspection is consistent with tbe law? 

The Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) 

provides that a person ·'may not be charged with a violation at a particular retail outlet 

unless the Secretary has provided notice to thc retailer of all previous violations at that 

outlet"' (section I 03(q)(l )(D)). The language in this provision refers to ··violations:' not 

to '"inspections." FDA has interpreted this to mean that each violation is a separate 

tinable offense, even if several violations are observed within one inspection. We do not 

interprct the requirement to provide notice of "previous" violations as implying a 

restriction on charging contemporaneous violations. 

That being said, the Tobacco Control Act requires that FDA provide "timely and 

effective notice by certified or registered mail or personal delivery to the retailer of each 

alleged violation at a particular retail outlet prior to ('(}fuil/cling afollow-uf7 compliance 

checL . .. (section I 03(q)(l )(B)). Following is a deScliption of how FDA complies with 

this requirement. FDA has contracted with states and U.S. territories to conduct tobacco 

compliance check inspections of retailers that sell or advertise regulated tobacco products 

to determine whether those retailers are complying with the Tobacco Control Act and its 

implementing regulations. Inspectors working under these contracts are commissioned 

by FDA to conduct such activities on the Agency's behalf. After each inspection is 

conducted, the commissioned inspector submits observations and inspection results to 

FDA. FDA tllen takes appropriate regulatory actions based on its review of the 

illspection data and evidence. Although FDA is not required to issuc a Warning Letter 
207 


76491.127

Page 5 TI1C Honorable Joscph R. Pitts 

bet()fc taking further regulatory action, the first time FDA identitIes vioJation(s) at a retail 

Olltlet, we generally issue n Warning Letter that describes each violation. FDA then 

issues an assignment to a commissioned inspector to conduct follow-up inspections of 

this retail establishment. Subscqucnt violations may result in FDA issuing a complaint 

seeking civil money penalties. Thus, violations documented during initial inspections by 

FDA-commissioned inspectors are communicated to retailers via an FDA Warning Letter 

(not a fine). It is only violations documented during subsequent inspections that have 

precipitated complaints seeking civil money pcnalties. 

4. Wbere is the FDA in the process of updating and finalizing FDA '52007 draft 

guidance for obesity drugs? Please provide information on when this guidance 

will be updated and finalized. 

FDA is working with stakeholders, such as patient and physician groups, to explore the 

complex issues related to development and approval of drugs to treat obesity. These 

interactions include an FDA public advisory committee meeting that was held March 28 

and 29, 2012, and participation in a series of roundtable meetings spearheaded by George 

Washington Univcrsity (OWU) that includes key players in the obesity community. FDA 

is participating in the OWU-Ied discussions as an observer, and we will he participating 

in several roundtable meetings in 2012. These meetings provide a forum to discuss 

clinical trial designs, endpoints, and indications for drugs to treat obesity. Both the 

public advisory committee meeting and the OWU effort are important steps for FDA as 

we continue the process of developing guidance for obesity drugs. 

5. The draft menu labeling regulation issued by FDA require calorie labeling based 

on tbe total calorie count of the menu item, not the portion of the menu item that 

customers are accustomed to consuming. For example, it appears that FDA is 

insisting that pizza be labeled by the whole pie, not by calories per slice. Yet, 

most consumers eat a few pizza slices, not the entire pizza. Would it be better to 

give restaurants flexibility in posting calorie counts, especially for items like 

pizza? 

In the proposed rule, FDA tentatively concluded that a "standard menu item" means a 

restaurant or restaurant-type food that is routinely included on a menu or menu board or 

routinely offered as a self-service food or food on display, regardless of how many 

servings are included in the item. Consequently, under the proposed rule, if a multi· 

serving item such as a pizza is listed on the menu or menu board, then it is a standard 

menu item and calorie information would be disclosed for the entire pizza. In contrast, if 

the standard menu item is a slice of pizza, the calorie infomlation would be presented for 

the slice. FDA requested comment on this tentative conclusion and proposed definition, 

and we are considering the comments we have received carefully before promulgating a 

final rule. 
208 


76491.128

Page 6 The Honorable Joseph R. Pitts 

The Honorable Mike Rogers 

I. The Family Smoking Prevention and Tobacco Control Act called for user 

fees to fund the Center for Tobacco Products at FDA. What kind of 

information can you provide regarding the IIser fee funds spent at FDA ou 

tobacco-related activities? For example, as part of PDUFA, the FDA puts 

out financial and performance reports that show how the FDA spends user 

fee mouey. 

a. Does the FDA put out a report 011 how it spends the tobacco user fee 

money? 

h. Is this a statutory requirement? 

c. Should the Agency put out such a report? 

The Tobacco Control Act required FDA to produce a quarterly report to the House and 

Senate Appropriations Committees through FY 20 10. FDA submitted each of those 

quarterly reports to those Committees. There is no statutory requirement to issue a report 

on FDA use of tobacco user fees similar to requirements for reporting on PDUFA or any 

of FDA 's other user fees. FDA intends to publish an annual tobacco user fees report with 

tinancial infomlation related to its use of the tobacco user fees, including collection rates. 

arrears. and obligations beginning in the first quarter of fiscal year 20] 3. 

2. Under the Family Smoking Prevention and Tobacco Control Act, how 

many substantial equivalent applications have been filed since March 

23,2011? 

a. Has the Agency aeted on any of these? If not, why? 

h. Has the Agency announced a time frame ill which it will provide a 

final Agency response to a submitter'? 

Between March 23, 2011, and July I, 2012, FDA received 390 substantial equivalence 

reports. 

As general background, on January 5. 2011, FDA published a final guidance on 

substantial equivalence entitled "Section 9050) Reports: Demonstrating Substantial 

Equivalence for Tobacco Products 

()I'II'II\/iia.gOl'ldolvn/oads/TohaccoPl'oductsIGuidanceComplianceRegll[atolyln/ormationl 

UCM239021,p(!f).·' This guidance provides recommendations and infonnation related to 

the submission and review of substantial equivalence reports. In addition, the Agency 

published a draft guidance entitled "Demonstrating the Substantial Equivalence of a New 

Tobacco Product: Responses to Frequently Asked Questions" in September 2011. This 

draft guidance. when finalized. will represent FDA's current thinking on this topic 

(1\ 'I'll 'fda.govITobacco ProductslGlIidlillceC ompliwlceRegu[atoryil!fhrmationIUCM2 712 

42.htm). In these documents, FDA describes the information needed for the Agency to 

make a determination of substantial equivalence. 
209 


76491.129

Page 7 The Honorable Joseph R. Pitts 

As ofJuly L 2012, FDA has carried out a jurisdictional review on 338 of the 390 

substantial equivalence reports received since March 23, 20 11, and provided infomlation 

to the manufacturers about whether their product falls under the current jurisdictional 

authority of the Center for Tobacco Products (CTP). As of July 1,2012, FDA has 

performed an initial "Completeness Review" on 133 substantial equivalence reports 

received since March 23, 2011. As of July 1, 2012. FDA has sent "Advice and 

Infonnation"letters to all 133 of those parties W}lO have submitted reports, which have 

been reviewed for completeness. These Ictters ask that the partics either provide 

clarification about their report or submit the missing infol111ation to facilitate FDA's 

review of the substantial equivalence reports. As of July 1,2012, FDA has received 

responses ITom ]30 of the advice and information letters and is proceeding with its 

substantial equivalence evaluation on these reports. 

FDA is developing final policies and procedures about the time ITaJl1e for responding to 

substantial equivalence repOlts, Submission of substantial equivalence reports for 

tobacco products is nllw to both FDA and tobacco product manufacturers. The optimal 

time it might take for various tobacco manufacturers to develop substantial equivalence 

reports for tobacco products and respond to FDA requests for additional information is 

not yet known. Thus, FDA will base final policies on this experience. 

3. How many tobacco ingredient substantial eqnivalent exemption requests 

have been filed since July 5,2011? How many has the Agency acted 

upon? 

FDA published a tinal rule entitled "Tobacco Products, Exemptions from Substantial 

Equivalence Requirements" on July 5, 2011. In this document the Agency describes the 

procedures for submitting a product for exemption from substantial equivalence 

requirements. As of July 2012, FDA has received 22 substantial equivalence exemption 

requests, and is in the process of reviewing all ofthe requests. 

4. Outside of FDA-initiated contacts, how many requests for meetings have 

been submitted by tobacco manufacturers to the Center for Tobacco 

Products and how many meetings has it granted? 

As of July 1,2012, FDA has received 78 requests for meetings ITOm tobacco 

manufacturers or related trade associations and eTP has granted 59 of the requests. One 

meeting request was cancelled by the manufacturer. 

In addition, CTP has initiated meetings with the tobacco industry. Specifically, CTP has: 

• Met seven times with either individual manufacturers or multiple manufacturers 

on the general science of smoked and smokeless tobacco products; 

• Met thrce times with individual manufacturers on science related to dissolvable 

tobacco products; 

.. Met three times with individual manufacturers on science related to e-cigarettes: 

• Conducted in December 2011, six manufacturing site visits at the invitation of 
210 


76491.130

Page 8 The Honorable Joseph R. Pitts 

industry to learn more about the manufacturing, marketing, and distribution of 

tobacco products. Several more educational site visits are planned this year; and 

• Sponsored two specific stakeholder discussion meetings for industry. The tlrst 

was held with large and small tobacco manufacturers and growers in December 

20 I 0 and was attended by more than 30 industry leaders. The second was 

conducted in August 2011 with tobacco distributors, wholesalers, importers. and 

retailers. 

Also. at the request of the Tobacco Manufacturers Association, CTP leadership has 

presented at the last thrce annual meetings in 2010,2011, and 2012. 

5. How many meetings have been requested by third-party smoking cessation 

groups and how many of those requests for meetings have been granted by 

the Center for Tobacco Products? 

As of July 2012. FDA has received 31 requests from third-party smoking cessation or 

similar groups and granted 26 meetings. In addition. CTP sponsored a stakeholder 

discussion meeting for public health and medical associations in April 2011, which 

was attended by 13 organizations. 

6. With respect to tbe Tobacco Control Act, FDA is now starting to impose 

fines for retailers that fail inspections, but they arc imposing multiple fines 

and alleging multiple violations for a single iuspcction. That seems to be 

contrary to the provisions of the law establishing the Ccuter for Tobacco 

Products, which specifically states that retailers must be informed of all 

previous yiolations before being charged with another violation. Can YOIl 

explain how FDA imposing multiple fines for a single inspection is consistent 

with the law? 

The Tobacco Control Act provides that a person "may not be charged with a violation at 

a particular retail outlet unless the Secretary has provided notice to the retailer of all 

previous violations at that outlet" (section 103(q)(I)(Dl). The language in this provision 

refers to "violations," not to "inspections." FDA has interpreted this to mean that each 

violation is a separate finable offense. even if several violations are observed within one 

inspection. We do not interpret the requirement to provide notice of"previous" violations 

as implying a restriction on charging contemporaneous violations. 

That being said. the Tobacco Control Act requires that FDA provide "timely and 

effective notice by certified or registered mail or personal delivery to the retailer of each 

alleged violation at a pmiicular retail outlet prior to conducling afolhrw-up compliance 

check.. . .. (section I 03(q)(l )(8)). Following is a description of how FDA complies with 

this requirement. FDA has contracted with states and U.S. territories to conduct tobacco 

compliance check inspections of retailers that sell or advertise regulated tobacco products 

to detelmine whether those retailers are complying with the Tobacco Control Act and its 

implementing regulations. Inspectors working under these contracts are commissioned 
211 


76491.131

Page 9 The Honorable Joseph R. Pitts 

by FDA to conduct such activities on the Agency's behalf. After each inspection is 

conducted, the commissioned inspector submits obscn'ations and inspection results to 

FDA. FDA then takes appropriate regulatory actions based on its review of the 

inspection data and evidence. Although FDA is not required to issue a Warning Letter 

before taking further regnlatory action, the first time FDA identifies violation(s) at a retail 

outlet, we generally issue a Warning Letter that describes each violation. FDA then 

issues an assignment to a commissioned inspector to conduct follow-up inspections of 

this retail establishmcnt. Subsequent violations may result in FDA issuing II complllint 

seeking civil money penalties. Thus, violations documented during initial inspections by 

FDA-commissioned inspectors are communicated to retailers via an FDA Warning Letter 

(not a fine). It is only violations documented during subsequent inspections thllt have 

precipitated complaints seeking civil money penalties. 

The Honorable Marsha Blackburn 

L How many substantial equivalent applications have been filed since March 

23,20l1? Has the Agency acted 011 any of these? Why not? 

Between March 23, 20 II, and July 1,2012, FDA reccived 390 substantial equivalence 

reports. 

As general background, on January 5, 2011, FDA published a final !,'1.lidance on 

substantial cquivalence entitled "Section 9050) Reports: Dcmonstrating Substantial 

Equivalence for Tobacco Products 

(H'Il'll'fda.gm·ldo;\·nloudsITobaccoProductsIGlIidUllceCompliul1ceRegulatOlylt!/ormuliolll 

UCM239021.pdf)." This guidance provides recommendations and infoTIl1ation related to 

the submission and review of substantial equivalence reports. In addition, the Agency 

published a draft guidance entitled "Demonstrating the Substantial Equivalence ofa New 

Tobacco Product: Responses to Frequently Asked Questions" in September 201 1. This 

draft guidance, when finalized. will represent FDA' s current thinking on this topic 

(1111'11 jila.gOlfTobaccoProductslGuidanceCompiianceRegulatolyillfomwlionlUCM2 7 J 2 

42,htm). In these documents, FDA describes the information needed for the Agency to 

make a detemlination ofsubstantial equivalence, In these documents, FDA describes the 

infoTIllation needed for the Agency to make a detenl1ination of substantial equivalence. 

As of July 1,2012, FDA has carried out a jurisdictional review on 338 of the 390 

substantial equivalence reports received since March 23,2011, and provided information 

to the mannfacturers about whether their product falls under the current jurisdictional 

authority of the Center for Tobacco Products (CTP). As of July I, 2012, FDA has 

perfbrnled an initial "Completeness Review" on 133 substantial equivalence reports 

received since March 23, 2011. As ofJuly 1, 2012, FDA has sent "Advice and 

Infonnation" letters to all 133 of those parties who have submitted reports, which have 

been rcviewed for completeness. These letters ask that the parties either provide 

clarification about their report or submit the missing infOlmation to facilitate FDA's 

review ofthe substantial equivalence reports. As of July 1. 2012, FDA has received 
212 


76491.132

Page J 0 - The Honorable Joseph R. Pitts 

responses from 130 of the advice and infonnation letters and is proceeding with its 

substantial equivalencc cvaluation on these rcports. 

2. Has the Agency announced a time frame ill which it will provide a filial 

Agency response to a submitter? 

FDA is developing final policies and procedures about the time !Tame for responding to 

substantial equivalence reports. Submission of substantial cquivalence reports is new to 

both FDA and tobacco product manufacturers. The optimal time it might take for various 

tobacco manufacturers to develop substantial equivalence reports for tobacco products 

and respond to FDA requests for additional information is not yet known. Thus. FDA 

will base final policies on this experience. 

3. How many tobacco ingredient substantial equivalent exemption requests have 

been filed since July 5, 20ll? How lIlany bas the agency acted upon? 

FDA published a tinal rule entitled "Tobacco Products, Exemptions from Substantial 

Equivalence Requirements" on July 5, 20 II. In this document the Agency describes the 

procedures for submitting a request for exemption !Tom substantial equivalence 

requirements. As of July 2012. FDA has received 22 substantial equivalence exemption 

requests, and is in the process of reviewing all of the requests. 

4. Outside of FDA-initiated contacts, how many requests for meetings have been 

submitted by tobacco manufacturers to the Center for Tobacco Products and 

bow many meetings has it granted? 

As of July I, 2012, FDA has received 78 requests for meetings !Tom tobacco 

manufacturers or related trade associations and CTP has granted 59 of the requests. One 

meeting request was cancelled by the manufacturer. 

In addition, CTP has initiated meetings with the tobacco industry. Specifically, CTP has: 

• Met seven times with either individual manufacturers or multiple manufacturers 

on the general science of smoked and smokeless tobacco products; 

• Met three times with individual manufacturers on science related to dissolvable 

tobacco products; 

• Met three timcs with individual manufacturers on science related to e-cigarettes; 

• Conducted in December 2011, six manufilcturing site visits at the invitation of 

industry to learn more about the manufacturing, marketing, and distribution of 

tobacco products. Several more educational site visits are planned this year; and 

• Sponsored two specific stakeholder discussion meetings for industry. The first 

was held with large and small tobacco manufacturers and growers in December 

20 I 0 and was attended by more than 30 industry leaders. The second was 

conducted in August 201 I with tobacco distributors, wholcsalers, importers, and 

retailers. 
213 


76491.133

Page II The Honorable Joseph R. Pitts 

Also, at the request ofthe Tobacco Manut~1cturers Association. CTP leadership has 

presented at the last three annual meetings in 20 10, 20! I, and 2012. 

5. How nUlll~' meetings have been requested by third-party smoking cessation 

groups and how maIlY or those requcsts for mcetings have been granted by the 

Center for Tobacco Products? 

As of July 2012, FDA has received 31 requests &om third-party smoking cessation or 

similar groups and granted 26 meetings. In addition, CTP sponsored a stakeholder 

discussion meeting for publie health and medical associations in April 2011, which was 

attended by 13 organizations, 

6, As I mentioned earlier, Section 919 of the Family Smoking Prevention and 

Tobacco Control Act requires manufacturers and importers of tobacco 

products to pay user fees. Are YOll aware of any companies that have registered 

as establishments with the FDA that have not paid uscr fees'! 

The Tobacco Control Act did not give FDA authority to collect user fees for all types of 

tobacco products immediately upon enactment, so there are some registered 

establishments that have not paid user fees because the types of products they produce are 

not currently subject to assessment by FDA. However, as of August 9, 2012, there were 

27 registered establishments that were in arrears to FDA for either all or part of the user 

fees that they owe. Overall, the collection rate of tobacco user fees has been 99.4 percent 

off'ees billed. 

7. Are you aware of the current phenomena involving retail establishments seIling 

consumers pipe tobacco that has been dried out for use by the consumer to 

convert this pipe tobacco into a cigarette through the use of a rol!-your-own 

machine? Would you agree that tobacco sold by a retailer for the intended 

purpose of manufacturing a cigarette makes the tobacco cigarette tobacco the 

resulting product a cigarette'? And if that is the case, doesn't that require the 

retail establishment to register the store as a manufacturer establishment under 

the Act? 

FDA is aware of retail establishments selling consumers pipe tobacco for use in rol1-

your-own cigarette machines and is gathering more infonnation about this practice to 

determine the appropriate regulatory response, 

8. Community pharmacists have long felt tbat there exist certain prescription drugs 

that could be placed in a limited "class" and that could be dispensed to a patient 

pursuant to or following a one-on-one cOllsultation with a pharmacist. What is 

the FDA's opinion on tbe feasibility or likelihood of the creation ofthis type of 

limited drug "class"? 

FDA is exploring a potential new paradigm under which the Agency would approve 

certain drugs that would otherwise require a preSCription for nonprescription use (also 
214 


76491.134

Page 12 - The Honorable Joseph R. Pitts 

known as over-the-counter or OTC) under conditions of safe use specific to the drug 

product. Thcse conditions of safe use would be specific to the drug product and might 

require sale in certain pre-defined health care settings, such as a phannacy. FDA held a 

public hearing on March 22-23, 2012, "Utilizing Innovative Technologies and Other 

conditions of Safe Use (0 Expand Access to Nonprescription Drugs," to obtain 

infonnation and comments from the public on the fcasibility of this paradigm and its 

potential benetits and costs. For infonnation regarding this meeting, including slide 

presentations and transcripts, please see: 

11·11·H'jila.g01>1DrugsINewsEl·lflllslucm289290.hlm. 

9. Community pharmacists have a long history of advocating for the simplification 

of the written materials that currently are required to be distributed to the 

patient with each prescription. What is the cllrrent status of moving towards a 

"olle-document solution" to address this issue? 

FDA welcomes community phannucists' support of our efforts to simplify written 

materials given to patients with their prescription medications. We are developing a new 

framework, Patient Medication Infomlation (PM!), to provide accurate and balanced 

medication intormation that is delivered in one consistent and easily understood tOnnat. 

CllITently, patients may receive infomlation about their prescriptions in a variety of 

fonnats, each with different content requirements or standards, including Patient Package 

Inserts (PPI) and Medication Guides (MG), which are required for certain products, 

and/or Consumer Medication Information (CMT), which pharmacies voluntarily dispense 

with prescriptions. FDA has detennincd that this current approach is not adequate to 

ensure that patients receive the essential infonnation needed to use a drug safely. FDA is 

considering how to ensure that patients receive accurate and balanced PMl in a consistent 

and easily understood format. Among other things, FDA is considering developing 

content and form at standards for PM!, II range of distribution and infonnation 

accessibility mechanisms, and methods to ensure that PM! for each product is useful and 

comprehensible (e.g., consumer testing). 

Currently, FDA is testing prototypes with consumers and is conducting ongoing 

stakeholder meetings to help FDA detennine the appropriate regulatory path forward, 

FDA anticipates that two studies will be completed in late 2012 or 2013: an ongoing 

FDA study (75 FR 23775, May 4,2010) and a study being performed under a cooperative 

agreement with the Engelberg Center for Health Care Refonn at the Brookings Institution 

(currently in the design phase). Stakeholder discussions will also continue as FDA 

considers how best to accomplish its goal of ensuring that patients receive accurate and 

balanced infoffi1ation about their prescription medications, in an easily understood 

fomlat. 

The Honorable Brett Guthrie 

1. Why has FDA not approved a single tobacco product submission since the 

creation of the Center for Tobacco Products was created? 
215 


76491.135

Page 13 The Honorable Joseph R. Pitts 

As general background, on January 5, 2011, FDA published a final guidance on 

substantial equivalence entitled "Section 9050) Reports: Demonstrating Substantial 

Equivalence for Tobacco Products 

(wwwfda.gavldawnlaadslTabaccaPraductsIGuidanceComplianceRegulatarylnfarmalionl 

UCM239021.P4f)." This guidance provides recommendations and information related to 

the submission and review of substantial equivalence reports. In addition, the Agency 

published a draft guidance entitled "Demonstrating the Substantial Equivalence of a New 

Tobacco Product: Responses to Frequently Asked Questions" in September 2011. This 

draft guidance, when finalized, will represent FDA's current thinking on this topic 

(wwwfda. gavlTobaccaPraductslGuidanceCamplianceRegulatorylnformaiianlUCM2 712 

42.htm). In these documents, FDA describes the information needed for the Agency to 

make a detennination of substantial equivalence. 

FDA received 3,126 provisional substantial equivalence reports before March 23, 2011. 

Products for which a substantial equivalence report was received before March 23,2011, 

can remain on the market unless FDA finds that they are "nat substantially equivalent." 

Additionally, between March 23, 2011 and July 1,2012, FDA received 390 substantial 

equivalence reports. Those products cannot be marketed unless and until FDA issues a 

finding of substantial equivalence. The Agency has received seven modified-risk tobacco 

product applications. 

See response to Question 2 below for discussion of the status ofCTP's response to these 

submissions. 

2. Please outline the specific backlog of submissions that have not been evaluated 

and how eTP is planning to address this backlog. 

As you are aware, premarket review and marketing authorization of tobacco products is a 

new area for FDA. Given the enormous public health impact of tobacco products, there 

are critical scientific questions that must be answered and review decisions that must be 

made so that an effective, careful, and consistent review process is created and 

implemented. To date, FDA has taken a number of actions related to its review of 

substantial equivalence (SE) reports for tobacco products. 

FDA has published several rules and guidance documents to assist industry and the 

public in understanding and responding to the requirements of the Tobacco Control Act. 

For example: 

• In January 2011, FDA issued a final guidance on SE entitled "Section 905(j) 

Reports: Demonstrating Substantial Equivalence for Tobacco Products". This 

guidance provided recommendations and information related to the submission 

and review of SE reports. The guidance is available at 

http://wwwfda.ga~.;TobaccoProductsIGuidanceCamplianceRegulatary1nformatio 

nlucm253273.htm, 
216 


76491.136

Page 14 - The Honorable Joseph R. Pitts 

.. In July 2011, FDA issued a final rule entitled "Tobacco Products, Exemptions 

from SE Requirements" (http://www.gpo.govlfdsys/pkgIFR-201 1-07-05/pdf/2011-

16766.pdfJ. This rule described the procedures for submitting a request for 

exemption from SE requirements. 

.. [n September 2011, FDA issued a draft guidance entitled "Demonstrating the 

Substantial Equivalence of a New Tobacco Product: Responses to Frequently 

Asked Questions" 

(hllp:/lwwwfda. govrrobaccoProdlictslGuidance Compliance Reg ulatorylnformati 

on/ucm271242.htm). 

FDA is working diligently to provide as much information and feedback as possible to 

affected parties because this is a new process and many of the companies are unfamiliar 

with FDA and product regulation. CTP is also interested in hearing and understanding 

industry concerns and has been very active in meeting with manufacturers to discuss a 

variety of issues. As of July 1,2012, CTP has received 78 requests for meetings from 

tobacco manufacturers or related trade associations, and CTP has granted 59 of the 

requests. Additionally, we also have developed public webinars to explain our processes 

and describe the kind of information the Agency needs tobacco manufacturers to submit. 

In response to industry feedback, where possible, FDA is trying to streanlline the SE 

report review process: 

• FDA has increased opportunities for communication with industry by 

encouraging teleconferences between the assigned regulatory project manager and 

the applicant. We have also taken steps to facilitate quicker responses to 

questions. 

• FDA is taking industry concerns into account and has streamlined the SE report 

review process by modifying the preliminary review so that it focuses only on 

administrative issues (allowing submission deficiencies to get back to the 

applicant more quickly). 

FDA has taken other actions based on industry feedback and questions including 

modifying the wording in our Advice and Information Request letters and informing 

submitters of potential contact by the Office of Compliance and Enforcement in our 

acknowledgement letters. 

SE reports received before March 23, 2011, are considered "provisional," and the 

products covered by those reports can remain on the market unless FDA finds that they 

are "no 1 substantially equivalent." FDA received 3,126 provisional SE reports before 

March 23, 2011. SE reports received on March 23, 2011, or after are "regular" reports, 

and products covered by those reports cannot be marketed unless FDA first issues a 

finding ofSE. Between March 23, 2011, and July 1,2012, FDA received 390 regular SE 

reports. 
217 


76491.137

Page 15 - The Honorable Joseph R. Pitts 

As of July 1, 2012, FDA has completed the following steps in its review of these SE 

reports: 

• Completed jurisdictional reviews for 3,464 of the reports (including 338 of the 

390 regular SE reports), with notifications made to the submitters about whether 

or not their product is currently being regulated by the Center for Tobacco 

Products (CTP); 

• Performed an initial "Completeness Review" on 133 ofthe regular SE reports; 

• Sent 133 "Advice and Information Request" administrative andlor scientific 

completeness review letters to submitters whose reports were missing 

infonnation; and 

" Received and processed 130 responses to the "Advice and Tnfonnation Request" 

letters and is proceeding with the scientific evaluation of the supplemented SE 

reports. 

3. How many Full Time Equivalents (FTEs) are dedicated to product 

submissions at CTP? 

As of July 1, 2012, CTP has 98 staff members who had some specified duties that include 

the review of tobacco product submissions, development ofreview process, or support 

for the review process. 

4. RRS has hundreds of millions of dollars in the Prevention and Public Health 

Fund established in the Patient Protection and Affordable Care Act. A February 

9,2011, press release from HRS announced that a $750 million "investment in 

prevention," which includes $298 million for Community Prevention to, among 

other things, prevent and reduce tobacco use. How does FDA ensure that 

activities at CTP funded by user fees are not duplicating or at cross purposes 

with these efforts by HHS'! 

The Tobacco Control Act authorizes FDA to collect quarterly fees from the tobacco 

industry. These fees are to be "available only for the purposes of paying the costs of the 

activities of the Food and Drug Administration (FDA) related to the regulation of 

tobacco products .... " (section 919(c)(2)(A) of the Act». Furthermore, the Act specifies 

that these tobacco user fees "are the only funds authorized 10 be made available for 

tobacco regulation activities" (section 919(c)(2)(B)(i)). 

FDA has put a comprehensive financial stewardship and accounting plan in place to 

ensure that tobacco user fees are appropriately used. While many agencies and offices in 

the Department of Health and Human Services (HHS), including FDA, are working 

together to address the significant public health concerns created by the use of tobacco 

products, the Agency does not provide cessation services or engage in community-based 
218 


76491.138

Page 16 The Honorable Joseph R. Pitts 

tobacco prevention activities that are funded by the Prevention and Wellness Fund 

section of the American Recovery and Reinvestment Act of2009, or the Prevention and 

Public Health Fund authorized by the Affordable Care Act. FDA works closely with 

other HHS components to ensure that the various tobacco programs are coordinated and 

arc not duplicative. For example, the Centers for Disease Control and Prevention's 

(CDC) Tobacco Information and Prevention Source (TIPS) communication campaign 

targets entrenched smokers (primary target is adult smokers 18-54) and focuses on the 

long-term chronic health effects to encourage cessation. Using its authorities under the 

Tobacco Control Act, FDA's public education etIorts will educate teen and young adult 

consumers about the harms of tobacco products and the dangers of their use to decrease 

youth initiation. 

The Honorable Brian P. Bilhray 

L Dr. Hamburg, did you know that California is the only state in the United 

States that still requires both a state inspection as well as an FDA inspection 

for their life science facilities. What do you think of having FDA be the sole 

authority over facility inspections'! Do you think this will save money and 

time? 

The California Department of Public Health Food and Drug Branch (CDPH FOB) 

conducts periodic licensing inspections of drug and device facilities, which are required 

by California state law. FDA conducts both pre-approval and post-approval inspections 

of drug and device establishments. The state of California pre-licensing inspection is not 

equivalent to FDA's pre-approval inspections. CDPH FOB and FDA meet on a semiannual basis to share information about the drug and device manufacturing facilities that 

are subject to both CDPH FOB and FDA jurisdiction inventory. FDA and CDPH FOB 

also conduct joint inspections of drug and device firms. These joint inspections are a 

conscious effort to increase uniformity between federal and state agencies and provide 

training. 

FDA collaborates with our counterpart authorities at the state level, as we do with other 

regulatory agencies, when doing so reduces unnecessary duplication of effort. There are 

some drug manufacturing facilities, like medical gas transfilling operations, that FDA is 

not able to inspect as frequently as other types offacilities. Relying on state inspection 

information has at times proven helpful to FDA in establishing our inspection priorities. 

FDA has also relied upon states to administratively embargo violative drugs while wc 

pursued court action. If states cease to maintain the capacity to inspect and license 

facilities also under federal jurisdiction, FDA may not be able to collaborate, when 

efficient to do so. 

2. Are you aware/familiar with any areas where CA Food and Drug Branch 

(FDB) inspections look at issues that FDA does not'! Are yOll aware of FDB 

identifying issues that FDA missed'! 
219 


76491.139

Page 17 The Honorable Joseph R. Pitts 

The state of California inspects under its own authority to ensurc compliance with its 

state laws. Also, the state of California performs food inspections under contract with 

FDA and is required to report violations encountered when perfonning work under this 

contract. The state of California does not perform human drug product inspections for 

FDA. 

3. With several products on the market and hundreds of clinical trials undenvay, 

many obsen'ers believe that regenerative medicine holds the promise of 

t .. ansforming treatment for diseases such as stroke, heart disease, diabetes, 

various cancers and spinal cord injury. Do you agree? 

Cell-based therapies show great promise for repairing, replacing. restoring, or 

regenerating damaged cells, tissues, and organs. The Agency recognizes that 

regenerative medicine products are novel and very complex and supports the 

development of these new innovative products. We encourage and work with sponsors to 

facilitate the development of safe and effective products. 

Currently, FDA oversees over 500 investigational applications for regenerative medicine 

products that include clinical trials designed to treat serious diseases such as heart 

diseases, diabetes, cancer. and spinal cord injuries. 

4. In your view, what are the obstacles to faster commercialization of regenerative 

medicine and cell therapy products? What specific steps can the FDA take to 

facilitate commercialization of these products? 

Novel biological products containing living cells and tissues show great promise for use 

as therapies, but design, manufacture, and testing of these products have proven to be 

very challenging. FDA understands that the development of these novel and very 

complex products is an iterative process, and this is why FDA works closely with 

sponsors/innovators to close the science gaps and address any potential challenges. 

One challenge to successfully developing cellular therapies has been the uncertainty 

about how to test these products to ensure that they are safe and effective. Testing will 

need to focus on safety to ensure the products are free from bacterial contamination and 

infectious agents, as well as on cellular characteristics, such as differentiation of 

immature cells (such as stem cells) to mature cell types, because both have the potential 

to affect the safety and effectiveness of these novel products. 

Another challenge is ensuring that the cells manufactured outside of their natural 

environment in the human body do not become ineffective or dangerous and produce 

significant adverse effects, such as tumors, severe immune reactions, or growth of 

unwanted tissue. 

In response to these and many other challenges, FDA interacts with individual sponsors 

multiple times prior to, and following, submission ofregulatory files, such as 

Investigational New Drug (fND) applications and Investigational Device Exemption 
220 


76491.140

Page 18 The Honorable Joseph R. Pitts 

(IDE) applications, to discuss how to develop the data needed to support premarket 

notifications (51 O(k)s), premarket approval (PMA) applications, and biologics license 

applications (BLA) in order to market these products. 

FDA also has active discussions with regenerative medicine stakeholder organizations to 

enable the Agency to recognize opportunities for the development of guidance, standards, 

or other tools needed to support product development in this area. FDA works with the 

clinical, research, academic, industry, and standards communities in various ways 

to ensure that there is useful and ongoing communications about issues related to the 

development of regenerative medicine products. When FDA has gained enough 

experience through their review process in a particular area, the Agency works in tandem 

with outside organizations to develop consensus standards. Additionally, FDA labs work 

on mission-related regulatory science research in cross-cutting areas. These research 

efforts support FDA's regulation of these novel products and can be useful to private and 

government entities as they develop their products. In this nove! product area, the 

development of cross-cutting evaluation or development tools (for example, test methods 

that can be used for cell/scaffold characterization in many products) support product 

development. FDA's research is published in scientific and medical journals and 

presented at scientific meetings so that this infornlation is available to all sponsors. 

FDA has published several guidance documents to help sponsors develop their products. 

These guidances can be accessed through FDA's website at 

http://wwwfda,govIBiologicsBloodVaccinesIGuidanceComplianceRegulatory1f!formation 

/GuidancesICeliularandGeneTherapyldefault,htm, 

5. In 2006, the U.S. Department of Health and Human Services issued a report 

saying tbat it was essential to establish a cross-agency council to develop a set of 

coordina.ted federal research and regulatory policies on regenerative medicine 

products. Do you agree with this recommendation? 

As discussed below in response to Question 6, FDA participates in an established and 

effective cross-agency working group, the Multi-Agency Tissue Engineering Science 

(MATES). FDA's Center for Biologics Evaluation and Research (CBER) is the lead for 

coordination of FDA activities in this area, including providing leadership in review 

policy as well as in coordination with our international regulatory counterparts. 

6. How can key federal agencies such as FDA, NIH, DOD and others better 

collaborate to develop a coordinated national strategy to support regenerative 

medicine" 

The established and effective cross-agency working group, MATES, member agencies 

include the HHS agencies involved in the area: FDA; National Institutes of Health 

(NIH); Centers for Medicare & Medicaid Services (CMS); Department of Defense (DoD) 

agencies: Defense Advanced Research Projects Agency (DARPA), Army Medical 

Research and Material Command (MRMC), NavyINavy Research Lab (NRL), 

Department of Veteran Affairs; Department of Commerce (National Institute of 
221 


76491.141

Page 19 - The Honorable Joseph R. Pitts 

Standards and Technology (NIST), Department of Energy; National Aeronautics and 

Space Administration (NASA); U.S. Environmental Protection Agency (EPA); and the 

National Science Foundation (NSF). 

MATES facilitates communications, enhances cooperation among agencies, monitors 

teclmology in the field, fosters technology transfer and translation, and promotes 

formulation and use of standards. Current project highlights are an active interface with 

the National Nanotechnology Initiative, and a MATES Workshop, co-sponsored by NIH 

and NSF, on "Imaging in Tissue Engineering," held at NIST in May 2012. Agencies 

participate on specific cooperative MATES projects. according to their specific agency 

missions and capabilities, and also participate in additional cross-agency efforts as 

missions align. For example. FDA and NIH are in the midst of a series of workshops on 

"stem cells in translation" to advance translation of products fTom bench to bedside. 

Additionally, FDA and NIH participate, as their individual mandates allow, in the Armed 

Forces Institute of Regenerative Medicine efforts (which, as a DoD-led project, is a 

MATES member). MATES published a Multi-Agency Strategic Plan for advancing this 

field that incorporates overarching scientific goals and strategic priorities for federal 

agencies. The plan can be accessed at http://www.tissueengineeringgov/. 

In addition to working with all of our partners noted above, such as NIH, the Health 

Resources and Services Administration (HRSA), 000, and NIST, FDA also works with a 

number of other organizations that are not federal agencies, such as: 

• ASTM International (formerly known as the American Society for Testing and 

Materials and the International Standards Organization (ISO»; 

.. Califomia Institute for Regenerative Medicine (CIRM); 

.. Intemational Society of Cellular Therapies (ISCT); 

• Alliance for Regenerative Medicine (ARM); and 

• American Society of Gene & Cell Therapy (ASGCT). 

Joint efforts by FDA and NIH on regenerative medicine have resulted in three recent 

workshops: the NIH/FDA Workshop, "Pluripotent stem cells in Translation: Early 

Decisions" (March 2011) and the Production Assistance for Cellular Therapies 

(PACT)INational Heart, Lung, and Blood Institute (NHLBI) Workshop, "Cell Therapy 

for Pediatric Diseases-A Growing Frontier" (September 2011), and a third workshop 

with NIH, "Pluripotent Stem cells in Translation: Preclinical Considerations." 

FDA staff are members and co-chairs of a variety of NIH scientific interest groups that 

sponsor seminars on regenerative medicine topics, e.g., the FDAlNHLBI interagency 

group that meets to share information on cell, gene therapy, and regenerative medicine 

products relevant to studies funded by NHLB!. FDA is also a participant in the NHLBI 

Centers for Accelerated Innovation Program. The focus of this initiative is to establish 

centers that will address problems that hinder the critical steps necessary to translate 

novel scientific advances and discoveries, such as regenerative medicine, into 

commercially viable therapeutics. FDA representatives also participate on the NIH 

Center for Regenerative Medicine (CRM) Advisory Council. NIH serves as a resource 
222 


76491.142

Pagc 20 - The Honorable Joseph R. Pitts 

for the scientific community in translating advances in stem cell and progenitor cellbased technologies to the clinic. One function of the CRM will be to provide services as 

a repository for human stem cell line. CRM is within the NIH Intramural Research 

Program. FDA also serves as an Ex-officio member on the NIH Recombinant DNA 

Advisory Committee (RAC). The RAC discusses in a public forum gene therapy clinical 

protocols. FDA staff provides NIH/RAC with Agency perspective and clarifies FDA 

policy. 

FDAlCBER also has strategic goals to improve global public health through international 

collaboration. The International Program at CBER uses a range of mechanisms to 

achieve its strategic goals: regulatory hannonization, infonnation sharing, international 

standards development, regulatory capacity building, and regulatory science 

collaborations. CBER is focused on international activities and standards development as 

they relate to cellular therapy products, gene therapy products, and tissue engineering 

products. 

7. FDA recently issued a report on regulatory science research. Please describe 

specific regulatory science initiatives that would support development and 

approval of regenerative medicine products. 

FDA has published two reports to address how initiatives in regulatory science will 

support development and approval of new treatments and interventions, including 

regenerative medicine products. The 2010 report, "Advancing Regulatory Science for 

Public Health: A Framework for FDA's Regulatory Science Initiatives," explains how 

FDA's new Regulatory Science Initiative can speed progress in FDA's high-priority 

public health areas. The initiative will be characterized by a four-part framework: 

Leadership, coordination, strategic planning, and transparency to support science 

and innovation 

Support for mission-critical applied research, both at FDA and collaboratively 

Support tor scientific excellence, professional development, and a learning 

organization 

Recruitment and retention of outstanding scientists 

To thal end, most of the FY 2011 resources were used to mobilize external collaborations 

and partnerships and support studies in four major regulatory science research areas: 

I. Transfonning Product Development for Patients: Bringing Progress to Patients 

(e.g., Methods for Modernizing Toxicology, Biomarkers for Personalized 

Medicine, the Stem Cell Initiative and Updating Drug Review Standards) 

2. Science to Address Emerging Technologies in FDA-regulated Products 

(e.g., Nanotechnology and Expertise to Regulate New Animal Biotech Products) 

3. Infonnation Sciences for Health Outcomes 

(e.g., Medical Device Registry and Scientific Computing for Data Analyses) 

4. Addressing Unmet Public Health Needs 

(e.g., Nutrition and Public Health) 
223 


76491.143

Page 21 The Honorable Joseph R. Pitts 

In addition, the 2011 report, "Advancing Regulatory Science at FDA: A Strategic Plan," 

identifies eight priority areas of regulatory science to which FDA will apply resources to 

fulfill its public health and regulatory mission. The priority areas are: 

I. Modernize Toxicology to Enhance Product Safety 

2. Stimulate Innovation in Clinical Evaluations and Personalized Medicine to 

Improve Product Development and Patient Outcomes 

3. Support New Approaches to Improve Product Manufacturing and Quality 

4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies 

5. Harness Diverse Data through Information Sciences to Improve Health Outcomes 

6. Implement a New Prevention-focused Food Safety System to Protect Public 

Health 

7. Facilitate Development of Medical Countermeasures to Protect Against Threats to 

U.S. and Global Health and Security 

8. Strengthen Social and Behavioral Science to Help Consumers and Professionals 

Make Informed Decisions about Regulated Products 

8. Are there regulatory science research initiatives that could address some of the 

scientific obstacles to product approval in regenerative medicine? 

As noted in the response to Question 4, development and approval of regenerative 

medicine products is challenging in part due to the uncertainty about the safety and 

efficacy of regenerative medicine products and the unknown, potentialiy adverse effects 

of cells manufact\lfed outside the human body. To expand its knowledge of these issues, 

FDA conducts a variety of research programs. For example, FDA is engaged in the 

following ongoing research efforts: 

I. Ensuring safety and efficacy of stem-cell-based products 

2. Developing ways to measure safety and efficacy of tissue-engineered products 

3. Predicting the safety and efficacy of cell and tissue products used for repair of 

damaged tissue and structures through cell growth and maturation pathways 

4. Developing predictive indicators of cell maturation as measures of cell therapy 

product safety and efficacy 

5. Developing new methods to evaluate measurable stem cells using a variety of 

analytic methods that correlate measurable cell characteristics with a desired 

result (such as repair of blocked blood vessels) and undesirable (toxic) effects 

The Honorable Bill Cassidy 

1. Can inspectors as part of their union contracts refuse to inspect overseas'! 

The provisions in the Collective Bargaining Agreement related to foreign inspections are 

not a hindrance to our ability to conduct these inspections. We have procedures in place, 

agreed to by the union, for managing our foreign inspection program. For example, 

although the union agreement states that we must seek volunteers before directing 
224 


76491.144

Page 22 The Honorable Joseph R. Pitts 

assignments, we may and have directed individuals when there are no volunteers for an 

assignment Our procedures are working and we continue to increase the number of 

foreign inspections we conduct each year. 

The Honorable Edolpbus Towns 

1. Many tobacco retailers operate on Native American reservations. Can you 

tell me bow many inspections of retail facilities bave occurred on 

reservations? 

To date, there have been no inspections of retailers on "Indian country." FDA is working 

to develop a contracting mechanism for Indian tribes and/or tribal organizations to 

conduct inspections, similar to the state contract mechanisms that have been used to date 

for 37 states and the District of Columbia. CTP is currently reaching out to tribes and 

Native American organizations through meetings and discussions to learn about the 

tribes, their government, and laws in an effort to develop a working relationship with 

them to continue to expand our compliance program. The goal is to begin awarding 

contracts to tribes in FY 2013 to conduct inspections of retail establishments on tribal 

land. 

FDA has met with various tribal representatives in a number of fonuns, including official 

Departmental Consultation, a public stakeholder discussion, and individually requested 

meetings, to discuss the broad range ofimpJications the Tobacco Control Act has on 

tribally owned, operated, or located activities. These discussions are ongoing. 

2. Many tribes and tribal leaders are, in fact, the owners of smoke shops or other 

retail outlets that sell tobacco. Who is inspecting these outlets to ensure 

compliance with the law? 

As mentioned above, there have been no inspections of retailers on Indian country to 

date. FDA is working to develop a contracting mechanism for Indian tribes and/or 

tribal organizations to conduct inspections, similar to the state contract mechanisms 

that have been used to date for 37 states and the District of Columbia. In addition, 

CTP has begun to work with tribes and tribal organizations to educate tribal retailers 

about the Tobacco Control Act and its implementing regulations. 

J. Internet sellers of cigarettes do a brisk business-- and continue to evade taxes 

on many sales. Simply typing "tax free cigarettes" into II search engine 

produces pages of options. Are these Internet sellers being inspected to see 

whether people delivering their products actually verify the age of the person 

to whom cigarettes are delivered? If not, how do you plan to enforce the law? 

The (Prevent All Cigarette Trafficking) PACT Act of 201 0, which was enacted after 

the Tobacco Control Act, imposes a number of restrictions related to the sale of 
225 


76491.145

Page 23 - The Honorable Joseph R. Pitts 

cigarettes and smokeless tobacco through the U.S. mail, including through Internetbased and other remote sellers. The purpose of the PACT Act, among others, is to 

create disincentives for the illegal smuggling of tobacco products and stem 

trafficking, and to prevent youth access through illegal Internet and contraband sales. 

The U.S. Attorney General is responsible for administering and enforeing the PACT 

Act. 

The Honorable Frank Pallone, Jr. 

1. Under section SOS-llof the FD&C Act, as amended by the Food and Drug 

Administration Amendments Act of 2007 (FDAAA)J FDA may require a 

REMS when necessary to ensure that the benefits of a drug outweigh its risks. 

Sponsors provide information on the safety of the product via REMS materials, 

but they also provide information on their labels. Both of these materials are 

updated periodically to re11ect new safety information, but it is my 

understanding, that [under FDAAAJ the process for review and approval of 

updated materials is not done simultaneously. Is that correct? 

We nole that this question was posted in March 2012, and was based on the Risk 

Evaluation and Mitigation Strategies (REMS) provisions in the Food and Drug 

Administration Amendments Act of2007 (FDAAA). Under FDAAA, when it has been 

determined that new safety information must be added to the labeling and corresponding 

modifications to the REMS are required to reflect the new safety information, the sponsor 

has been notified and directed to submit these changes in Prior Approval Supplements. 

Safety labeling changes are required to be submitted to FDA within 30 days of 

notification. However, under FDAAA, a supplement that included REMS modifications 

may not have had this same deadline. Sometimes, the corresponding modifications to the 

REMS to include the new safety information have involved the REMS document and 

mUltiple appended REMS materials, such as enrollment forms, prescriber training 

materials, and pharmacy training materials, and more time may have been allowed for the 

submission of these REMS modifications than the safety labeling changes. When 

possible, FDA has worked to promptly review and approve the safety labeling changes 

and the REMS modifications at the same time. 

In addition, if the safety labeling changes and corresponding REMS modifications have 

involved a class of drugs, sponsors within the class may each submit different language 

for the REMS and REMS-appended materials. Additional time may be needed in this 

case to harmonize the language across the class so that the safety message is consistent 

with all of the products and then to incorporate it into the REMS. Given the differences 

in FDAAA's requirements for submission, review, and approval for safety labeling 

changes and modifications to a REMS, there have been times when the materials 

available to the public may have been inconsistent. 

We also nOle that in July 2012, after this question was posed, the Food and Drug 

Administration Safety and Innovation Act, (FDADIA) (P.L. 112-144) was enacted. 
226 


76491.146

Page 24 - The Honorable Joseph R. Pitts 

Section 1132 ofFDASIA includes a number of changes to the REMS provisions in 

FDAAA, including changes intended to help ensure that when a safety-related change is 

approved for a drug product's labeling, conforming changes to a REMS arc made in a 

timely manner. More specifically, under FDASIA, FDA will review and act upon 

proposed modifications to conform the REMS to approved safety labeling changes within 

60 days. 

So it seems to me that [under FDAAA] the information contained in updated 

labeling and promotional materials may differ, for a significant period of time, from 

the safety information in the REMS materials. 

a. Does that potential, indeed exist? 

Yes, for the reasons described above, under FDAAA the safety changes to the labeling 

and corresponding modifications to the REMS document and REMS-appended materials 

have been submitted, reviewed, and approved on different time clocks. 

However, also as noted above, FDASIA, which was enacted in July 2012 after this 

qucstion was posed, includes changes to the REMS intended to help address this concern. 

b. So, recognizing that different entities within FDA review these materials, 

is there something tbat FDA can be doing [under FDAAA] to better 

coordinate the updating of REMS materials and product labeling and 

promotional materials to reilect new safety information so that the 

materials are not inconsistent? 

FDA is working on improving coordination between the various offices that review 

safety labeling changes and REMS modifications, which could improve the process of 

implementing the different FDAAA provisions. 

In addition, as noted above, FDASIA, which was enacted in July 2012 after this question 

was posed, includes changes to the REMS provisions intended to help address this 

concern. For example, in accordance with FDASIA, FDA will review and act upon 

modifications to conform the REMS to approved safety labeling changes, and minor 

REMS modifications (as defined by FDA in guidance), within 60 days. 

2. As I understand it, [under FDAAAJ the process for making changes to a REMS 

is pretty complex and time consuming. While FDA allows companies to make 

minor labeling changes without pre approval from FDA, the same is not true 

for minor changes to REMS. Currently, FDA requires pre approval for every 

change to a REMS, including minor changes, such as updating forms or 

adding a newly approved drug to a list of current medications and changes 

related to operational improvements, such as using a website or iPad, rather 

than a fax machine, to submit such data. Can you explain why a similar 

process that allows companies to make minor label changes without pre 
227 


76491.147

Page 25 The Honorable Joseph R. Pitts 

approval from FDA bas not bccn implemented [u n d c r FDA A A J for 

minor changes to a REMS? 

We note that this question was posed in March 2012, and was based on the REMS 

provisions in FDAAA. However FDASIA made a number of changes to the REMS 

provisions in FDAAA that may help to address this concern, by streamlining the process 

for certain REMS modifications. For example, in accordance with FDASIA, FDA will 

review and act upon minor modifications to REMS, as defined by FDA in guidance, 

within 60 days. In addition, under FDASIA, FDA will establish through guidance that 

certain REMS modifications may be implemented following notification to FDA. 

We also note that FDA is working on improving coordination between the various offices 

that review safety labeling changes and REMS modifications, which could improve the 

process of implementing the different FDAAA provisions. 

The Honorable Edward J. Markey 

Deferral Requests [Under Section 402 of the Food and Drug Administration Act of 

2007 (FDAAA)j 

1. What percentage of requcsts to defer postmarket pediatrie requirements 

under PREA does FDA approve? 

Under FDAAA, FDA has not denied a company's petition for deferral. Part of the reason 

for this is that one of the legislative criteria for a deferral is that the product is ready for 

approval in adults. Most requests for deferrals are granted because pediatric studies are 

not completed but adult studies are complete and an application is ready for approval. 

This is the case regardless of the reason the pediatric studies are not complete. 

Current Enforcement Authority [Under Section 402 of the Food and Drug 

Administration Act of 2007 (FDAAAJI 

1. If a company fails to submit its plan for pediatric studies at the time of 

submission, as required by PREA, what enforcement options does FDA 

currently have? 

Under FDAAA, if a company fails to submit its pediatric plan at the time of submission, 

FDA currently has three options: 1) refuse to file the application and inform the sponsor 

that they must submit a pediatric plan before we will file the application; 2) inform the 

sponsor in the filing communication that their application is deficient because they have 

not submitted a pediatric plan and they must do so prior to an action being taken; or 3) 

work with the sponsor to get a pediatric plan during the review period and if they still do 

not submit one, we could decide to not approve the application. 
228 


76491.148

Page 26 The Honorable Joseph R. Pitts 

FDA has generally worked with the applicant, rather than refusing to file an application. 

It is often a challenge to consider not reviewing data that may prove beneficial for one 

segment of the population (adults) because the applicant has not addressed another 

population (pediatrics). If the indication in the application was largely a pediatric 

indication, it is likely that FDA would consider refusing to file the application. In 

addition, there are provisions in FDA regulations, in the event of a refuse-to-file action. 

for sponsors to require FDA to file the application "over protest," 

2. If FDA determines that a company isn't complying with its post-market 

pediatric requirements under PREA, is it true that the only enforcement 

tool FDA has at its disposal is misbranding of the product? 

Under FDAAA, the only enforcement mechanism provided under PREA is that FDA 

consider the product to be misbranded. Again, this enforcement mechanism places 

FDA in the position of potentially making a product unavailable, when that product is 

beneficial for one segment of the population (adults) because the applicant has not 

addressed another population (pediatrics). 

3. What are the implications for access to lifesaving treatments for adults if 

FDA were to deem a drug misbranded because the company failed to 

comply with its PREA requirements? 

Under FDAAA, the only enforcement mechanism provided under PREA is that FDA 

consider the product to be misbranded. FDA has not brought a misbranding case for 

failure to comply with PREA. If FDA were to exercise the misbranding provision under 

PREA, doing so would potentially prevent access to a safe and effective therapy for an 

adult population. This would have a negative impact on the public health. 

4. What are the implications for access to lifesaving treatments for children 

being prescribed a drug off-label if FDA were to deem the drug misbranded 

because the company failed to comply with its PREA requirements? 

Under FDAAA, if FDA were to deem a lifesaving treatment misbranded because the 

company failed to complete its pediatric requirements, children who were being 

prescribed the drug off-label would lose access to it. Adults would also lose access to 

the drug. 

5. How often has FDA used their misbranding authority in cases where 

companies failed to comply with its post-market pediatric requirements 

under PREA? 

Under FDAAA, FDA has never brought a misbranding case for failure to comply with 

PREA. 
229 


76491.149

Page 27 The Honorable Joseph R. Pitts 

Current Levels of Company Compliance [Under Section 402 of the Food and Drug 

Administration Act of 2007 (FDAAA)} 

1. What percentage of drug and biologics applieations and supplements that 

have NOT received a PREA waiver do not contain a plan for pediatric 

studies at the time of submission, as required by PREA? 

For the time period January I, 2011, to May 2012, 94 percent of applications that 

were filed and triggered PREA appropriately addressed PREA in the submission, 

either by requesting a waiver, requesting a deferral and induding a plan for the 

studies to be deferred, submitting pediatric studies or documentation that the 

product was already appropriately labeled for pediatrics, or some combination of the 

three. Of the applications that did not include a request for a full waiver, 88 percent 

contained a pediatric plan, pediatric studies, or documentation that the product was 

already appropriately labeled for pediatrics. 

2. FDA data shows that 78% of the PREA postmarket pediatric study 

requirements due since 2007 were not completed by their due dates. Does FDA 

track -either internally or publieally-why the companies missed their 

postmarket pediatric requirements under PRE A? 

The 78 percent figure is not accurate. It is based on a calculation that does not fairly 

represent the status of pediatric studies under PREA. That figure was derived using 

the number of deferrals granted since FDAAA was enacted and the number of 

studies that were completed by the due date. It does not take into account the fact 

that the due date for many of those studies may be several years in the future. 

FDA is currently working to revise the table from which this calculation was 

derived to more accurately reflect the status of PRE A studies and plans to begin 

posting the new version of the table in the near future. The new table will show that 

the percentage of PRE A post-market studies delayed or incomplete is much lower. 

We do currently track the reasons why companies miss study due dates based on 

information the company provides in their NDA or BLA annual report. Once an 

annual report is reviewed by the FDA clinical review division and the information 

about the study status is verified, the information can be posted in the Explanation 

of Status in the Post-marketing Requirements (PMR) database on our website. 

Because FDA has no deadline for review of these annual reports, the timing of such 

posting about the pediatric PMR status is variable. 

3. If FDA does not currently request or track this information, does the agency 

intend to start? If so, when? Will this information be publicly available? 
230 


76491.150

Page 28 The Honorable Joseph R. Pitts 

All PMRs are tracked and are included in a PMR database that is available to the public 

using the following link: http://www.accessdata.fda.govlscriptslcderlpmclindex..cfm. 

The Honorable Elliot L. Engel 

1. Commissioner Hamburg, I was tbe lead sponsor of the Paul D. Wellstone 

Muscular Dystrophy Act and the ALS Registry Act, both of which were signed 

into law by President George W. Bush. These laws promoted medical research 

and data collection with regard to these specific diseases, both of which have no 

cure and are always fatal. I am keenly aware of the challenges patients with 

these diseases face, as well as the incredible trials their families go through to 

care for their loved ones. 

Therefore, I am pleased that the new PDUFA V agreement developed by 

industry and FDA includes some provisions for the advancement of drugs for 

rare diseases. Can you please elaborate on how the FDA plans to reduce 

barriers to getting safe and effective drugs to patients with rare diseases'! 

FDA has taken several steps to help facilitate the development and approval of safe and 

effective drugs for Americans with rare diseases. Because of the small numbers of 

patients who suffer from each disease, FDA often allows non-traditional approaches to 

establishing safety and effectiveness. We have also established the Rare Disease 

Program within the Center for Drug Evaluation and Research CCDER). This program 

coordinates the development of policy, procedures, scientific development, and training 

for review and approval of treatments for rare diseases. 

The PDUFA V agreement includes enhancements to FDA's Rare Disease Program. As 

part of the agreement, FDA will develop relevant guidance, increase the Agency's 

outreach efforts to the rare disease patient community, and continue to provide 

specialized training in rare disease drug development for sponsors and FDA slaff. 

PDUFA V will also add additional staff to CDER's Rare Disease Program and a Rare 

Disease Liaison in the Center for Biologics Evaluation and Research, which will enhance 

collaboration within the Agency as well as with external rare disease stakeholders. 

Therapies for rare diseases-those affecting fewer than 200,000 people in the United 

States-represent the most rapidly expanding and innovative areas of drug development. 

Although each disease affects a relatively small population, collectively, rare diseuses 

affect about 25 million Americans. Approximately one-third of the new molecular 

entities (NMEs) and new biological products (those products for which the active 

ingredient had not previously been approved by FDA) approved in the last five years 

have been drugs for rare diseases. 

Also, Section 902 of FDASIA, establishes a new pathway for breakthrough therapies, 

which are defined as drugs that are intended to treat a serious or life-threatening disease 

or condition and for which preliminary clinical evidence demonstrates substantial 
231 


76491.151

Page 29 The Honorable Joseph R. Pitts 

improvement over existing therapies. Drugs that receive this designation are eligible for 

additional consultation with the Agency to design an expedited drug development 

pathway. 

2. I was pleased to read in the PDUFA commitment letter that one of the FDA's 

goals includes, " ... encouraging flexibility and scientific judgment, as 

appropriate, on the part of reviewers when evaluating investigational studies 

and marketing applications for drugs for rare diseases." Can you explain to me 

what this will look like in praeticc at the FDA under the terms of the PDUFA 

reauthorization'? 

FDA's oversight of rare disease drug development is complex and resource-intensive. 

Rare diseases are a highly diverse collection of disorders, their natural histories are often 

not well-described, only small population sizes are often available for study, and they do 

not usually have well-defined outcome measures. Thus the design, execution, and 

interpretation of clinical trials for rare diseases require frequent interaction between FDA 

and drug sponsors. If recent trends in orphan designations are any indication, FDA can 

expect an increase in investigational activity and marketing applications for orphan 

products in the future. 

But as stated above, FDA has taken several steps to help facilitate the development and 

approval of safe and effective drugs for Americans 'With rare diseases, and the PDUF A V 

agreement will build on these accomplishments. Existing regulations allow for the 

application of flexibility and scientific judgment in the development and approval of rare 

disease therapeutics. FDA's orphan drug approval history was recently analyzed in a 

study sponsored by the National Organization for Rare Disorders, which found that FDA 

exercised this flexibility in approximately two-thirds of orphan drug approvals.l 

As a recent example, FDA approved Voraxaze (glucarpidase) in January 2012 to treat 

patients with toxic methotrexate levels in their blood due to kidney failure, which affects 

a small population of patients each year. Methotrexate is a commonly used cancer 

chemotherapy drug normally eliminated from the body by the kidneys. Patients receiving 

high doses of methotrexate may develop kidney failure. Voraxaze was approved based 

on data in 22 patients from a single clinical trial, which showed decreased levels of 

methotrexate in the blood. Prior to the approval ofVoraxaze, there were no effective 

therapies for the treatment of toxic methotrexate levels in patients with renal failure. 

3. I have heard from advocatcs with rapidly progressing diseases that they have 

different levels of risk that they are willing to tolerate. Would the FDA consider 

more proactive efforts to better derme New Drug Applications (NDAs) benefitrisk expectations for rare disorders, in order to expedite approvals for such 

unmet nceds without compromising paticnt safety" 

I Sasinowski FJ., Quantum of Effectiveness Evidence in FDA's Approval of Orphan Drugs. Cataloguing 

FDA's Flexibility in Regulating Therapies for Persons with Rare Disorders (2010). available at 

htlp:llwww.rarediseases.orgldocs/policyINORDsludyqfFDAapprovalojorphandrugs.pdf. 
232 


76491.152

Page 30 The Honorable Joseph R. Pitts 

FDA has been developing an enhanced, structured approach to benefit-risk assessments 

that accurately and concisely describes the benefit and risk considerations in the 

Agency's drug regulatory decision-making. Part of FDA's decision-making lies in 

thinking about the context of the decision-an understanding of the condition treated and 

the unmet medical need. Patients who live with a disease have a direct stake in the 

outcome of drug review. The FDA drug review process could benefit from a more 

systematic and expansive approach to obtaining the patient perspective on disease 

severity and the potential gaps or limitations in available treatments in a therapeutic area. 

PDUF A V enhancements include expanded implementation of FDA's benefit-risk 

framework in the drug review process, including holding public workshops to discuss the 

application of frameworks for considering benefits and risks that are most appropriate for 

the regulatory setting. FDA would also conduct a series of public meetings between its 

review divisions and the relevant patient advocacy communities to review the medical 

products available for specific indications or disease states that will be chosen through a 

public process. 
233 


76491.153

DEPARTMENT OF HEALTH" HUMAN SERVICES 

The Honorable Michael C. Burgess, M.D. 

House of Representalives 

Washington,D.C. 20515·4326 

Dear Dr. Burgess: 

Food and Drug AdminIstration 

Sliver Spring, MD 20993 

ITB () 92012 

This letter responds to questions you raised during the February 1, 2012, Committee on Energy 

and Commerce, Subcommittee Oil Health hearing entitled "Reauthorization ofPDUFA: What It 

Means for JODs, Innovation, and Patients," regarding the Food and Drug Administration's (FDA 

or the Agency) responsiveness to the Committee's letter of February 23,201 J, requesting 

infornlation IDld documents related to the 2008 heparin contamination. Specifically, you 

expressed concern that the Committee had not received the requested documents. 

FDA is committed to responding to all inquiries trom Congress in a timely, responsive, and 

appropriate manner. The Department of Health and Human Services, ofwl1ich FDA is a 

component, has a long-standing policy of complying with Congressional requests for information 

to the fullest extent consistent with our Constitutional and statutory responsibilities. 

With regard (0 the February 23, 2011, letter you asked about during the hearing, the Agency has 

delivered 30 document productions to Chainnan Upton, totaling nearly 50,000 pages of 

docmnents. The Agency delivered documents to the Chairnlall on the following dates: March 

16,2011; March 31,2011; AprilS, 201 I; April 13, 2011; May 5, 2011; May 13,2011; May 24, 

20] I; May 26, 2011; June 1,2011; June 15,2011; June 27,2011; July 14, 2011; July 19,2011; 

July 21, 201 I; August 5, 2011; August!2, 201 I; August 26, 2011; September 12, 2011; 

September 20, 2011; October 14, 2011; October 21, 2011; November 22, 201 1; December 2, 

2011; December 9, 2011; December 16.2011; December 23, 2011; January 6,2012; January 13, 

2012; January 24, 2012; and February 1,2012. Although the documents were delivered to the 

full Committee Chainnan, the Agency provided written notification to you and to Chainnan 

Stearns each time we delivered documents. As the Committee's request for records was broad in 

scope and is requiring significant personnel resources to search for responsive rccords~ additional 

document deliveries will be forthcoming. 

Generally, with regard to heparin-related inquiries from the Committec, the Agency has been 

actively cooperating with the Committee since 2008. Since 2008, the Committee has written to 

FDA regarding heparin a total of 141imes. ineluding three letters during the current Congress: 

• February 14,2008, letter to then Commissioner Andrew von Eschenbach from then 

Chairman ofthe Committee on Energy & Commerce, John Dingell and then 

Chairman oflhe Committee's Subcommittee on Oversight and Investigations, Ban 

Stupak 
234 


76491.154

Page 2 - The IlonorabJe Michael C. Burgess, ]\'1.D. 

Q Febmary 21,2008, ietter to then Commissioner Andrew von Eschenbach from then 

Chairman of the Committee on Energy & Commerce, John Dingcll and thcn 

Chaimlan of the Committee's Subcommittee on Oversight and Investigations, Bart 

Stupak 

March 19,2008, Jdter to then Commissioner Andrew von Eschenbach from then 

Chairman of the Committee on Energy & Commerce, .1ohn Dingcll; then Ranking 

Member of tile Committee on Energy & Commerce, Joe Barton; then Chairman of the 

Committee's Subcommittee on Oversight and Investigations, Bart Stupak; and then 

Ranking lvfember of the Committee's Subcommiltec on Oversight and Investigations, 

J OM Shimkus 

e March 28, 2008, Jetter to then COllUllissioncr Andrew von Eschenbach from then 

Chairman ofthe CommiLtec on Energy & Commerce, Jolm Dingell and then 

Chaimlan of the Committee's Subcommittee on Oversight and investigations, Bart 

Stupak 

Q April 24,2008, letter to Janet Woodcock, Director, Center for Dmg Evaluation and 

Research, FDA from then Chainnan of the Committee's Subcommittee on Oversight 

and Investigations, Bart Stupak 

" December 10, 2008, letter to then Commissioner Andrew von Eschenbach from then 

Ranking Member of the Committec on Energy & Commerce, Joe I3arton 

Q December 16,2008, letter to then Commissioner Andrew von Eschenbach from then 

Ranking Member of the COIfUnitlee on Energy & Commerce, Joe Borton 

<) May 6, 20()9, letter to then Acting Commissioner Joshua Sharfsteill from then 

Ranking Memher of the Committee on Energy & Commcrce, Joe Barton; and then 

Ranking Member ofthe Committee's Subcommittee on Oversight and Investigations, 

Greg Walden 

April 30, 2010, letter to Commissioner Margaret Hamburg from thcn Ranking 

Member oflhe Committee on Encrgy & Commerce, Joe Barton; and then Ranking 

Member of the Committee's Subcommittee on Oversight and Investigations, Michael 

Burgess 

.. July 22, 2010, letter to Commissioner Margaret Hamburg from then Ranking Member 

of the Conunittee on Energy & Commerce, Joe I3arton; and thell Ranking Member of 

the Committee's Subcommittee Oll Oversight and Investigations, Michael Burgess 

$ July 29,2010, letter to COllUllissioner Margaret Hamburg from then Ranking Member 

of the Committee on Energy & Commerce, Joe Barton; and then Ranking Member of 

the Conunittee's Subcommittee on Oversight and Investigations, Michael Burgess 

" February 23, 2011, letter to Commissioner Margaret Hamburg from Chainnan of the 

Conunittee on Energy & Commerce, Fred Upton; and Chairman of the Committee's 

Subcommittee on Oversight and Investigations, Cliff Steams; and Member ofthe 

Committee, Rep, Michael Burgess 

" September 16, 20 II, letter to Commissioner Margaret Hamburg from Chairman of 

the Committee on Energy & Commerce, Fred Upton; Chairman Emeritus of the 

Committee, Joe Barton; Chairman of the Committee's Subcommittee on Oversight 

and Investigations, Cliff Steams; Chaimlan ofthe Subcommittee on Health, Joe Pitts; 

and Vice Chair of the Subcommittee on Health, Michael Burgess 

" October 26, 2011, letter to Commissioner Margaret I lamburg from Chaimlan (lfthe 

Committee on Energy & Commerce, Fred Upton; Chairman Emeritus of the 
235 


76491.155

Page 3 The Honorable Michael C. Burgess, M.D. 

Committee, Joe Barton; Chairman of the Committee's Subcommittee on Oversight 

and Investigations, Cliff Steams; Chairman of the Subcommittee on Health, Joe Pitts; 

and Vice Cbair of the Subcommittee on Healtb, Micbael Burgess 

To date, FDA has responded to the Committce's inquiries in writing 46 times. Forty-two of 

those rcsponses included document productions. In addition, since 2008, the Agency has 

respunded to hundreds of telephone and e-mail inquiries from Committee staff. In just the last 

year, the Agency has also participated in four briefings for Committee staff with more than a 

dozen senior Agency officials regarding thc 2008 heparin C<llllaminalion. As documented above, 

the Agency has worked diligently to make documents, other information, and Agency personnel 

available to the Committee in a timely manner. 

Lastly, in your letter dated October 26, 2011, you ~tatt: that you have reason to believe that two 

Chinese tirms that may have supplied Baxter and Scientific Protein Laboratories with 

contaminated heparin are still supplying crude heparin that is being imported into the United 

States. Although you have identified such a potentiality as a matter of significant public 

concem, Committee staff has declined FDA's request to identify these firms so that the Agency 

may investigate further. We would appreciate YOlrr assistance in obtaining this information. 

Thank you for your continued interest in the strength and effectiveness of FDA. TIle Agency 

will continue to make every effort to respond to the Committce's inquiries in a timely manner, 

while at the same time remaining focused on the Agency's mission to protect and promote the 

public health. 

cc; 

The Honorable Fred Upton 

Chairman 

Committee on Energy and Commerce 

The Honorable Joe Pitts 

Chairman 

Subcommittee on Health 

Committee on Energy and Commerce 

Sincerely, 

Jeanne Ireland 

Assistant Commissioner 

for Legislation 
236 


76491.156

Page 4 - The Honorable Michael C. Burgess, J'v1.D. 

The Honorable Clift· Stearns 

Chairman 

Subcommittee on Oversight and Investigations 

Committee on Energy and Commerce 

The Honorable Henry A. Waxman 

Ranking Member 

Committee on Energy and COlllmerce 

The ]'hmorable Frank Pallone, Jr. 

Ranking Member 

Subcommittee on Health 

Committee on Energy and Commerce 

Tbe Honorable Diana DeGette 

Ranking Member 

Subcommittee on Oversigbt and Investigation 

Committee on Energy and Commerce 

Mr. Alan Slobodin 

Ms. Stacia Cardille 
237 


76491.157

Geno J. Germano 

Pl!:~sidl2'nl & ClE::'nernl MWlOgC'{ 

Spcrtnlty eme ond Onco!o9Y 

April 15,2012 

The Honorable Fred Upton 

Chairman 

Committee on Energy & Commerce 

U.S. House ofRepresenlatives 

2 I 25Raybum House Otlicc Building 

Washington, DC 20515 

Dear Mr. Chairman: 

Pfi?t'f 

500 Arcolo RO(l(t Collegeville, Pi\ 191;26 

T pi MI, 865 ?081 Fox 1,81. 865 0900 

qeno.gE'HrlOno@ipl1?efHlrn 

Attached, please tind the answers in response to questions by Representative Eliot Engel 

related to my testimony at the February 1" hearing on the Prescription Drug User Fee 

Act. Should you have any question, please contact John Halliwell in our Federal 

Government Relations office at 202-783-7070 or John.P.Halliwel1rtVpf1zer.com 
238 


76491.158

Questions from Representative Eliot Engel 

I. Several of you mentioned in your written testimony that the user fees included in 

PDUF A V are meant (0 be in addition to a solid base of annually appropriated 

fund for the FDA. I was pleased to see that for Fiscal Year 2012, the FDA 

received a $50 million increase in funding over Fiscal year 2011 funding leveL 

But this was a hart fought vietory, given that House Republicans first proposed a 

$285 million cut in FDA funding for Fiscal Year 2012. Please elaborate on why it 

is so important that the FDA be adequately funded and how cuts to the FDA could 

impact your industry or the patients your associations serve? 

A. Pilzer believes it is critieal for the Administration and Congress to adequately 

fund the FDA to ensure the Agency is able to carry out one of its eore missions 

which is the timely review ornew products to treat the myriad diseases afflicting 

Americans. We remain concerned that our user fees account for an ever 

increasing share of the FDA review budget 'vvhieh is approaching 70% under 

PDUFA V. 

2. In addition to my legislative work on ALS and muscular dystrophy, 1 scrve on the 

rarc and orphan disease caucus, which is why I anl particularly interested in the 

provisions of the PDUF A V agreement related to the development and approval 

of drugs for rare disease. 

• What balTiers do you perceive in moving new eandidate therapies through the 

development proeess? 

• Do you feel that PDUFA V adequately addresses these balTiers or what additional 

provisions arc necessary to ensure that patients with rare diseases have access to 

promising drug treatments? 

A: Specific rare diseases impact only a small number ofpalients. However, as a 

group, they affect millions of people around the world, including more than 25 

million patients here in the U.S. Pfizer understands the impact ofrare diseases 

on individual patients and their caregivers. We are dedicated to addressing these 

serious unmet needs through our foeus on research, development and 

commercialization of orphan medicines. 

The development ofthcrapics for rare diseases poses many unique challenges; 

designing and eonducting clinical trials is constrained as there is usually little 

information about the natural progression of the disease to inform endpoint 

selection. In addition, investigators often have difiieulty identifying and enrolling 

a large number of patients due to the smallnwnber of patients with the disease. 

Even the most basic tools for product development, such as validated animal 
239 


76491.159

models may not exist for specitlc rare disorders. Finally, the limited number of 

available patients dictates small sample sizes, which pose signitlcant statistical 

hurdles tmder the current FDA regulations. 

PDUF A V otters the potential for guidance and policy development on 

understanding approaches to studying rare diseases, non-traditional clinical 

development programs, study design, endpoints and statistical analysis. Public 

meetings \\lith FDA, industry, academia and the patient community will improve 

the communication between all parties involved in developing new products and 

help inform the evolving Regulatory policy in this important area. 

Pfizer believes PDUFA V has the potential to enhance development of new drugs 

for rare diseases through FDA policy development and training of review staff on 

scientific issues unique to rare diseases, as well as support outreach to industry, 

patients, and the scientific community. 
240 


76491.160

The Honorable Joseph Pitts 

Chairman, Subcommittee on Health 

House Energy & Commerce Committee 

2125 Rayburn I-louse Building 

Washington, DC 20515 

March 28, 2012 

Dear Chairman Pitts: 

C· H I CALIFORNIA HEAlTHCARE 

INSTITUTE 

Thank you for the opportunity to appear before the Subcommittee during its heming on '"Reauthorization of 

PDUFA:" What It Means for Jobs, Innovation. and Patients" on February \,2012, Below, please find responses to 

the additional questions provided by Congressmen Brian Bilbray and Eliot Engel. 

The Honorable Brian Bilbray 

Whnt impact has duplicative inspections had on the industry in my state of California? 

New medicines and medical technologies submitted for U.S. Food and Drug Administration (FDA) approval 

incluue not only information, such as clinical trial uata, demonstrating products' safety and effectiveness, but 

information regarding how they will be manufactured, Anu prior to the munufm.:ture and sale of a drug, biologic 

or medical device for human lise, companies must have each facility that is engageu in the product's 

manufacturing inspecteu by the FDA. Indeed, manufaclllling issues are among the reasons that product approval 

may be deJayed or denied by the Agency. Following approval. manufacturers arc also required to have each 

facility inspected every two years hy the FDA to ensure compliance with standards for current Good 

Manufacturing Practices (GMP). The penalties for failing to comply with these standards arc significant -- FDA 

may bring a seizure and injunction case before a fedcral court that would allow the federal government to seize all 

urugs still on the market and ban the manufucturer from further prouuction of the drug until all the outstanding 

GMP noncompliance issues and defidt'ndes have been addressed. 

These requirements arc important to ensure patient and public safety and health. Howevcr, some states, such as 

California, require their own inspections. Unfortunately, these state inspections arc normally duplicative of 

federu! FDA inspections, Indeed, California's slate Food and Dmg Branch (FDB) inspections, also carried out 

every two years, use the same GMP compliance standnrds as the FDA. And according: to CHI member 

companies, there is little uiffercntiation in what is inspected and frequent lack of coordination in the state and 

federu! inspection timcJines. In sum, these waste state resources and cause companies to divert time and money 

from research and development, while contributing nothing: to puhlic health and safety. 

Can you tell me what kind of impact the duplicative inspection issue has for California life sciences 

companies'! What are your thoughts ou having FilA as the sole authority for inspection with caveats for 

state emergencies'? 

As mentioned above. California's swte Foou and Drug Branch (FDB) inSpcLCtions use the same GMP compliance 

standards;]s the FDA And according to CHI memher companies, there is little ditTere,ntiation in what is 
241 


76491.161

inspected and frequent lack of coordination in the state and federal inspection timelines. In sum, these waste state 

resources and cause companies to divert time and money from research and development, while contributing 

nothing to public health and safety. 

Ending these unnecessary and duplicative state inspections would save time, money and resources of hoth 

companies and our cash-strapped slates while maintaining protections for patient and public safety and health. 

We support making the FDA the sole authority for such inspections. while maintaining inspection authority for 

states and state agencies when determinations are made that a drug or device manufactured there presents threat of 

serious adverse health consequences or death, when the federal government orders a recall of a product 

manufactured or processed at a facility in the state, or upon the request of or authorization by the federal 

government. 

The Honorahle Eliot Engel 

Several of you mentioned in yonr written testimony that the user fees included in PDUFA V are meant to 

be in addition to a solid base of annually appropriated funds for the FDA. I was pleased to see that for 

l"iscal Year 2012, the FDA received a $50 million increase in funding over Fiscal Year 2011 funding levels. 

But this was a hard fought victory, given that House Republicans first proposed a $285 million cut in FDA 

funding for Fiscal Year 2012. 

Please elahorate on why it is so important that the FDA be adequately funded and how cuts to the FDA 

could impact your industry or the patients your associations serve? 

CHI strongly supports bolstering congressionally appropriated resources for the Food and Drug Administration 

(FDA), providing the agency the tools it needs to ensure that innovative products continue to reach patients in a 

timely fashion. Currently. industry user fees constitute a large percentage FDA funding. CHI believes that the 

FDA should he funded primarily through congressional appropriations. a step that will help in restoring the 

public's trust and faith in the agency. 

In addition to my legislative work on ALS and muscular dystrophy, I serve on the rare and orphan disease 

caucus, which is why I am particularly interested in the provisions of the PDUFA V agreement related to 

the development and approval of drugs for rare diseases. 

a. What harriers do you perceive in moving new candidate therapies through the development 

process? 

One balTier to moving new candidate therapies through the development and review process entails the 

quality and quantity. or lack thereof, of communications between sponsor companies and the FDA. 

Communication between the FDA and drug and device developers is critical. The earlier questions can be 

raised, and answers provided, the more likely that the review process won't be affected by late-breakjng or 

unexpected complications. One of the primary FDA-relaled issues CHI hears rrom its membership, and 

especially from OUf smaller. emerging company members, regards concerns with these development stage 

communications and discussions. 

A second banier enlails the quality of expert advice and counsel to the FDA from its Advisory Councils. 

This is especially the case for therapies to treat rare discases and conditions and other unmet medical needs. 

Unfortunately. intensified Advisory Committee conflict of interest rules enacted as part of the FDA 

Amendments Act of 2007 (FDAAA). have made it increasingly difficult for experienced medical experts to 
242 


76491.162

serve on Agency Advisory Committees. Members of the Subcommittee and the FDA itself have spoken to 

the importance of addressing this issue. CHI supports a solution that acknowledges the need for contlict of 

interest rules but better rationalizes the approach (through improved transparency processes. for example) to 

ensure that advisory committees arc comprised of the most qualified, objective and experienced experts in 

the relevant field. 

A third barrier entails how the Agency. as well as policymakers and the public. addresses the benefit-risk 

equation. Virtually all medicines bear some capacity for harm. A zero-risk approach would shut down the 

development of beneficial drugs. In this regard, however. the Agency focuses almost exclusively on the 

direct risks of drugs: side effects, adverse events and so forth. These are comparatively discrete and 

measurable. But indirect risks are both difficult to observe and suhject to a much longer lime horizon. 

Where are data that allow one to calculate the harm to public health if investors avoid an important disease 

because the FDA's demands for data arc so extensive and its standards for drug approval so uncertain? 

h. Do you reel that PDUFA V adequately addresses these harriers or what additional provisions are 

necessary to ensure that patients with rare diseases have access to promising drug treatments? 

CHI lauds provisions in the PDUFA V agreement to advance the development of new medicines for rare 

<Iiscnses. such as through provisions to bolster the COER Rare Disease Program and through the 

establishment of a Rare Disease liaison with the omce of the COER Director. 

We also lnud provisions in the PDUFA V agreement to improve and enhance Agency-sponsor 

communications. such as through the new review program for New Molecular Entities (NMEs) and 

measures to both enhance communications between FDA and sponsors during drug development and meet 

the challenges of emerging science in the areas of clinical trial endpoint assessment tools, biomarkers and 

pharmacogenomics, meta-analysis. and development of drugs for rare diseases. 

CHI similarly acknowle<lges and lauds PDUFA V provisions to enhance Agency benefit-risk assessment as 

well as a concentration on patient-focused drug development. 

Finally. while the PDUFA V agreement did not address the Advisory Committee cont1ict of interest rules 

issue, CHI is strongly supportive of efforts to address this prohlem tluring the reauthorization process. 

Thank you for the opportunity to provide CHI's responses to these questions. And please do not hesitate to 

contact me or Todd Gillenwater, CHI's Senior Vice President for Public Policy. if we may be of any further 

assistance. 

Sincerely. 

'U~~ Da vid L. Gollaher 

President & CEO 
243 


76491.163

8S2\\':inkr,srrl'ct 

\X~dlhJm 

,\'l~\::.sat.:bu,~etl;-; 

02T':;1,1120 

l'SA 

March 23, 2012 

r;tlllermes· 

.. PatIent 1fHpfred 

The Honorable Joseph R. Pitts 

Chairman, House Energy and Commerce Committee 

Subcommittee on Health 

2125 Rayburn House Office Building 

Washington, D.C. 20515-665 

Dear Chairman Pitts: 

Thank you for the opportunity to present my views on the reauthorization of the Prescription 

Drug User Fee Act (PDUFA V) at the February 1

st subcommittee hearing on "PDUFA V: What 

it Means for Jobs, Innovation, and Patients." 

On behalf of the Biotechnology Industry Organization (BIO), I am pleased to provide the 

following responses to subcommittee member questions for the hearing record. 

If you have any additional questions or need of clarification, please feel free to contact me or 

Brent Del Monte, BIO's Vice President tor Federal Govemment Relations at bfklmQl1(e(iI~:Q.io.or,g 

or (202) 962-9200. 

Sincerely, 

A:d&<iV 

Chairman and CEO 

Alkermes 

cc: The Honorable Frank Pallone, Jr., Ranking Members, Subcommittee on Health 

The Honorable Eliot Engel 
244 


76491.164

Responses to Questions from the Honorable Eliot Engel; 

1. Several of you mentioned in yOUl' written testimony that the user fees included in 

PDUFA V are meant to be in addition to a solid base of annually appropriated funds 

for the j<'DA. I was pleased to see that for Fiscal Year 2012, the FDA received a $50 

million increase in funding over Fiscal Year 2011 funding levels. But this, was a hard 

fought victory, given that House Republicans first proposed a 8285 million cut in FDA 

funding for Fiscal Year 2012, Please elaborate on why it is so important that the FDA 

be adequately funded and how cuts to the F'DA could impact your industry or the 

patients your associations serve? 

While industry user fees play an important role in supporting FDA's medical product review 

program, user fees should be complementary and additive to a sound base of appropriated 

resources for the Agency. BIO appreciates Congress' recognition of the importance of 

FDA's role in promoting biomedical innovation and protecting the public health, and we 

applaud the Congress for enacting increases to FDA's base budget in recent years. We 

encourage ongoing support for the Agency. 

BIO supports a strong, fuUy-funded FDA with the resources necessary to keep pace with 

rapidly-evolving biomedical science and to make sound regulatory decisions in a timely and 

efficient manner. For FY2013, BIO recommends $506 million for the Human Drugs 

program and $224 million for the Biologics program. For people with devastating diseases 

and disabilities, roadblocks to getting new cures developed and approved ean be a matter of 

life or death. For patients who are still waiting for trcatment options - such as a first-ever 

broadly-effective treatment for amyotrophic lateral sclerosis, a next generation treatment for 

multiple sclerosis, or the next miracle therapy for cancer nothing is more important than 

seeing safe and eflicacious products developed and approved as efficicntly as possible 

without unnecessary impediments. 

Adequate FDA funding is an economic imperative as well as a public health priority. FDA 

regulates approximately $] trillion in consumer products, or 25 cents of every U.S. consumer 

dollar spent, and it is critical to American economic health and competitiveness that FDA has 

the tools and resources necessary to effectively and efficiently ensure medical product 

quality. FDA suppOli for medical im10vation is also critical to tackling the nation's longterm fiscal health. Dnme! medical needs for diseases such as Alzheimer's, cancers, diabetes, 

and Parkinson's will be signiticant drivers of our nation's entitlement spending as the Baby 

Boomer Generation continues reaching retirement age. Modern FDA regulatory approaches 

that promote the development oftrcatments that slow the advancement of Alzheimer's and 

other devastating diseases will have a profound impact on the nation's fiscal health, as well 

as public health. BIO also supports adequate resources to advance regulatory science at FDA 

and for the Agency's Medical Countenneasures Initiative (MCMi). 
245 


76491.165

2. In addition to my legislative work on ALS and muscular dystrophy, I serve on the rare 

an orphan disease caucus, which is why I am particularly interested in the provisions of 

the PDUFA V agreement related to the development and approval of drugs for rare 

diseases. 

a. What barriers do you perceive in moving new candidate therapies through 

the development process'? 

Over the last thirty years, initiatives and market-based incentives to support the drug 

development for rare disease, such as the Orphan Drug Act (ODA) of 1983, have brought 

success. To date, in excess of 1,000 orphan product designations have been granted by the 

FDA's Office of Orphan Product Development and more than 250 drugs and biologics have 

received approval by the FDA with Orphan designation, collectively helping millions of adults 

and children with rare diseases worldwide. We have come a long way, indeed. In the decade 

prior to cnactment of the ODA, fewer than ten products for rare diseases came to market. Today, 

there are an estimated 7,000 rare diseases, each one affecting 200,000 or fewer individuals, but 

collectively affecting nearly 30 million Americans. 

However, treatments exist for only a fraction of these devastating, lite-threatening diseases 

leaving so many people of all ages with signi.ficant unmet medical needs. And of those 

treatments, the majority of approved orphan drugs are for those rare diseases with higher 

prevalence. Most of these diseases are associated with significantly shortened life span, poor 

quality oflife, severe iUld many times painful co-morbidities, and major costs to the U.S, 

healthcare system. 

Basic scientific, biomedical and preclinical research is taking place with groundbreaking 

technology in laboratories at colleges and universities, independent academic medical centers, at 

the National Institutes of Health, and in the biotechnology industry. The biotechnology industry 

has made a significant contribution to this .field over the ye.ars. Indeed, the mission of many 

biotech companies is to bring hope to the patients who suffer from rare diseases, and reHefto 

their families. 

As a key entity in our nation's biomedical innovation ecosystem, the FDA must also continue to 

evaluate the cuncnt regulatory environment and the FDA's review process for orphan products. 

For instance. the sheer size of patient populations is an important factor for consideration in 

clinical study design. Affected individuals arc part of such small individual patient populations; 

they may represent disease prevalence of as many as 67: 100,000 to as fcw as 2: 1 00,000. No one 

rare disease exceeds an incidence of 200,000 in the United States. Limited individual disease 

experience makes it unlikely that there are organized registries from which to draw information 

for the majority of these diseases, and unrealistic to consider condueting natural history studies 

as prelude to or in parallel wifh clinical trials. Numbers of subjects for any orphan product study 

should be carefully considered based on cun'ent disease situations. Given the signi.ficant 

morbidity and mOltality often associated with rare and orphan diseases, the unmet medical need, 

the societal costs, and the challenges of conducting trials in these patient populations, the 

regulatory approval pathway needs to accommodate non-traditional approaches to drug 

development and be predictable, faster, and one that more clearly balances risk/benefit for these 

orphan disease patients and their families. 
246 


76491.166

b. Do you feei that PDUF A V adequately addresses these barriers or what 

additional provisions are nccessary to ensure that patients with rare diseases 

havc access to promising drug treatments? 

The PDUFA V rare disease proposal helps to address many of the challenges associated with 

rare disease drug development. This provision would SUppOlt rare disease drug development 

through FDA focus on policy development, training of fDA review staff on unique scientific 

issues related to rare diseases, and education/outreach to industry, patient, and investigator 

communities. Engaging experts and developing FDA policy and guidance on key issues such as 

endpoint selection, clinical trials design, dose selection, statistical analysis, and the utilization of 

other drug development tools will help to ensure transparency and consistency in the use of these 

approaches in non-traditional drug development programs for rare diseases. The program also 

ensures that FDA medical reviewers arc trained on novel approaches to rare disease drug 

development so that these approaches are integrated into regulatory practice at all levels of FDA. 

The PDUFA V enhanced communication proposal will also facilitate the development of 

treatments for rare diseases by reducing the impact of regulatory barriers and scientific obstacles 

experienced by Sponsors during drug development. 

Additionally, modernizations to FDA's Accelerated Approval pathway made by the Faster 

Access 10 Specialized Treatments (FAST) Act of 20J 2, sponsored by Reps. Stearns (R-FL) and 

Towns CD-NY), will help to expand the application of FDA's Accelerated Approval pathway to 

more rare diseases and expedite the development of therapies for these serious and lifethreatening conditions. This bill will broaden the use of surrogate and clinical endpoints under 

Accelerated Approval, leverage modern dnlg development tools to provide additional supporting 

evidence, and take into account the severity, rarity, and availability of alternate treatments in 

FDA's approval determination. Importantly, this legislation in no way reduces the FDA's cutTent 

standard for approval, nor does it remove the requirement that clinical work be conducted prior 

to approvaL BIO strongly supports the enactment of the provisions of the FAST Act when the 

Congress considers reauthorizing PDUFA. 
247 


76491.167

FRED UPTON, M1CH1GAN 

CHAlRMAN 

ONE HUNDRED TWEl.FTH CONGRESS 

HENRY A. WAXMAN, CAUF-ORNiA 

RANKING MEMBER 

qtongress: of tbe Wnitei) ~tates: 

j'!)Otl!.lC of ~epre!.lC1ltatl\Jt!.l 

COMMITTEE ON ENERGY AND COMMERCE 

2125 RAYBURN HOUSE OFF1CE BUILDING 

WASHINGTON, DC 20515-6115 

Dr. David E. Wheadon 

Senior Vice President 

Scientific and Regulatory Affairs 

M&IOrity W)2) 22S· 2927 

M'nonty i20:() Z25-~11l41 

March 9, 2012 

Phannaceutical Research and Manufacturers of America 

950 F Street, N.W., Suite 300 

Washington, D.C. 20004 

Dear Dr. Wheadon: 

Thank you for appearing before the Subcommittee on Health hearing entitled 

"Reauthorization ofPDUFA: What It Means for Jobs, Innovation, and Patients" on February 1,2012. 

Pursuant to the Rules of the Committee on Energy and Commerce, the hearing record 

remains open for 10 business days to pennit Members to submit additional questions to witnesses, 

which are attached. The fonnat of your responses to these questions should be as follows: (I) the 

name of the Member whose question you are addressing, (2) the complete text of the question you 

are addressing in bold, and (3) your answer to that question in plain text. 

To facilitate the printing of the hearing record. please e-mail your responses, in Word or PDF 

format, to carly.mcwilliams@mail.house.gov by the close of business on Friday, March 23, 2012. 

Thank you again for your time and effort preparing and delivering testimony before the 

Subcommittee. 

Joseph R. Pitts 

Chainnnn 

Subcommittee on Health 

cc: The Honorable Frank Pallone, Jr., Ranking Member, Subcommittee on Health 

Attachment 
248 


76491.168

The Honorable Eliot Engel: 

1. Several of you mentioned in your written testimony that the user fees 

included in PDUFA V are meant to be in addition to a solid base of annually 

appropriated funds for FDA. I was pleased to see that for fiscal ye~r 2012, the 

FDA received a $50 million increase in funding over fiscal year 2011 funding 

levels. But this was a hard fought victory, given that House Republicans first 

proposed a $285 million cut in FDA funding for Fiscal Year 2012. Please 

elaborate on why it is so important that the FDA be adequately funded and 

how cuts to the FDA can impact your industry or the patients your association 

serve. 

Congressman Engel, thank you for asking this very important question. The FDA has 

as its core mission to promote and protect the public health of American citizens. In 

carrying out that mission, the FDA has regulatory responsibility for roughly 25% of 

the United States' Gross Domestic Product (GOP). Given this weighty responsibility, 

it is imperative that FDA: 

1. Have the necessary resources to insure that US citizens have access to safe, 

unadulterated food, as well as safe and efficacious drugs, biological products, and 

medical devices. FDA also has responsibility for regulating the manufacturing, 

marketing and distribution of tobacco products to protect the public health. At the 

same time, FDA must be given adequate resources to employ state of the art science 

to promote innovative approaches to the development of new products in these 

domains of responsibility. Due to these critical public health goals, it is jmportant 

that FDA be adequately funded. Failure to fund FDA adequately will needlessly 

delay the availability of new medical treatments to patients and healthcare 

professionals. 

2. Avoid disastrous cuts in resources allocated to FDA such that its ability to carry 

out its important public health mission would be severely curtailed. 

For the biopharmaceutical industry, cuts to the FDA's drug and medical device 

review budget would have a significant impact on the ability of this industry to 

invest in discovering and developing new medical products focused on addressing 

such unmet medical needs as Alzheimer's Disease, multi-drug resistant bacterial 

infections, Cancer, Diabetes, cardiovascular diseases and HIV prevention among 

many others. The biopharmaceutical industry depends upon an adequately funded 

FDA, resourced to attract up-to-date scientific and medical expertise to serve as a 

partner in the industry's developmental efforts and, ultimately, to make sound 

scientific regulatory decisions in a timely, efficient and thorough manner. 

Appropriate FDA funding will help speed the availability of needed medical 

advances to help patients who are suffering from these many diseases. Without a 

well-funded and resourced FDA, patients will ultimately be the ones who suffer the 

most. 
249 


76491.169

2. In addition to my legislative work on ALS and muscular dystrophy, I serve 

on the rare and orphan disease caucus which is why I am particularly 

interested in the provision in the PDUFA V agreement related to the 

development and approval of drugs for rare diseases. 

a. What barriers do you perceive in moving new candidate therapies through 

the development process? 

b. Do you feel PDUFA V adequately addresses these barriers or what 

additional provisions are necessary to ensure that patients with rare diseases 

have access to promising drug treatments? 

The development process can be challenging for any therapeutic entity, given the 

basic nature of the science underlying drug discovery and development. This 

process is even more challenging when the therapeutic entity is targeted towards a 

particularly small patient population- as is the case for rare and orphan diseases. 

The barriers for developing drugs and biologics for rare and orphan diseases grow 

exponentially in the clinical trial process. First, researchers need to establish the 

molecular or genetic targets the drug or biological product is intended to impact. 

This entails having a reasonably sizable database of patients to confirm that these 

targets are indeed pathognomonic for the disease under study. Researchers then 

need to validate tests of efficacy to illustrate that the product under development 

indeed has the intended effect. Lastly pivotal proof of safety and efficacy must be 

carried out in clinical trials, utilizing these validated tests of efficacy. As you know, 

such clinical testing can require a fairly large set of patients and for many rare and 

orphan diseases this may not be tenable given the small numbers of affected 

patients. Such a reality requires that companies developing products targeted 

towards rare diseases utilize novel approaches for establishing that a product is safe 

and effective for the target population. FDA must be able and willing to work with 

these companies in developing and accepting these alternative approaches. 

PDUFA V recognizes this need and specifically calls for increasing the number of 

FDA resources focused on the very unique needs of developing and, ultimately. 

approving a product for a rare or orphan disease. These resources will be imbedded 

in the various divisions ofthe Center for Drug Evaluation and Research (CDER) and 

the Center for Biologics Evaluation and Research (CBER), thus insuring that the 

specific considerations that must be employed for rare disease research will be 

institutionalized throughout the FDA review divisions. Additionally. FDA will 

engage public stakeholders, including patients and clinicians, in an open and 

transparent process to discuss complex issues in clinical trials for studying drugs for 

rare diseases, including such questions as endpoint selection and the use of 

surrogate endpoints/Accelerated Approval, reasonable safety exposures, and the 

development of patient-reported outcome instruments for rare diseases in order to 
250 


76491.170

develop and implement specialized staff training and to facilitate the formulation of 

Guidance for developing drugs for rare diseases. 

It is our opinion that these provisions in PDUFA V will be a significant asset in 

improving the industry's and FDA's ability to enhance development and approval of 

drug and biological products targeted towards rare and orphan diseases. 
251 


76491.171

March 20, 2012 

The Honorable Joseph R. Pitts, Chairman 

Energy and Commerce Subcommittee on Health 

US House of Representatives 

Washington, DC 20515 

Dear Mr. Chairman: 

This letter is in response to your March 9, 2012, request to respond to two questions posed by 

Congressman Eliot Engel following the February I hearing, "Reauthorization ofPDUFA: What 

It Means for Jobs, Innovation, and Patients." 

Questions 1 

Several of you mentioned in your written testimony that the user fees included in PDUFA V are 

meant to be in addition to a solid base of annually appropriated funds for the FDA. I was pleased 

to see that for Fiscal Year 2012, the FDA received a $50 million increase in funding over Fiscal 

Year 2011 funding levels. But this was a hard fought victory, given that House Republicans tirst 

proposed a $285 million cut in FDA funding for FY 2012. Please elaborate on why it is so 

important that the FDA be adequately funded and how cuts to the FDA could impact your 

industry or the patients your associations serve? 

NORD Response 

The Food and Drug Administration (FDA) is unique-in that it is the only federal agency that 

touches every American multiple times each day. NORD and the entire rare disease community 

rely on FDA for the safety of the foods we eat and the safety and effectiveness of the drugs and 

devices we use. Rare disease patients are totally reliant on FDA for the review and approval of 

the orphan drugs that alleviate symptoms, improve quality of life and are often, life-saving. The 

bulk of this work is done using appropriated funds. The provisions in the new PDUFA legislation 

are welcome and truly needed, but additive to the review and approval process wc depcnd upon. 

FDA's mission and responsibilities continue to grow and additional funding is required to handle 

them. An obvious source of agency growth is new legislation-from which the rare disease 

community expects to benefit with the enactment of a new biosimilars drug approval pathway as 

well as elimination of the barriers to the development of humanitarian use devices. In FY 13, 

FDA will need a minimum of $20 million in appropriated funding to match the funds that will 

become available upon passage of the biosimilars user fee. 
252 


76491.172

Additionally, most new demands on the agency do not come through legislation. The agency's 

efforts to address problems of drug shortages is of great interest to the rare disease community 

because the shortages are heavily centered in biologic products, particularly generics that are 

cost-effective alternatives for our patients and often the only source for a particular therapeutic. 

There is also a resource-intensive demand on the agency created by the growing complexity of 

science. The rare disease community is experiencing major advances in new scientific 

knowledge-but this also means that FDA needs the funds to hire more and better-trained 

scientists. Because of the growing complexity of science, we all must recognize that reviewing a 

new drug application or evaluating a clinical trial take longer now than five years ago. 

Finally, consumers, patients, industry, NIH, Congress and international regulatory bodies are 

asking FDA at all levels for greater interactions, improved clarity, and clearer proactive 

guidance. In the specific case of the rare disease community, we have benefited greatly from the 

many meetings and conferences that FDA participates in to discuss new scientific findings and 

medical products that will help our community. 

Question 2 

In addition to my legislative work on ALS and muscular dystrophy, I serve on the rare and 

orphan disease caucus, which is why I am particularly interested in the provisions of the PDUFA 

V agreement related to the development and approval of drugs for rare diseases. 

a. What barriers do you perceive in moving new candidate therapies through the 

development process? 

b. Do you feel that PDUFA V adequately addresses these barriers, or what 

additional provisions are necessary to ensure that patients with rare diseases have 

access to promising drug treatments? 

NORD Response 

The agreement between the FDA and industry representatives contains a number of provisions 

NORD believes will provide the agency the flexibility and resources needed by both the Agency 

and industry to move orphan drugs and biologics through the development and approval process. 

Specifically: 

Enhancing Benefit-Risk Assessment in Regnlatory Decision-making 

"FDA will develop a five-year plan to further develop and implement a structured 

benefit/risk assessment in the new drug approval process. FDA will publish its draft plan for 

public comment by the end of the first quarter ofFY 2013. FDA will begin execution of the 

plan to implement the benefit-risk framework across review divisions in the pre- and post-
253 


76491.173

market human drug review process by the end of the fourth quarter ofFY 2013, and the 

Agency will update the plan as needed and post all updates on tbe FDA website:' 

As the FDA commits to a more patient-centric posture, and as patients themselves become more 

knowledgeable and sophisticated about diseases and their treatment options, we hope that more 

systematic processes will enable contributions from the patient community at the time that 

critical decisions on risk tolerance are being made, and from a representative sample of patient 

views. Wc believe the process should be well-defined and well-understood within the review 

divisions, and provide a universally applied opportunity for patients to make such input. We are 

conscious that FDA reviewers and other relevant FDA staff have many demands on their time, 

but strongly believe that this suggested new process for input will improve product analysis and 

approval and access to necessary treatments. 

Advancing Development of Drugs for Rare Diseases 

Please note that NORD believes the public meetings and other initiatives scheduled to begin in 

2014 should be moved up by one year. For example, the public meeting scheduled by mid-FY 

2014, should be conducted by no later than mid-FY 2013. 

"By the end of FY 2013, FDA will complete a staffing and implementation plan for the COER Rare 

Disease Program within tbe Office of New Drugs and a CBER Rare Disease liaison within the Office 

of Center Director. 

FDA will increase by five the staff of the CDER Rare Disease Program and establish and fill 

the CBER Rare Disease liaison position. 

On an ongoing basis, the staff in the Rare Disease Programs of the two Centers will develop 

and disseminate guidance and policy related to advancing and fucilitating the development of 

drugs and biologics for rare diseases, including improving understunding among FDA 

reviewers of approaches to studying such drugs; considering non-traditional clinical 

development programs, study design, endpoints. and statistical analysis; recognizing 

particular challenges with post-market studies; and encouraging flexibility and scientific 

judgment, as appropriate, on the part of reviewers when evaluating investigational studies 

and marketing applications for drugs for rare diseases. Rare Disease Program statfwill also 

engage in increased outreach to industry regarding development of such drugs and to patient 

representatives and organizations. 

By mid-FY 2014, FDA, through the Rare Disease Program, will conduct a public meeting to 

discuss complex issues in clinical trials for studying drugs for rare diseases, including sucb 

questions as endpoint selection. use of surrogate endpoints/Accelerated Approval, and 

clinical significance of primary endpoints; reasonable safety exposures; assessment of dose 

selection; and development of patient-reported outcome instruments. Participants in the 

discussion will include FDA slafT. academic and clinical experts, and industry experts. A 

summary from the meeting will be made available publicly through the FDA website. 

By thc end of FY 2015, FDA will develop and implement staff training related to 

development, review, and approval of drugs for rare diseases. The training will be provided 

to all CDER and CBER review staff, and will be part of the reviewer training core 
254 


76491.174

curriculum, Among the key purposes of this training are to familiarize review staff with the 

challenges associated with rare disease applications and strategies to address these 

challenges; to promote best practices for review and regulation of rare disease applications; 

and to encourage flexibility and scientific judgment among reviewers in the review and 

regulation of rare disease applications, The training will also emphasize the role of the Rare 

Disease Program staff as members of the review team to help ensure consistency of scientific 

and regulatory approaches across applications and review teams, 

By the end of FY 2016, FDA, through the Rare Disease Program, will develop an evaluation 

tool to evaluate the success of the activities of the Rare Disease Program, including the 

reviewer training, Among potential measures of success are the development of a system to 

track rare disease applications from IND submission through the post-marketing period, 

increased number of reviewers receiving rare disease-specitic training, increased number of 

activities contributing to regulatory and biomedical science for rare disease drug 

development, and meeting ofPDUFA goals for rare disease applications," 

Respectfully Submitted, 

Diane Edquist Dorman 

Vice President, Public Policy 

National Organization for Rare Disorders (NORD) 

1779 Massachusetts Avenue, NW, Suite 500 

Washington, DC 20036 

(202) 588-5700 

ddonnan(iilrarediseases,org 

Cc: The Honorable Frank Pallone, Jr., Ranking Member, Subcommittee on Health 

The Honorable Eliot Engel 
255 


76491.175

AAP Headquarters 

141 Norlhwest Point Bhrd 

Elk Grove ViRage, IL 60oo7·1019 

Phollo: 8471434-4000 

Fax: 847(434-8000 

E-mail: kidsdocs@aap.orl;l 

WNW.aap.org 

Reply to 

Oopartmant of Federal Affairs 

Homer Building, Suite 400 N 

60113thStNW 

Washingtoll, DC 20005 

Phone: 202/347·B600 

Fax: 202/393-6137 

E-mail: kid.s1 st@aap.org 

EJl9Cutive Committee 

Pnu,ldent 

Roberl W. Block, MD, FAA? 

Pntaldent·Elect 

Thomas K. Mcinerny, MD. I"-'AAP 

Immediate Past President 

O. Marion Burton, MD, FAA? 

Executive Diro-ctor/CEO 

Errol R. Alden, MD, FAAP 

Board of Dintctors. 

DistrictJ 

Carole E. AUen, MD, FAAP 

Aningtoll,MA 

District II 

Danielle Laraqu6, MD, FAAP 

Brooklyn, NY 

District iii 

Sandra Gibson Hassink, MD, FAAP 

Wilminl;lton, DE 

District IV 

Franas E. Rushton, Jr, MD, FAAP 

Beaufort,SC 

District V 

Marilyn J. Bull. MO, FAA? 

Indianapo!is,lN 

District VI 

Michael V. Severson, MD, FAAP 

Shakopee, MN 

DistrIct VII 

Kenneth E. Matthews, MD, FAAP 

College Station, TX 

DistrictVIIl 

Ky1e Yasuda, MO, FAAP 

Seattle, WA 

Oistric:tlX 

Myles B. Abbott, MD, FAA? 

8er1o:eley, CA 

Distrlc1X 

Sara H. Gom, MD, FAAP 

Fayetle-.;lUe, GA 

American Academy of Pediatrics 

DEDICATED TO THE HEALTH OF ALL CH1LDREN" 

March 23, 2012 

The Honorable Joseph R. Pitts 

Chairman 

Energy and Commerce Committee 

Subcommittee on Health 

U.S. House of Representatives 

Washington, D.C. 20515 

Dear Chairman Pitts and Ranking Member Pallone: 

The Honorable Frank Pallone, Jr 

Ranking Member 

Energy and Commerce Committ, 

Subcommittee on Health 

U.S. House of Representatives 

Washington, D.C. 20515 

On behalf of the 62,000 primary care pediatricians, pediatric medical subspecialists, 

and surgical specialists of the American Academy of Pediatrics CAAP) who are 

committed to the attainment of optimal physical, mental and social health and wellbeing for all infants, children, adolescents, and young adults, I thank you for 

inviting me to testifY before the Subcommittee on Health on February 1,2012, and 

welcome this opportunity to respond to questions for the record for the hearing 

entitled "Reauthorization ofPDUFA: What It Means for Jobs, Innovation, and 

Paticnts," 

The Honorable Eliot Engel 

Several of you mentioned in your written testimony tbat tbe user fees included 

in PDUFA V are meant to be in addition to a solid base of annually 

appropriated funds for tbe FDA. I was pleased to see tbat for Fiscal Year 

2012, tbe FDA received a $50 million increase in funding over Fiscal Year 2011 

funding levels. But tbis was a bard fougbt victory, given tbat House 

Republicans first proposed a $285 million cnt in FDA funding for Fiscal Year 

2012. Please elaborate on wby it is so important tbat tbe FDA be adequatelY 

funded and bow cuts to tbe FDA could impact your industry or the patents 

your associations serve? 

Adequate funding for the FDA is critical in order for the agency to fulfill its 

mission. The FDA regulates roughly twenty-five percent of all products consumed 

by Americans and, as such, it is critical that Congress provide the agency adequate 

funding to ensure that these products are safe, effective, and of high quality. The 

FDA relies on discretionary, appropriated funding in order to carry out many of the 

responsibilities in the Best Phannaceuticals for Children Act CBPCA), the Pediatric 

Research Equity Act (PREA), the Pediatric Medical Device Consortia program and 

other successful pediatric medical product initiatives. The AAP urges Congress to 

provide $6 million in funding for the Pediatric Device Consortia program in the 

Omce of Orphan Products Development at the FDA in Fiscal Year 2013. The 

Pediatric Device Consortia program at FDA has helped to foster job growth and 

increased the commercial availability of pediatric medical devices in the United 

States. According to the FDA, the five FDA-funded Pediatric Device Consortia 

have assisted in advancing the development of 135 proposed pediatric medical 

devices. 
256 


76491.176

Page 2 

In addition to my legislative work on ALS and muscular dystrophy, I serve on the rare and 

orphan disease caucus, which is why I am particularly interested in the provisions ofthe 

PDUFA V agreement related to the development and approval of drugs for rare diseases. 

a. What barriers do you perceive in moving new candidate therapies through the 

development process? 

Drug development for children and other smaller market populations such as individuals 

with rare diseases has traditionally faced economic and scientific barriers.- Congress has 

shown great leadership in helping to address these challenges through market incentives 

and requirements. The AAP applauds this Subcommittee for its longstanding support of 

BPCA and PREA. Through BPCA and PREA we have gained more useful information 

on drugs and biologics used in children than we had in the seventy years prior to their 

enactment. Since BPCA was first enacted in 1997, more than 426 drug labels have been 

updated with important pediatric information. 

BPCA and PREA work together as an effective two-pronged approach to generate 

pediatric studies. BPCA provides a voluntary incentive to drug manufacturers of an 

additional six months of marketing exclusivity for conducting pediatric studies of drugs 

that the FDA determines may be useful to children. PREA provides FDA the authority to 

require pediatric studies of drugs when their use in children is for the same indication as 

for adults. 

BPCA and PREA have advanced medical therapies for infants, children, and adolescents 

by generating substantial new information on the safety and efficacy of pediatric 

pharmaceuticals where previously there was little. It is vitally important for these 

pediatric subpopulations that these laws be reauthorized and strengthened. 

The AAP also underscores the importance ofthe Orphan Drug Act in stimulating drug 

development for populations with rare diseases, half of whom are children. Families with 

children facing these devastating diseases require the special consideration the Orphan 

Drug Act, BPCA and PREA provide. 

b. Do you feel that PDUFA V adequately addresses these barriers or what additional 

provisions are necessary to ensure that patients with rare diseases have access to 

promising drug treatments? 

Although the AAP does not have an official position on PDUF A V, about half of all rare 

diseases affect children. The AAP supports efforts to increase the availability of 

treatment options for children, including children with rare diseases. As previously 

discussed, the Orphan Drug Act, BPCA and PREA have all helped to stimulate drug 

development in rare disease populations but the lack of insurance coverage or inadequate 

insurance coverage for many of these treatments denies access and can harm patients. 
257 

Æ 


76491.177

Page 3 

Despite the success of these programs, many children and families find that insurance 

companies treat FDA-approved treatments or off-label uses of treatments for children as 

experimental and routinely deny coverage. This must change. 

Since half of drugs used in children still lack pediatric labeling, off-label use remains an 

unfortunate but necessary practice. In pediatrics, off-label use falls within the standard of 

care for our patient population and insurance companies must account for this reality so 

that our patients have coverage of needed treatments. 

The AAP appreciates this opportunity to provide additional information to the Subcommittee. If 

you have further questions, please contact Tamar Magarik Haro in AAP's Washington Office at 

202/347-8600. 

Sincerely, 

~~//:::;":t::!::>'(( Danielk Frattarelli, MD, FAAP 

DF/tmh