U.S. GOVERNMENT PUBLISHING OFFICE

26–958 PDF WASHINGTON : 2018

EXAMINING MEDICAL PRODUCT MANUFACTURER 

COMMUNICATIONS 

HEARING 

BEFORE THE

SUBCOMMITTEE ON HEALTH 

OF THE

COMMITTEE ON ENERGY AND 

COMMERCE 

HOUSE OF REPRESENTATIVES 

ONE HUNDRED FIFTEENTH CONGRESS 

FIRST SESSION 

JULY 12, 2017 

Serial No. 115–44 

( 

Printed for the use of the Committee on Energy and Commerce 

energycommerce.house.gov 

COMMITTEE ON ENERGY AND COMMERCE 

GREG WALDEN, Oregon 

Chairman 

JOE BARTON, Texas 

Vice Chairman 

FRED UPTON, Michigan 

JOHN SHIMKUS, Illinois 

TIM MURPHY, Pennsylvania 

MICHAEL C. BURGESS, Texas 

MARSHA BLACKBURN, Tennessee 

STEVE SCALISE, Louisiana 

ROBERT E. LATTA, Ohio 

CATHY MCMORRIS RODGERS, Washington 

GREGG HARPER, Mississippi 

LEONARD LANCE, New Jersey 

BRETT GUTHRIE, Kentucky 

PETE OLSON, Texas 

DAVID B. MCKINLEY, West Virginia 

ADAM KINZINGER, Illinois 

H. MORGAN GRIFFITH, Virginia 

GUS M. BILIRAKIS, Florida 

BILL JOHNSON, Ohio 

BILLY LONG, Missouri 

LARRY BUCSHON, Indiana 

BILL FLORES, Texas 

SUSAN W. BROOKS, Indiana 

MARKWAYNE MULLIN, Oklahoma 

RICHARD HUDSON, North Carolina 

CHRIS COLLINS, New York 

KEVIN CRAMER, North Dakota 

TIM WALBERG, Michigan 

MIMI WALTERS, California 

RYAN A. COSTELLO, Pennsylvania 

EARL L. ‘‘BUDDY’’ CARTER, Georgia 

FRANK PALLONE, JR., New Jersey 

Ranking Member 

BOBBY L. RUSH, Illinois 

ANNA G. ESHOO, California 

ELIOT L. ENGEL, New York 

GENE GREEN, Texas 

DIANA DEGETTE, Colorado 

MICHAEL F. DOYLE, Pennsylvania 

JANICE D. SCHAKOWSKY, Illinois 

G.K. BUTTERFIELD, North Carolina 

DORIS O. MATSUI, California 

KATHY CASTOR, Florida 

JOHN P. SARBANES, Maryland 

JERRY MCNERNEY, California 

PETER WELCH, Vermont 

BEN RAY LUJA ́ N, New Mexico 

PAUL TONKO, New York 

YVETTE D. CLARKE, New York 

DAVID LOEBSACK, Iowa 

KURT SCHRADER, Oregon 

JOSEPH P. KENNEDY, III, Massachusetts 

TONY CA ́ RDENAS, California 

RAUL RUIZ, California 

SCOTT H. PETERS, California 

DEBBIE DINGELL, Michigan 

SUBCOMMITTEE ON HEALTH

MICHAEL C. BURGESS, Texas 

Chairman 

BRETT GUTHRIE, Kentucky 

Vice Chairman 

JOE BARTON, Texas 

FRED UPTON, Michigan 

JOHN SHIMKUS, Illinois 

TIM MURPHY, Pennsylvania 

MARSHA BLACKBURN, Tennessee 

CATHY MCMORRIS RODGERS, Washington 

LEONARD LANCE, New Jersey 

H. MORGAN GRIFFITH, Virginia 

GUS M. BILIRAKIS, Florida 

BILLY LONG, Missouri 

LARRY BUCSHON, Indiana 

SUSAN W. BROOKS, Indiana 

MARKWAYNE MULLIN, Oklahoma 

RICHARD HUDSON, North Carolina 

CHRIS COLLINS, New York 

EARL L. ‘‘BUDDY’’ CARTER, Georgia 

GREG WALDEN, Oregon (ex officio) 

GENE GREEN, Texas 

Ranking Member 

ELIOT L. ENGEL, New York 

JANICE D. SCHAKOWSKY, Illinois 

G.K. BUTTERFIELD, North Carolina 

DORIS O. MATSUI, California 

KATHY CASTOR, Florida 

JOHN P. SARBANES, Maryland 

BEN RAY LUJA ́ N, New Mexico 

KURT SCHRADER, Oregon 

JOSEPH P. KENNEDY, III, Massachusetts 

TONY CA ́ RDENAS, California 

ANNA G. ESHOO, California 

DIANA DEGETTE, Colorado 

FRANK PALLONE, JR., New Jersey (ex 

officio) 

(II) 

(III) 

C O N T E N T S 

Page 

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

Texas, opening statement .................................................................................... 1 

Prepared statement .......................................................................................... 2 

Hon. Gene Green, a Representative in Congress from the State of Texas, 

opening statement ................................................................................................ 4 

Hon. Greg Walden, a Representative in Congress from the State of Oregon, 

opening statement ................................................................................................ 5 

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

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

New Jersey, opening statement .......................................................................... 7 

Prepared statement .......................................................................................... 9 

WITNESSES

Coleen Klasmeier, Partner, Sidley Austin, LLP ................................................... 10 

Prepared statement .......................................................................................... 13 

Answers to submitted questions ...................................................................... 154 

R. Alta Charo, Warren P. Knowles Professor of Law, University of Wisconsin . 23 

Prepared statement .......................................................................................... 26 

Answers to submitted questions ...................................................................... 164 

George Van Hare, M.D., President, Heart Rhythm Society ................................. 28 

Prepared statement .......................................................................................... 30 

Answers to submitted questions ...................................................................... 169 

Aaron S. Kesselheim, Associate Professor of Medicine, Harvard Medical 

School and Brigham and Women’s Hospital ...................................................... 36 

Prepared statement .......................................................................................... 38 

Answers to submitted questions 1 ................................................................... 174 

Linda House, President, Cancer Support Community ......................................... 46 

Prepared statement .......................................................................................... 49 

Answers to submitted questions ...................................................................... 178 

Katherine Wolf Khachatourian, Vice President, Delegation Oversight, Pharmacy Services, and Strategy, Qualchoice Health Plan Services, Inc. .............. 55 

Prepared statement .......................................................................................... 57 

Answers to submitted questions 1 ................................................................... 183 

SUBMITTED MATERIAL

Discussion Draft, H.R. lll, Facilitating exchange of information prior to 

approval ................................................................................................................ 108 

Discussion Draft, H.R. lll, Communications regarding intended uses of 

drugs and devices; scientific exchange ............................................................... 112 

Letter of July 10, 2017, from Academy of Managed Care Pharmacy, et al., 

to Mr. Guthrie, submitted by Mr. Guthrie ......................................................... 115 

Letter of May 2, 2017, from the Alliance of Specialty Medicine, to Mr. Griffith, 

submitted by Mr. Griffith .................................................................................... 117 

Letter of May 16, 2017, from Dystrophic Epidermolysis Bullosa Research 

Association of America, Inc., et al., to Mr. Griffith, submitted by Mr. Griffith ......................................................................................................................... 118 

Letter of May 5, 2017, from Mary R. Grealy, President, Healthcare Leadership Council, to subcommittee leadership, submitted by Mr. Griffith ............ 120 

1Dr. Kesselheim and Ms. Khachatourian did not answer submitted questions 

for the record by the time of printing. 

Page

IV 

Letter of July 11, 2017, from Michael Carome, M.D., Director, Public Citizen’s 

Health Research Group, to Mr. Burgess and Mr. Green, submitted by 

Mr. Green .............................................................................................................. 122 

Statement of John Rother, Executive Director, The Campaign for Sustainable 

Rx Pricing, July 12, 2017, submitted by Mr. Green .......................................... 143 

Statement of America’s Health Insurance Plans, July 12, 2017, submitted 

by Mr. Green ........................................................................................................ 147 

(1) 

EXAMINING MEDICAL PRODUCT 

MANUFACTURER COMMUNICATIONS 

WEDNESDAY, JULY 12, 2017 

HOUSE OF REPRESENTATIVES, SUBCOMMITTEE ON HEALTH, COMMITTEE ON ENERGY AND COMMERCE, Washington, DC. 

The subcommittee met, pursuant to call, at 10:18 a.m., in Room 

2322, Rayburn House Office Building, Hon. Michael C. Burgess 

(chairman of the subcommittee) presiding. 

Members present: Representatives Burgess, Guthrie, Barton, 

Upton, Shimkus, Blackburn, Lance, Griffith, Bilirakis, Bucshon, 

Brooks, Mullin, Hudson, Collins, Carter, Walden (ex officio), Green, 

Engel, Schakowsky, Butterfield, Matsui, Castor, Sarbanes, Kennedy, Ca ́ rdenas, Eshoo, and Pallone (ex officio). 

Staff present: Adam Buckalew, Professional Staff Member, 

Health; Daryll Dykes, Health Fellow; Paul Edattel, Chief Counsel, 

Health; Adam Fromm, Director of Outreach and Coalitions; Jay 

Gulshen, Legislative Clerk, Health; Alex Miller, Video Production 

Aide and Press Assistant; Jennifer Sherman, Press Secretary; 

Danielle Steele, Policy Coordinator, Health; John Stone, Senior 

Counsel, Health; Hamlin Wade, Special Advisor for External Affairs; Jeff Carroll, Minority Staff Director; Samantha Satchell, Minority Policy Analyst; Andrew Souvall, Minority Director of Communications, Member Services, and Outreach; Kimberlee Trzeciak, 

Minority Senior Health Policy Advisor; and C.J. Young, Minority 

Press Secretary. 

Mr. BURGESS. The Subcommittee on Health will now come to 

order. I will recognize myself for 5 minutes for the purpose of an 

opening statement. 

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A 

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS 

From last year’s 21st Century Cures Act to this year’s Food and 

Drug Administration reauthorization, this subcommittee has been 

committed to bringing Federal regulation into the modern era of 

medicine. Today, we continue that work by examining legislation to 

update the regulatory framework affecting the dissemination of 

truthful and nonmisleading information about products approved 

by the Food and Drug Administration. 

I practiced medicine for several decades. I know firsthand how 

challenging it is it and how challenging it can be for providers to 

stay up to the minute with cutting-edge information in both medicine and science. Following the Food and Drug Administration’s apVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00005 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
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proval of a product, the use of that product rapidly evolves based 

on patient and provider experience. Frequently, the standard of 

care for a condition is outside of the Food and Drug Administration-approved labeling. Ensuring that healthcare providers have access to new information generated by real-world evidence is critical 

to optimizing patient care and outcomes. Particularly in medicine, 

the old adage holds true, knowledge is power. 

Our legal framework for the regulation of manufacturer communications sometimes prevents healthcare professionals from receiving the most current scientific information available about the benefits and risks of FDA-approved medicines. A lack of relevant information can lead to physicians making patient care decisions with 

incomplete information. This is both unfair to the physician and 

unsafe for the patient. 

We owe it to the patient and medical communities to ensure that 

there is free and full dissemination of truthful and nonmisleading 

scientific and medical information for healthcare professionals. 

I certainly want to thank two of our committee members, the 

vice chairman of the committee, Brett Guthrie, and Representative 

Morgan Griffith from Virginia for offering the bills that will be 

under discussion today. I feel they offer a targeted approached to 

addressing the problems presented by our regulatory framework for 

medical product communication. And, if he would like time, I am 

prepared to yield to the gentleman from Kentucky, if he would like 

time for an opening statement. 

[The prepared statement of Mr. Burgess follows:] 

PREPARED STATEMENT OF HON. MICHAEL C. BURGESS

From last year’s 21st Century Cures Act, to this year’s FDA Reauthorization, this 

subcommittee has been steadfast in its commitment to bring Federal regulation into 

the modern era of medicine. Today we will continue that work by examining legislation to update the regulatory framework affecting dissemination of truthful and nonmisleading information about FDA-approved products. 

I practiced as a physician for several decades, and so I know firsthand how challenging it can be for providers to stay abreast of cutting-edge information in medicine and science. Following FDA-approval of a product, the use of that product rapidly evolves based on patient and provider experience. Frequently the standard of 

care for a condition is outside of the FDA-approved labeling. Ensuring that 

healthcare providers are able to access new information generated by real-world evidence is critical to optimizing patient care and outcomes. Particularly in medicine, 

the old adage holds true-knowledge is power. 

Unfortunately, our legal framework for the regulation of manufacturer communication prevents healthcare professionals from receiving the most current scientific 

information available about the benefits and risks of FDA-approved medicines. A 

lack of relevant information can lead to physicians making patient care decisions 

with incomplete information. This is both unfair to the physician and unsafe for the 

patient. 

We owe it to the patient and medical communities to ensure that there is free 

and full dissemination of truthful and nonmisleading scientific and medical information to healthcare professionals. 

I would like to yield the balance of my time to Vice Chairman Guthrie and Representative Griffith to discuss their bills—each of which is a targeted approach to 

addressing the problems presented by our outdated regulatory framework for medical product communication. 

Mr. GUTHRIE. Thank you, Mr. Chairman. There is another very 

important hearing on opioids going on downstairs, and we have our 

Kentucky Justice Secretary there. 

3 

Mr. Chairman, I want to thank you for holding this hearing 

today to examine communications between manufacturers and 

healthcare payers which I addressed in my bill, H.R. 2026, the 

Pharmaceutical Information Exchange Act. My bill will enable 

greater information exchange in order to guide health plans, pharmacy benefit managers, and others who develop prescription drug 

formularies and medical devices to make well-informed decisions 

about the benefits and costs of medications and medical devices for 

the populations they cover. 

Patients benefit when these formulary decisions are informed by 

the most recent and reliable scientific evidence on drugs and devices beyond just what we learn from the clinical trials conducted 

by FDA approval. Our committee has addressed post-approval information exchange. We should take the next logical step by addressing what information can and should be exchanged 

preapproval by considering the updated discussion draft we are examining today. 

I would like to submit for the record a letter of support for my 

bill by a number of organizations, including the Academy of Managed Care Pharmacy, Humana, Sanofi, and Mayo Clinic. 

Mr. BURGESS. Without objection, so ordered. 

[The information appears at the conclusion of the hearing.] 

Mr. GUTHRIE. Thank you, Mr. Chairman. I yield back. 

Mr. BURGESS. The Chair thanks the gentleman. The Chair would 

like to recognize the gentleman from Virginia, Mr. Griffith, if he 

would seek time for an opening statement. 

Mr. GRIFFITH. Thank you very much, Mr. Chairman, I do appreciate it. Mr. Guthrie and I were both downstairs introducing former 

colleagues from the House of Delegates, so we apologize that we 

came rushing in, but we got that done. 

The draft version of my bill that we are discussing today will responsibly set the rules of the road so that manufacturers have the 

most accurate and up-to-date information about their products that 

can provide doctors and researchers with that information, and in 

the appropriate context, to improve patient care and facilitate additional research. 

Not only does the lack of clear rules have a public health ramification, but also it has legal consequences. There have been a 

number of court decisions that raise significant First Amendment 

questions about the FDA’s authority to restrict a drug or device 

manufacturer from communicating truthful and nonmisleading offlabel information about their products. 

The Judiciary Branch should not be turned into de facto policy 

makers because of FDA’s misunderstanding of the law or our inaction here in Congress. 

I remain open to any and all suggestions from both sides of the 

aisle and from stakeholders as to how this legislation may be improved, but I am glad we are continuing the dialogue. Also, I also 

forward to hear from witnesses today about how the FDA’s vague 

policies hinder the facilitation of information to healthcare providers and how this legislation could be a first step in addressing 

some of the challenges that we will hear about. Thank you. I yield 

back. 

4 

Mr. BURGESS. The gentleman yields back, and the Chair yield 

back. The Chair recognizes the ranking member of the subcommittee, Mr. Green, 5 minutes for an opening statement, please. 

OPENING STATEMENT OF HON. GENE GREEN, A 

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS 

Mr. GREEN. Thank you, Mr. Chairman. Today, we are considering two draft bills addressing pharmaceutical manufacturer communications on medical products. The Medical Product Communications Act and the Pharmaceutical Information Exchange Act 

suggest the changes of the rules surrounding the communications 

from medical product manufacturers will likely have far-reaching 

implications for decisions made by healthcare providers about 

which therapies are appropriate for their patients. It is critically 

important for us to fully consider and appreciate the impact those 

proposed changes could have on patient safety, health outcomes, 

and the promotion of value in our healthcare system. 

My concern with the two bills we are considering today is that 

as drafted they would undermine public health, discourage pharmaceutical research, and undermine the FDA’s central capacity to 

ensure medical products used on patients have demonstrated safety 

and efficiency. Opening the floodgates for off-label communication 

puts patients at risk, puts a dent in the armor that ensures patients get effective therapies, and not snake oil. 

Broadening off-label communications could erode FDA’s approval 

standard as it would enable the uses of products never found to be 

safe or effective in patients and weaken consumer confidence in the 

FDA approval process. FDA’s approval standard of safety and efficiency is considered to be the gold standard globally. As the FDA 

Commissioner Dr. Scott Gottlieb has said, the most important incentive to developing useful information remains the ability for 

companies to market drugs based on what has been proven scientifically. There is an incentive currently for companies to seek FDA’s 

approval for all uses of a drug product if they wish to market the 

product for those uses and gain coverage for these uses. 

Allowing manufacturers to communicate about unproven uses of 

their products reduces the incentive to go through the FDA’s approval process as clinical trials are the most expensive part of the 

development. Thus, it is not hard to imagine a scenario where a 

company seeks the narrowest indication for their product, gets on 

the market, and forgoes on continuing large, well controlled, randomized clinical trials that would prove a product is both safe and 

effective for broader populations or indications. Patients and doctors should fully be empowered to make joint decisions about their 

care. This includes the efficiency, risk, and cost of their options. 

Information is key, however, and the best decisions are based on 

accurate, evidence-based information, not just for information that 

may be incomplete, inconclusive, or at worst inaccurate. The discussion draft of the Medical Product Communications Act would 

not provide or ensure that patients and care providers have access 

to better research and evidence. Rather, it would allow drug manufacturers to communicate information about prescription drugs that 

have not been approved by the FDA. The lack of approval may be 

5 

due to contradictory evidence or the lack of any evidence at all, or 

the need for additional research. 

While I have concerns with both discussion drafts as written, I 

do appreciate that our audience matters. The discussion draft of 

the Pharmaceutical Information Exchange Act would expand the 

ability of drug and device manufacturers to communicate 

healthcare economic information, and scientific information to payers, formularies, technology review committees, or other entities 

about unapproved uses of products. These audiences are sophisticated and have an inherent interest in being skeptical of claims 

made outside a product’s label. Therefore, it is less problematic in 

its premise than the other bill we are considering. 

While I am willing to work with my colleagues on the proposal, 

it is critical that these communications promote patient safety, 

public health, and the appropriate safeguards are in place to avoid 

damaging unintended consequences. As we consider the issue of 

off-label communication, we must always keep in mind that the 

way to truly help patients get the most effective treatments is to 

maintain the highest standards of safety and evidence and appropriate risk of benefit balance. 

Scientifically validated safety and efficiency and the incentives 

for manufacturers to seek FDA approval are clear and should be 

preserved. I look forward to hearing from our witnesses and if anybody wants time, I will yield my 45 seconds back. Thank you, Mr. 

Chairman. 

Mr. BURGESS. The gentleman yields back. The Chair thanks the 

gentleman. The Chair recognizes the gentleman from Oregon, the 

chairman of the full committee, Mr. Walden, 5 minutes for an 

opening statement, please. 

OPENING STATEMENT OF HON. GREG WALDEN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF OREGON 

Mr. WALDEN. I thank the subcommittee chairman, Chairman 

Burgess. Thanks for this holding this hearing. It is a really important topic, and it is a topic that has been important for our Members for some time. 

Approximately 40 percent, 40 percent of prescriptions in the 

United States are for indications or uses not included in the FDAapproved product labeling. Although off-label uses of drugs and devices are often the recognized standard for care for treating many 

conditions, the lack of clarity in the statute and implementing regulations has stifled important information about such uses for 

being communicated in a responsible and nonpromotional manner 

by manufacturers. 

The FDA has attempted to address this issue, but it has been in 

a piecemeal fashion or the last 2 decades with various nonbinding 

guidance documents and policy statements that frankly fall woefully short, particularly given the criminal penalties in play. 

As the Supreme Court affirmed in 2011 that First Amendment 

commercial speech protections extend to medical product manufacturers, every subsequent judicial decision, every decision, has 

raised significant questions about the extent of FDA’s authority to 

restrict truthful and nonmisleading off-label communications. 

6 

So where are we today? The regulators and the courts have spoken. Everyone is left with a vast amount of uncertainty that does 

nothing to protect or benefit patients. So it is time for Congress to 

act. And as FDA’s authorizing committee, it is our job to clarify 

this statute and get it right which brings us to this hearing. Neither of these bills are new to my fellow committee members. We 

discussed an earlier version of both bills during a markup in this 

subcommittee back in May and we reviewed these updated versions 

of the full committee markup of the FDA Reauthorization Act last 

month. Both bills were ultimately withdrawn as amendments to 

FDARA with a commitment from our colleagues on the other side 

of the aisle to work with us together to iron out a compromise so 

we could move these important policies forward and speak as the 

Congress and not leave this up to a mishmash of court decisions. 

So I look forward to continuing that work today. 

I believe Morgan Griffith’s bill, H.R. 1703, is a serious, wellthought-out policy proposal that responsibly sets the rules of the 

road in a constitutionally sound manner. I greatly appreciate his 

willingness to continue to address concerns. He has heard about 

the legislative language. 

I also appreciate Ranking Member Pallone’s commitment at the 

user fee markup to work with us in good faith on this issue 

through regular order which starts with this important hearing. 

In addition. Representative Guthrie’s amended version of H.R. 

2026 would clarify how drug and medical device companies can 

share healthcare, economic, or scientific information related to investigational uses of their products with payers and similar entities. These bills do not provide manufacturers with free reign to 

communicate any and all information about their products. They 

establish targeted, statutory boundaries within which manufacturers may responsibly disseminate accurate and up-to-date information about medical products. These clarifications will lead to a better informed healthcare system. They will ensure that patients receive high-quality care based on current sound, scientific, and clinical information. 

Today, we continue the dialogue. I look forward to a productive 

discussion and I appreciate the input of our witnesses who are before us today, and with that, unless there are other Members who 

would like to use the balance of my time, I will yield back the balance of my time. 

Mr. BURGESS. The Chair thanks the gentleman. The gentleman 

yields back. The Chair recognizes the gentleman from New Jersey, 

the ranking member of the full committee, 5 minutes for an opening statement, please. 

[The prepared statement of Mr. Walden follows:] 

PREPARED STATEMENT OF HON. GREG WALDEN

Thank you, Chairman Burgess, for holding today’s hearing on an increasingly important topic—one that has been a topic amongst our Members for some time. 

Approximately 40 percent of prescriptions in this country are for indications or 

uses not included in the FDA-approved product labeling. Although ‘‘off-label’’ uses 

of drugs and devices are often the recognized standard of care for treating many 

conditions, the lack of clarity in the statute and implementing regulations has stifled important information about such uses from being communicated in a responsible, nonpromotional manner by manufacturers. 

7 

FDA has attempted to address this issue in a piecemeal fashion over the last two 

decades with various nonbinding guidance documents and policy statements that 

fall woefully short, particularly given the criminal penalties in play. 

Since the Supreme Court affirmed in 2011 that First Amendment commercial 

speech protections extend to medical product manufacturers, every subsequent judicial decision has raised significant questions about the extent of FDA’s authority to 

restrict truthful and nonmisleading off-label communications. 

So, where are we today? The regulators and the courts have spoken. Everyone is 

left with a vast amount of uncertainty that does nothing to protect or benefit patients. 

It is past time for Congress to act, and as FDA’s authorizing committee it is our 

job to clarify the statute. 

Which brings us to this hearing. Neither of these bills are new to my fellow committee members. We discussed an earlier version of both bills during a markup in 

this subcommittee back in May, and we reviewed these updated versions at the full 

committee markup of the FDA Reauthorization Act (FDARA) last month. 

Both bills were ultimately withdrawn as amendments to FDARA, with a commitment from our Democrat colleagues to continue to work together to iron out a compromise on moving these important policies forward. I look forward to continuing 

that work today. 

I believe Morgan Griffith’s bill, H.R. 1703, is a serious, well-thought-out policy 

proposal that responsibly sets the rules of the road in a constitutionally sound manner. I greatly appreciate his willingness to continue to address concerns he has 

heard about the legislative language. I am also appreciative of Ranking Member 

Pallone’s commitment at the user fee markup to work with us on this issue through 

regular order, which starts with this important hearing. 

In addition, Rep. Guthrie’s amended version of H.R. 2026 would clarify how drug 

and medical device companies can share healthcare, economic, or scientific information related to investigational uses of their products with payers and similar entities. 

These bills do not provide manufacturers with free rein to communicate any and 

all information about their products. They establish targeted statutory boundaries 

within which manufacturers may responsibly disseminate accurate, and up-to-date 

information about medical products. These clarifications will lead to a 

betterinformed health care system and will ensure that patients receive high-quality 

care based on current, sound scientific and clinical information. 

Today we continue the dialogue, and I look forward to a productive discussion. 

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

Mr. PALLONE. Thank you, Mr. Chairman. I want to thank you for 

holding today’s hearing. The issue before us today is an important 

one and I hope that our discussion today will help to inform whether or not it would be appropriate for this committee to take further 

action. 

Today, under current law, medical product manufacturers are required to demonstrate the safety and effectiveness of each intended 

use of their medical product. This review process has been critical 

to protecting and promoting public health by ensuring that the 

benefits of medical products that are prescribed to patients outweigh the risk. It also is common sense. Just because a medical 

product approved for one use may be found to be safe and effective 

for that use, doesn’t necessarily mean that it will be safe and effective for another use or for another population. 

Recognizing that physicians may prescribe treatments off-label in 

response to individual patient needs, FDA allows the communication of truthful and nonmisleading scientific or medical information 

regarding unapproved uses of medical products that may assist 

physicians in making treatment decisions. In those instances, FDA 

has allowed for manufacturers to respond to requests from physiVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00011 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
8 

cians about unapproved uses and provide peer reviewed journal articles, scientific or medical texts, and clinical practice guidelines. 

Following 21st Century Cures, manufacturers are also now able 

to share healthcare economic information with payers to help them 

better understand the economic benefits of an approved treatment. 

These are commonsense approaches that allow doctors to address 

the individual needs of a patient, but also ensure that patients are 

not unnecessarily exposed to unproven or harmful medical products. 

Now today, we are here to examine discussion drafts from Representatives Griffith and Guthrie that would greatly expand the 

types of scientific information that manufacturers could share without any FDA oversight. While I understand that medical product 

manufacturers have voiced concerns about their ability to communicate with doctors about their products, I am concerned that these 

drafts would severely undermine the current protections against 

marketing unsafe and ineffective medical products. 

During this hearing, I hope to hear what materials manufacturers want to share with healthcare professionals and payers that 

they feel they can’t under current law. 

The scientific exchange discussion draft would severely restrict 

the types of evidence the FDA has always relied on to determine 

the intended use of a medical product. It would also hamstring the 

Agency from holding bad actors who distribute dangerous drugs or 

medical devices accountable. 

The preapproval communication discussion draft will blow a hole 

in the current approval process by allowing the communication of 

any scientific evidence or healthcare economic information to payers or formularies without any recourse to the FDA to prevent bad 

actors from communicating false or misleading information. Allowing manufacturers to communicate about unapproved products and 

unapproved uses of their products reduces the incentive of those 

through FDA’s approval process and that is grossly irresponsible in 

my opinion. 

For example, the proposed discussion draft would allow for a 

manufacturer to publish a biased, scientific study in any medium 

to constitute scientific exchange. This could simply include posting 

results of a nonpeer-reviewed study on a company’s website, and 

there is no requirement that this information be truthful. 

I am also concerned that these two discussion drafts could expose 

more patients to medical products that have never been proven to 

be safe or effective. One study found that 81 percent of medications 

prescribed for off-label purposes had poor or no scientific support, 

while another found that patients who received off-label prescriptions were 54 percent more likely to experience an adverse event, 

as compared to on-label use. And these are risks that we simply 

cannot ignore. 

So Mr. Chairman, if there is a need for greater certainty and 

clarity on the types of communications that manufacturers are permitted to use under current law, I am willing to have that discussion. However, broadening communication in the way it is proposed 

under these discussion drafts would, in my opinion, undermine 

FDA’s regulatory review process and the safety and effectiveness 

approval standard. 

9 

I have about a minute. I don’t know if anybody wants it. If not, 

I yield back, Mr. Chairman. 

[The prepared statement of Mr. Pallone follows:] 

PREPARED STATEMENT OF HON. FRANK PALLONE, JR. 

Mr. Chairman, I want to thank you for holding today’s hearing. The issue before 

us today is an important one, and I hope that our discussion will help to inform 

whether or not it would be appropriate for this committee to take further action at 

this time. 

Today, under current law, medical product manufacturers are required to demonstrate the safety and effectiveness of each intended use of their medical product. 

This review process has been critical to protecting and promoting public health by 

ensuring that the benefits of medical products that are prescribed to patients outweigh the risks. It is also commonsense—just because a medical product approved 

for one use may be found to be safe and effective for that use, does not necessarily 

mean that it will be safe and effective for another use or for another population. 

Recognizing that physicians may prescribe treatments off-label in response to individual patient needs, FDA allows the communication of truthful and nonmisleading scientific or medical information regarding unapproved uses of medical products that may assist physicians in making treatment decisions. In these instances, 

FDA has allowed for manufacturers to respond to requests from physicians about 

unapproved uses and provide peer-reviewed journal articles, scientific or medical 

texts, and clinical practice guidelines. Following 21st Century Cures, manufacturers 

are also now able to share health care economic information with payors to help 

them better understand the economic benefits of an approved treatment. 

These are commonsense approaches that allow doctors to address the individual 

needs of a patient, but also ensure that patients are not unnecessarily exposed to 

unproven or harmful medical products. 

Today, we are here to examine discussion drafts from Representatives Griffith 

and Guthrie that would greatly expand the types of scientific information that manufacturers could share without any FDA oversight. While I understand that medical 

product manufacturers have voiced concern about their ability to communicate with 

doctors about their products, I am concerned that these drafts would severely undermine the current protections against marketing unsafe and ineffective medical products. During this hearing, I hope to hear what materials manufacturers want to 

share with health care professionals and payors today that they feel they cannot 

under current law. 

The scientific exchange discussion draft would severely restrict the types of evidence the FDA has always relied on to determine the intended use of a medical 

product. It would also hamstring the agency from holding bad-actors who distribute 

dangerous drugs or medical devices accountable. 

The preapproval communication discussion draft would blow a hole in the current 

approval process by allowing the communication of any scientific evidence or health 

care economic information to payors or formularies without any recourse for the 

FDA to prevent bad actors from communicating false or misleading information. Allowing manufacturers to communicate about unapproved products and unapproved 

uses of their products, reduces the incentive to go through FDA’s approval process. 

This is grossly irresponsible. 

For example, the proposed discussion draft would allow for a manufacturer to 

publish a biased scientific study in any medium to constitute ‘‘scientific exchange.’’ 

This could include simply posting results of a nonpeer reviewed study on a company’s own website, and there is no requirement that this information be truthful. 

I am concerned these two discussion drafts could expose more patients to medical 

products that have never been proven to be safe or effective. One study found that 

81 percent of medications prescribed for off-label purposes had poor or no scientific 

support, while another found that patients who received off-label prescriptions were 

54 percent more likely to experience an adverse event as compared to on-label use. 

These are risks that we simply cannot ignore. 

If there is a need for greater certainty and clarity on the types of communications 

that manufacturers are permitted to use under current law, I am willing to have 

that discussion. However, broadening communication in the ways proposed under 

these discussion drafts would undermine FDA’s regulatory review process and the 

safety and effectiveness approval standard. 

Thank you. 

10 

Mr. BURGESS. The gentleman yields back. The Chair thanks the 

gentleman. This concludes Member opening statements, and I 

would like to remind Members that, pursuant to committee rules, 

all Members’ opening statements will be made part of the record. 

And we want to thank our witnesses for being here with us this 

morning, for taking time to testify before the subcommittee. Each 

witness will have the opportunity to give a summary of their opening statement, followed by questions from Members. 

This morning, we are going to hear from Coleen Klasmeier, a 

partner of Sidley Austin, LLP; Alta Charo, the Warren Knowles 

Professor of Law at the University of Wisconsin; Dr. George Van 

Hare, the Division Chief, Pediatric Cardiology; Louis Larrick Ward, 

Professor of Pediatrics at Washington University School of Pediatrics; and Co-Director of the St. Louis Children’s and Washington 

University Heart Center; Aaron Kesselheim, Associate Professor of 

Medicine, Harvard Medical School, Director of Program on Regulation, Therapeutics and Law from the Division of 

Pharmacoepidemiology and Pharmacoeconomics at the Brigham 

and Women’s Hospital; Linda House, President of the Cancer Support Community; and Katherine Wolf Khachatourian, Vice President, Delegation Oversight, Pharmacy Services of 

QualchoiceHealth Plan Services. 

We appreciate all of you being here today and Ms. Klasmeier, 

you are recognized for 5 minutes for the purpose of an opening 

statement. Thank you for being here. 

STATEMENTS OF COLEEN KLASMEIER, PARTNER, SIDLEY AUSTIN, LLP; R. ALTA CHARO, WARREN P. KNOWLES PROFESSOR 

OF LAW, UNIVERSITY OF WISCONSIN; GEORGE VAN HARE, 

M.D., PRESIDENT, HEART RHYTHM SOCIETY; AARON S. 

KESSELHEIM, ASSOCIATE PROFESSOR OF MEDICINE, HARVARD MEDICAL SCHOOL AND BRIGHAM AND WOMEN’S HOSPITAL; LINDA HOUSE, PRESIDENT, CANCER SUPPORT COMMUNITY; AND KATHERINE WOLF KHACHATOURIAN, VICE 

PRESIDENT, DELEGATION OVERSIGHT, PHARMACY SERVICES, AND STRATEGY, QUALCHOICE HEALTH PLAN SERVICES, INC. 

STATEMENT OF COLEEN KLASMEIER 

Ms. KLASMEIER. Thank you, Mr. Chairman. Chairman Burgess, 

Vice Chairman Guthrie, Ranking Member Green, Chairman Walden, members of the subcommittee, my name is Coleen Klasmeier. 

I am a partner and the head of the FDA Regulatory Practice at 

Sidley Austin in Washington, DC. I am appearing today on behalf 

of the Medical Information Working Group. 

Today, I would like to make three points. First, FDA’s rules governing manufacturer communications are neither clear nor precise. 

Decisions to prescribe and use lawfully marketed drugs and medical devices in ways that differ from the FDA authorized labeling, 

so-called off-label use, are a constituent part of medical and surgical practice and can also be the standard of care. FDA has long 

recognized the need for prescribers to receive and for manufacturers to have some ability to provide information outside of product 

labeling to help support clinical decision making. As a result, alVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00014 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
11 

though a manufacturer is prohibited from promoting its product for 

new uses, it can lawfully provide information about off-label uses 

within defined circumstances. 

Currently, there are four safe harbors. Only one is set forth in 

a binding regulation. The others are in nonbinding documents. 

They therefore lack the force of law. Moreover, two of the four safe 

harbors have been the subject of ongoing FDA proceedings since 

2011. Under these policies, a manufacturer can provide off-label information ostensibly without fear of enforcement in four scenarios 

involving scientific exchange, responses to unsolicited requests, 

continuing education, and reprints of journal articles, reference 

texts, and clinical practice guidelines. Each safe harbor is subject 

to a number of qualifying criteria and additional requirements 

which are unclear in many key respects. 

Moreover, FDA has been unable to complete its process of revising the safe harbor policies, so questions frequently arise regarding 

the relationship between the old policies and the new policies. 

In addition, there is a lack of symmetry between the safe harbors 

that apply to drugs and those that apply to medical devices. In 

short, the safe harbors are a mess. As a result, manufacturers cannot confidently rely on the safe harbors and that has public health 

consequences. For example, it is common for the Advisory Committee on Immunization Practices, a Federal statutory advisory 

committee to the CDC, to make recommendations for vaccines that 

are arguably off-label. ACIP recommendations might vary the dosing schedule or recommend use of a vaccine in a new patient population. The vaccine manufacturer would reasonably fear that communicating about the ACIP recommendation to physicians or payers could be characterized by Government as unlawful, off-label 

promotion. Ultimately, the public health would not be advanced because physicians would not receive manufacturer communications 

reinforcing that recommendation. 

The regulatory scheme also has legal consequences. The First 

Amendment case law makes clear that FDA is limited in its power 

to prohibit drug and device manufacturers from engaging in accurate communications about their product. FDA’s regulatory scheme 

also implicates the due process laws of the Fifth Amendment which 

requires Government agencies to establish rules that are clear and 

to give fair notice of what is prohibited, particularly in the context 

of free expression. 

Second, the existing FDA regulatory scheme for manufacturer 

communication is highly unstable. The lack of clear rules to allow 

manufacturers an appropriate measure of latitude to communicate 

about their products is only a part of the problem. FDA and the 

Justice Department impose aggressive restraints on manufacturers’ 

speech. Although manufacturers have indeed settled many cases 

involving off-label promotion allegations in recent years, in some 

instances individuals and firms have raised First Amendment arguments in court and those arguments have succeeded. FDA’s regulatory scheme continues to burden constitutionally protected 

speech and is therefore at risk from additional lawsuits. 

The Medical Information Working Group has for more than 10 

years and across more than 20 submissions, requested targeted 

clarifications to the existing FDA safe harbors and to key statutory 

12 

terms such as labeling and intended use. We have not asked for 

and we do not want a healthcare system in which manufacturers 

can market their product based on spurious or unsubstantiated 

claims of safety or efficacy. 

Third, legislation could dramatically improve the regulatory 

scheme. Although the MIWG has been dedicated to direct engagement with FDA on manufacturer communication issues since 2006, 

we also recognize the paramount role of Congress and we believe 

that legislation may be necessary for several reasons. 

For one thing, FDA action has been slow and ineffectual. It has 

been almost 6 years, for example, since FDA published a notice in 

the Federal Register asking for comment on scientific exchange and 

responses to unsolicited requests. Where FDA has taken action, the 

policy has tacked in the wrong direction becoming less clear and 

even more speech restrictive. For these reasons, it would be helpful 

for Congress to step in and set the overall policy direction for FDA 

to implement. 

Legislation is also more durable than unilateral FDA action. 

Statutory law is not subject to the same variability as agency pronouncements and cannot be undone in a future administration. 

Legislation would be less susceptible to legal challenge than a regulation or an FDA guidance document. Regulations have the force 

of law, but the Administrative Procedure Act creates a vehicle for 

challenge in court, whereas a statutory change could only be challenge successfully in court on constitutional grounds. 

Legislation may also be necessary given the likelihood of continued judicial involvement in this area. Although we value the contributions that recent judicial decisions have made to the body of 

relevant law, we also believe that litigation is not the best way to 

make law on important public health issues where there is little 

room for error. We are especially concerned that some future lawsuit might eviscerate the FDA regulatory scheme. 

We see great value in congressional engagement with FDA on 

manufacturer communication issues to help assure the regulatory 

scheme is put on to a more stable and sustainable footing. Thank 

you very much for the opportunity to testify today and I look forward to your questions. 

[The prepared statement of Ms. Klasmeier follows:] 

13 


Testimony of Coleen Klasmeier on Behalf of the Medical Information Working Group 

One-Page Summary 

1. FDA's rules governing manufacturer communications are neither clear nor precise. 

FDA has established four "safe harbor" policies recognizing the public health value of 

manufacturer dissemination of accurate information relating to off-label uses. Each safe harbor 

is subject to a number of vague qualifying criteria and burdensome additional requirements. 

The policies are also hard to follow because FDA has started but failed to complete proceedings 

to revise the safe harbor policies, and not all of the policies apply clearly to both drugs and 

medical devices. The lack of clarity corresponds to under-utilization of the safe harbors, which 

reduces clinically valuable manufacturer communication, undermines optimal patient care, and 

presents First and Fifth Amendment issues. 

2. The existing FDA regulatory scheme for manufacturer communications is unstable. 

FDA and the Department of Justice aggressively pursue enforcement actions with 

respect to "off-label" speech, but First Amendment arguments in those cases have been 

accepted by reviewing courts. Litigation has a destabilizing effect on the regulatory scheme and 

threatens FDA's ability to make incremental changes. The public health and legal consequences 

of the developing case law point up the need for modifications to the existing rules and policies. 

3. Legislation could dramatically improve the regulatory scheme. 

Legislation could be helpful in addressing FDA's seeming inability to make meaningful 

progress in reviewing and modifying the rules and policies governing manufacturer speech. 

Legislation could also stabilize the existing system in a more durable manner than regulations, 

which can be reversed through agency action or more easily invalidated through litigation. 

Legislation could also address the risk of a frontal assault on FDA regulation. 
14 


"Examining Medical Product Manufacturer Communications" 

Wednesday, July 12, 2017 

Committee on Energy and Commerce 

Subcommittee on Health 

Testimony of Coleen Klasmeier on Behalf of the Medical Information Working Group 

Good morning. I am Coleen Klasmeier, a partner and head of the FDA regulatory 

practice at the law firm Sidley Austin in Washington, DC. I am appearing today on behalf of the 

Medical Information Working Group. The MIWG is an informal working group of manufacturers 

of biopharmaceutical products and medical devices, formed in 2006 to seek clarity in the 

enforcement and regulatory environment affecting communications about investigational and 

lawfully marketed medical products. Although we have been involved in a variety of efforts on 

these issues, from educational outreach to amicus briefs and submissions to federal agencies, 

the bulk of our work in recent years has involved FDA. We have made twenty submissions to 

FDA on manufacturer communications since 2008. 1 Today I would like to make three points. 

1. FDA's rules governing manufacturer communications are neither clear nor precise. 

Decisions to prescribe and use lawfully marketed drugs and medical devices in ways that 

differ from the FDA-authorized labeling-"off-label use" -are a constituent part of medical and 

surgical practice, and can also be the standard of care. 2 FDA has long recognized the need for 

prescribers to receive, and manufacturers to have some ability to share, information outside of 

1 The MIWG's submissions to FDA are available at www.miwg.org and www.regulations.gov. 

2 See, g_,g., FDA Draft Guidance, Responding to Unsolicited Requests for Off-Label Information About Prescription 

Drugs and Medical Devices (Dec. 2011) ("FDA recognizes that these off-label uses or treatment regimens may be 

important therapeutic options and may even constitute a medically recognized standard of care."). 

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15 


product labeling to help support clinical decision-making. 3 As a result, although a manufacturer 

is prohibited from "promoting" its product for "new uses," it can lawfully provide information 

about off-label uses within defined circumstances. Currently there are four "safe harbors." 

Only one is set forth in a binding regulation; the others are in non-binding documents. 4 They 

therefore lack the force of law. Moreover, two of the four safe harbors have been the subject 

of ongoing FDA proceedings since 2011. 

Under these policies, a manufacturer is ostensibly permitted to provide off-label use 

information without fear of enforcement in four sets of circumstances, involving (1) "scientific 

exchange," (2) responses to unsolicited requests, (3) continuing education, and (4) reprints of 

certain journal articles, reference texts, and clinical practice guidelines. Each safe harbor is 

subject to a number of qualifying criteria and additional requirements which are unclear in 

many respects. Moreover, FDA has been unable to complete its process of revising the safe 

harbor policies, so questions frequently arise regarding the status of the old policies relative to 

3 See, g,g., 59 Fed. Reg. 59,820, 59,822-23 (Nov. 18, 1994) (recognizing "the importance of dissemination of 

reliable scientific information on both approved and unapproved uses," and describing "a number of policies" that 

permit manufacturer dissemination of information on "unapproved uses"); 37 Fed. Reg. 16,503, 16,504 (Aug. 15, 

1972) (FDA "is charged with the responsibility for judging the safety and effectiveness of drugs and the 

truthfulness of their labeling. The physician is then responsible for making the final judgment as to which, if any, 

of the available drugs his patient will receive in the light of the information contained in their labeling and other 

adequate scientific data available to him.") (emphasis added). 

4 See 21 C.F.R. § 312.7 (scientific exchange, for drugs); 59 Fed. Reg. at 59,823 (unsolicited requests); 62 Fed. Reg. 

64,093 (Dec. 3, 1997) (continuing education and similar activities); FDA Guidance, Good Reprint Practices for the 

Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses 

of Approved Drugs and Approved or Cleared Medical Devices (Jan. 2009) (reprints). 

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16 


the proposed new policies5 In addition, there is a lack of symmetry between the policies for 

drugs and those for devices. 6 In short, the safe harbors are a mess. 

As a result, manufacturers cannot confidently rely on the safe harbors, and that has 

public health consequences. For example, it is common for the Advisory Committee on 

Immunization Practices-a statutory advisory committee to the CDC-to make 

recommendations for vaccines that are arguably "off-label." 7 An ACIP recommendation might 

vary the dosing frequency for a vaccine, for example. Under FDA rules, the vaccine 

manufacturer would be prohibited from promoting the vaccine in accordance with the ACIP 

recommendation. Moreover, its ability to engage in non-promotional, "safe harbored" 

communications about the ACIP recommendation would be significantly frustrated by the lack 

of clarity in the safe harbors, and in particular, the fear that communicating about the ACIP 

recommendation could be characterized by the government as unlawful off-label promotion. 

Ultimately, the public health benefits of the ACIP recommendation would not be advanced fully 

5 For example, in December 2011, FDA launched a process to revise the "scientific exchange" and "unsolicited 

requests" safe harbor policies. The status of these efforts remains unclear. See 76 Fed. Reg. 81,508 (Dec. 28, 

2011); 76 Fed. Reg. 82,303 (Dec. 30, 2011). FDA published a revised draft guidance on reprints, but the draft has 

not been finalized. FDA Guidance, Distributing Scientific and Medical Publications on Unapproved New UsesRecommended Practices (Revised Draft Guidance) (Feb. 2014). In June 2014, FDA granted two citizen petitions 

filed by the MIWG, stating that the agency planned to issue guidance addressing "distributing scientific and 

medical information on unapproved new uses . .. and manufacturer discussions regarding scientific information 

more generally, by the end of the calendar year." Letter from Leslie Kux, Assistant Commissioner for Policy, FDA to 

MIWG Counsel, Docket Nos. FDA-2011-P-0512 and FDA-2013-P-1079 (June 6, 2014). 

6 For drugs, the "scientific exchange" safe harbor is codified at 21 C.F.R. § 312.7. The analogous regulation for 

medical devices, 21 C.F.R. § 812.7, omits the safe harbor language. 

7 See, g,g., Morbidity and Mortality Weekly Report 2013; 62(RR04);1-34, available at 

https:/lwww.cdc.gov/mmwr/preview/mmwrhtml/rr6204a1.htm?s cid=rr6204a1 w (recommending MMR 

vaccination for infants aged~ 6 months who plan to travel or live abroad). 

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because the intended audience for the recommendation would not receive manufacturer 

communications reinforcing the advisory committee's findings or advice. 

The regulatory scheme likewise has legal consequences. The First Amendment case law 

makes clear that FDA is limited in its power to prohibit drug and medical device manufacturers 

from communicating about their products. The familiar Central Hudson test for commercial 

speech holds that accurate speech about lawful activity-and off-label use is, with very limited 

exceptions, lawful activity-is subject to constitutional protection. 8 That means the 

government, in defending regulations that burden that speech, must demonstrate that those 

regulations are premised on a substantial government interest. 9 In addition, the government 

must prove that its regulations directly advance that interest, and that the regulations are 

sufficiently tailored to the interest. 10 More recently, the Supreme Court used a "heightened" 

scrutiny test in a case involving a state law restricting accurate manufacturer speech about 

prescription drugs, suggesting that the Central Hudson test for evaluating commercial speech 

regulation might not be protective enough of the speech. 11 The constitutional test for 

government regulation of scientific speech, 12 or "mixed" speech (communication that 

8 Central Hudson Gas & Elec. Corp. v. Pub. Serv. Comm'n. 447 U.S. 557 {1980). 

9 !Q. at 564 ("The State must assert a substantial interest to be achieved by restrictions on commercial speech."). 

10 !Q. ("First, the restriction must directly advance the state interest involved; the regulation may not be sustained 

if it provides only ineffective or remote support for the government's purpose. Second, if the governmental 

interest could be served as well by a more limited restriction on commercial speech, the excessive restrictions 

cannot survive."). 

11 Sorrell v. IMS Health Inc., 564 U.S. 552, 565 (2011). 

12 Miller v. California, 413 U.S. 15, 34 (1973); Keyishian v. Bd. of Regents, 385 U.S. 589, 603 (1967); Wash. Legal 

Found. v. Friedman, 13 F. Supp. 2d 51, 62 (D.D.C. 1998); Bd. ofTrs. v. Sullivan, 773 F. Supp. 472, 474 (D.D.C. 1991). 

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inextricably combines scientific and commercial speech), is the even more demanding "strict 

scrutiny" test, and FDA regulations affecting those two species of communication would almost 

certainly be invalidated by a court. 13 

FDA's regulatory scheme also implicates the Due Process Clause of the Fifth 

Amendment, which requires government agencies to establish clear rules that give fair notice 

of what is prohibited. 14 The adoption of clear, binding rules is essential to bring FDA's 

regulatory scheme into alignment with the Fifth Amendment. 

2. The existing FDA regulatory scheme for manufacturer communications is unstable. 

The lack of clear rules that allow manufacturers an appropriate measure of latitude to 

provide accurate information about their products is only part of the problem. FDA-and in 

important respects the Department of Justice, which represents FDA in court and brings its own 

investigations under the Federal Food, Drug, and Cosmetic Act, the False Claims Act, and other 

statutes-imposes aggressive restraints on manufacturer speech. Although manufacturers 

have settled many cases involving "off-label promotion" allegations in recent years, in some 

instances individuals and firms have raised First Amendment arguments in court, and those 

arguments have succeeded. 15 Arguably the most famous example involves the Caronia case, 

13 Riley v. Nat'l Fed .. 487 U.S. 781, 796 (1988) ("Thus, where, as here, the component parts of a single speech are 

inextricably intertwined, we cannot parcel out the speech, applying one test to one phrase and another test to 

another phrase. Such an endeavor would be both artificial and impractical. Therefore, we apply our test for fully 

protected expression."). 

14 FCC v. Fox Television Stations, Inc., 132 S. Ct. 2307, 2318 (2012) (quoting United States v. Williams, 553 U.S. 285, 

304 (2008)). 

15 But see United States v. Harkonen, 510 F. App'x 633 (9th Cir. 2013), cert. denied, 134 S. Ct. 824 (2014). 

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19 


invalidating a conspiracy conviction on First Amendment grounds. 16 The Amarin case involved 

a manufacturer's assertion that its product could be marketed with out-of-label efficacy claims 

that FDA had found accurate but nevertheless sought to prohibit. 17 In Pacira, FDA had granted 

approval for a prescription analgesic drug but later sought to prohibit the company from 

promoting the product according to its labeled indication. 18 This string of decisions has led 

some observers to decry judicial involvement in adjudicating drug efficacy claims. 19 In some 

cases, observers have gone further, claiming that the First Amendment case law is 

"incompatible with regulating drug promotion." 20 

But maintaining the status quo ignores the law and harms the public health. FDA's 

regulatory scheme is at risk from additional lawsuits because, despite some incremental 

improvements, the rules continue to burden constitutionally protected speech. Keeping things 

as they are also ignores the Fifth Amendment requirements for clear, prospectively defined 

rules. The First and Fifth Amendments represent the principle that the public health is 

advanced by more, rather than less, accurate information to inform clinical decision making. 

Observers who seek to set the Constitution on a collision course with their own ideas about 

16 United States v. Caronia, 703 F.3d 149 (2d Cir. 2012). 

17 Amarin Pharma Inc. v. FDA, 119 F. Supp. 3d 196 (S.D. N.Y. 2015). 

18 Stipulation and Order at 2, Pacira Pharms. Inc. v. FDA, No. 15-7055 (S.D.N.Y. Dec. 14, 2015), ECF No. 45. 

19 Joshua M. Sharfstein & Alta Charo, The Promotion of Medical Products in the 21st Century: Off-label Marketing 

and First Amendment Concerns, JAMA (published online Sept. 14, 2015). 

20 AaronS. Kesselheim, Michelle M. Mello, and Jerry Avorn, FDA Regulation of Off-Label Drug Promotion Under 

Attack, 309 JAMA 445 (2013). 

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20 


public health policy ignore the idea that free speech itself protects and promotes the public 

health. 

To be clear, the MIWG does not support any reform measure that would take FDA out 

of its current role in reviewing claims of drug and device effect in advance. The measures we 

have requested involve targeted clarifications to the safe harbors and key statutory terms such 

as "labeling" and "intended use." The MIWG has not sought dramatic changes to the 

regulatory scheme that would open the floodgates to off-label promotion. We have not asked 

for, and do not want, a health care system in which manufacturers can market their drugs and 

medical devices based on spurious or unsubstantiated claims of clinical utility. We have asked, 

instead, for clear rules that distinguish permitted from prohibited communications, and that 

provide manufacturers with reasonable latitude to communicate about their products. 

3. legislation could dramatically improve the regulatory scheme. 

Although the MIWG has been dedicated to direct engagement with FDA on 

manufacturer communication issues, we recognize the paramount role of Congress and we 

believe that legislation may be necessary, for several reasons. 

FDA action has been slow and ineffectual. It has been almost six years, for example, 

since FDA published a notice in the Federal Register soliciting public comment on the scope of 

the scientific exchange safe harbor and on a new draft guidance on unsolicited requests. 21 

Where FDA has taken action, the policy has tacked in the wrong direction, becoming less clear 

21 See 76 Fed. Reg. 81,508 (Dec. 28, 2011); 76 Fed. Reg. 82,303 (Dec. 30, 2011). 

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21 


and more speech restrictive. 22 It appears FDA has been hamstrung by differing views internally 

and with the Department of Health and Human Services. 23 FDA officials might also be reluctant 

to do or say anything publicly that they believe would help tee up more litigation that they 

might not win. 

For these reasons, it would be helpful for Congress to step in and set the overall policy 

and direction for FDA to implement. We believe that Section 3037 of the 21st Century Cures 

legislation, the so-called FDAMA 114 fix-is a paradigmatic example. There, Congress 

established a clear rule, and FDA promptly executed that rule through a reasonably clear and 

speech-enabling guidance document. 24 

legislation is more durable than unilateral FDA action. Statutory law is not subject to 

the same variability as agency pronouncements, and cannot be undone by agency leadership in 

a future Administration. Legislation would also be less susceptible to legal challenge than a 

regulation or a guidance document. Regulations have the force of law, but the Administrative 

Procedure Act creates a vehicle for challenge, whereas a statutory change could only be 

challenged successfully on constitutional grounds. 

22 The new draft guidance on unsolicited requests includes six pages of criteria for determining whether speech 

qualifies for the safe harbor. The earlier iteration of the policy, published in 1994, comprised a single paragraph. 

23 Sources: FDA, HHS Leaders Clash On Off-Label Communication Next Steps, Inside Health Policy (Jan. 22, 2016), 

available at httos://insidehealthpolicy.com/daily-news/sources-fda-hhs-leaders-clash-label-communication-next-

~-

24 The amended provision is codified at 21 U.S.C. § 352(a). See FDA Guidance, Drug and Device Manufacturer 

Communications With Payors, Formulary Committees, and Similar Entities-Questions and Answers (Draft) (Jan. 

2017), available at 

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorvlnformation/Guidances/UCM537347.pdf. 

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22 


Legislation may be necessary given the likelihood of continued judicial involvement. 

Although we value the contributions that recent judicial decisions have made to the body of 

relevant constitutional and regulatory law, we also believe that litigation is not the ideal 

method of making law on issues that leave little room for error. We are particularly concerned 

by the possibility of a broadside attack on the FDA regulatory scheme that could result in the 

entry of a judicial order with significant and far-reaching consequences for the entire regulatory 

framework, including the agency's ability to enforce premarket review requirements. 

We greatly appreciate the opportunity that this subcommittee had created for 

discussion of these important issues today. Thank you once again, and I look forward to your 

questions. 

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Mr. BURGESS. I thank the gentlelady for her testimony. 

Ms. Charo, you are recognized for 5 minutes, please. 

STATEMENT OF R. ALTA CHARO 

Ms. CHARO. Chairman Burgess, Vice Chairman Guthrie, Congressman Green, and members of the committee, thank you for the 

opportunity to address you on issues surrounding communication 

and marketing of off-label uses. 

My name is Alta Charo. I am the Warren P. Knowles Professor 

of Law at the University of Wisconsin. I am an elected member of 

National Academy of Medicine, formerly known as the Institute of 

Medicine, where I have served on a number of committees including the one that produced a report on ensuring the safety of the 

U.S. drug system. I also served as an advisor in the Office of the 

Commissioner at FDA from 2009 to 2011, but I would like to note 

for the record that I speak for myself only and not for FDA and 

not for the National Academies. 

There are two possible reasons to expand communication about 

off-label uses. One is to ensure that the law is consistent with the 

requirements of the First Amendment. The other is to protect public health by increasing patient access to safe and effective drugs. 

And I share those two goals. I don’t, however, believe that the two 

amendments under discussion are necessary to achieve those goals. 

Indeed, I fear the unintended consequence of adopting the language 

in these amendments would be to undermine public health, to discourage pharmaceutical research, and to set pharmaceutical regulation back by more than 100 years. 

As noted in an article I co-authored with Josh Sharfstein, formerly the principal deputy at FDA, our drug regulation system has 

prohibited false or misleading advertising since 1906. And in 1962, 

broad marketing for secondary uses of thalidomide caused thousands of severe birth defects worldwide, and Congress then recognized that a product can be ‘‘safe and effective’’ for one intended 

use where the benefits exceed the risks, but not ‘‘safe and effective’’ 

for another which why approval of a drug for a labeled indication 

does not mean it will be safe and effective for off-label uses and 

precisely why additional studies are needed. 

This requirement to demonstrate safety and effectiveness for an 

intended use applies both to the first approval of a new compound 

or a new drug, as well as to any supplemental indication. And 

while it is true there have been a handful of cases narrowing constraints on commercial speech regarding unapproved ‘‘off-label’’ 

uses, the courts have consistently upheld commercial speech restriction with respect to the first approval of a new product. If the 

First Amendment means that off-label promotion must be permitted, then promotion of entirely untested, never-approved drugs 

should also garner the same protection. In both cases, the majority 

of drugs will fail to show that they are safe and effective when the 

testing has been completed and the substantial public interest in 

achieving that certainty is the same regardless of whether it is an 

entirely new drug or a supplemental indication for an existing 

drug. 

If we were to eliminate the restrictions on commercial speech for 

entirely unapproved drugs, it would return us to the 1906 law 

24 

where prosecution for false and misleading marketing took place 

only after people had been harmed. 

Scientific journals and conferences are already allowed to present 

information about off-label uses. Sponsors can answer questions 

from physicians and provide reprints of peer-reviewed articles, even 

if related to off-label uses. And in April 2017, the FDA further 

clarified these rules and used guidances as a more flexible mechanism to provide that information. Legislation, regulation, and court 

decisions have not the kind of flexibility that guidances have. We 

have entered an era in which communication takes on many new 

forms ranging from tweets to Facebook to any number of internet 

sources and it is important to maintain flexibility in how we regard 

communication and its influence and its intended purpose, rather 

than solidifying it in legislation which can be difficult to change 

over time. 

Now the proposed amendment of Section 201 muddies the exceptions that FDA has outlined and I fear it risks eviscerating the 

general rule against off-label promotion even if that is not its intent. It also has the effect of immunizing sponsors from responsibility even if they know and take advantage of the now blurry line 

between legitimate scientific exchange and illegal marketing. 

The proposed amendment of Section 502, I fear, will exacerbate 

this problem, by allowing premature information to be delivered to 

formularies and payers with the probable effect of increasing patient use of unproven and unsafe therapies. And as has been noted 

already by Members here on the committee, studies have repeatedly shown that even products that look promising in early trials 

will usually be shown to be unsafe or ineffective when larger trials 

are completed. And indeed, overall only about one in five compounds, only one in five, will successfully move from Phase 2 to 

Phase 3 trial, with lack of efficacy as the most common reason for 

failure. 

In a series of articles recently produced by Professor Christopher 

Robinson at the University of Arizona, we can also see that multiple studies show that the majority of off-label uses also will turn 

out to be either unsafe or ineffective. Encouraging coverage before 

approval is to encourage expanded use before approval of treatments that we now know empirically are likely to fail. And I fear 

that the effect would be to increase use that will harm more patients than it helps. 

History amply demonstrates there is a compelling public interest 

in unbiased evaluation of evidence; in clear, accurate communication; in maintaining incentives for research. The combined effect of 

these amendments is to expand promotion and payment for 

unproven uses of drugs. It undercuts the marketing advantages 

that the law now uses as an incentive for sponsors to complete the 

research needed to see which uses are, in fact, safe and effective. 

And in turn, it leaves physicians, patients, formularies, and payers 

without independently verified information. For complex products 

like drugs, the marketplace of ideas cannot work properly with 

unvetted information from necessarily self-interested sources. And 

when using the wrong drug can injure patients or cause them to 

miss out on effective treatment, it is an invitation to another tragedy when we prevent FDA from doing its job to protect the public. 

25 

Thank you very much. 

[The prepared statement of Ms. Charo follows:] 

26 


Testimony of R. Alta Charo 

before the Subcommittee on Health 

Energy & Commerce Committee of the U.S. House of Representatives 

12 july 2017 

Chairman Burgess, Vice-Chairman Guthrie, Congressman Green, members of the 

committee, thank you for this opportunity to address you on issues surrounding 

communication and marketing of medical products for off-label uses. My name is 

Alta Charo. I am the Warren P. Knowles Professor of Law at the University of 

Wisconsin, and an elected member of the National Academy of Medicine (formerly 

known as the 10M), where I have served on a number of committees, including one 

that examined the system for ensuring drug safety. I also served as an advisor in the 

Office of the Commissioner at FDA from 2009 to 2011. I would note for the record 

that I am not here to represent either the National Academies or the FDA, and that 

the opinions I express here are my own. 

There are two possible reasons to expand communication about off-label uses. One 

is to ensure the law is consistent with the free speech protections of the First 

Amendment. The other is to promote public health by increasing patient access to 

safe and effective drugs. I share these goals, but do not find that the two 

amendments under discussion today are needed. Indeed, the unintended 

consequence of adopting this language would be to undermine public health, 

discourage pharmaceutical research, and set pharmaceutical regulation back by 

more than 100 years. 

As noted in an article I co-authored with Josh Sharfstein, 1 formerly the principal 

deputy commissioner at FDA, our drug regulation system has prohibited false or 

misleading advertising since 1906. In 1962, when broad marketing for secondary 

uses of thalidomide caused thousands of severe birth defects worldwide, Congress 

recognized that a product can be "safe and effective" for one intended use where the 

benefits exceed the risks, but not "safe and effective" for another. This is why 

approval of a drug for a labeled indication does not mean it will be safe and effective 

for off-label uses, and why additional studies are needed to explore them. 

This requirement to demonstrate safety and effectiveness for an intended use 

applies to both the first approval of a new drug and to any approval of a 

supplemental indication. Despite a handful of cases narrowing constraints on 

commercial speech regarding unapproved "off-label" uses, courts have consistently 

upheld commercial speech restriction with respect to the first product approval. If 

the First Amendment means that off-label promotion must be permitted, then 

promotion of entirely untested, unapproved drugs should also garner the same 

1 Sharfstein and Charo, "The Promotion of Medical Products in the 21st Century: 

Off· label Marketing and First Amendment Concerns," JAMA. 2015;314(17):1795-1796. 
27 


protection. But this would return us to the 1906 law, where prosecution for false 

and misleading marketing took place only after people had been harmed. 

Scientific journals and conferences are already allowed to present information 

about off-label uses. Sponsors can answer questions from physicians and provide 

reprints of peer-reviewed articles, even if related to off-label uses. The proposed 

amendment of Section 201 muddies these exceptions, and risks eviscerating the 

general rule against off-label promotion. It also immunizes sponsors from 

responsibility, even if they know and take advantage of the now blurry line between 

legitimate scientific exchange and illegal marketing. 

The proposed amendment of Section 502 exacerbates this problem, by allowing 

premature information to be delivered to formularies and payors, with the probable 

effect of increasing patient use of unproven or unsafe therapies. Studies have 

repeatedly shown that even products that look promising in early trials will usually 

be shown to be unsafe or ineffective when larger trials are completed. Indeed, 

overall only about 1 in 5 compounds successfully move from Phase 2 to Phase 3 

trial, 2 with lack of efficacy as the most common reason for failure.3 And as noted by 

University of Arizona professor Christopher Robinson, multiple studies show that 

the majority of off-label uses also turn out to be either unsafe or ineffective, 4 and 

increasing use without proper research will harm more patients than it helps. 

History amply demonstrates that there is compelling public interest in unbiased 

evaluation of evidence; in clear, accurate communication; and in maintaining 

incentives for research. The combined effect ofthese amendments is to expand 

promotion and payment for unproven uses of drugs. It undercuts the marketing 

advantages that the law uses as an incentive for sponsors to complete the research 

needed to see which uses are in fact safe and effective. In turn, it leaves physicians, 

patients, forumularies and payors without independently verified information. For 

complex products like drugs, the marketplace of ideas cannot work properly with 

un-vetted information from a self-interested source. And when using the wrong 

drug can injure patients or cause them to miss out on effective treatment, it is an 

invitation to another tragedy when we prevent FDA from doing its job to protect the 

public. 

Thank you for your attention. 

2 2015 CMR International Pharmaceutical R&D Executive Summary 

(http:jjcmr.clarivate.comjpdfjExecutive_Summary_Final.pdf} 

3 Harrison, "Phase II and phase III failures: 2013-2015," NATURE REVIEWS DRUG DISCOVERY 15, 

817-818 (2016) [Published online 04 November 2016]. 4 Arizona Legal Studies Discussion Paper No. 16-19, "The Tip of the Iceberg: 

A First Amendment Right to Promote Drugs Off-Label," by Christopher Robertson 

June 2017 (citing Tewodros Eguale eta!., "Association of Off-Label Drug Use and Adverse Drug 

Events in an Adult Population," 176 ]AMA INTERN MED. 55-63 (Jan. 2016) and David Radley, Stanley 

Finkelstein, & Randall Stafford, "Off-Label Prescribing Among Office-Based Physicians," 166 ARCH. 

INT. MED. 1021 (2006). 
28 

Mr. BURGESS. The Chair thanks the gentlelady. 

The Chair recognizes Dr. Van Hare, 5 minutes for your opening 

statement, please. 

STATEMENT OF GEORGE VAN HARE 

Dr. VAN HARE. Good morning, Chairman Burgess, Ranking 

Member Green, and members of the subcommittee. Thank you for 

holding this hearing and for inviting me to testify on this important topic. My name is George Van Hare. I am Chief of Pediatric 

Cardiology at St. Louis Children’s Hospital in St. Louis, Missouri. 

My clinical practice is focused on caring for children with heart 

rhythm disorders. This year I have the honor of serving as the 

president of the Heart Rhythm Society. The Heart Rhythm Society 

is the international leader in science, education, and advocacy for 

cardiac arrhythmia professionals. Its members include 6,100 physicians, scientists, nurses, and other allied health professionals in 

more than 90 countries. 

Sharing comprehensive, scientifically valid data is critical to the 

practice of medicine generally, and it is even more critical for particular specialties. It is sometimes claimed that the use of drugs or 

devices off-label is the result of a choice by physicians. Sometimes 

this is 

true. However, for pediatric sub-specialists, this is usually not 

the case. This is due to the fact that very few of the medications 

for arrhythmias that are on the market are formally approved for 

use in children. Thus, using treatments off-label is often our main 

method of 

treatment of children. Similarly, catheters that we use for catheter ablation procedures are labeled for a limited number of specific 

arrhythmias, but are used for treating and curing all types of arrhythmias in adults and children. 

By way of example, I would like to cite the specific drug, 

amiodarone, brand name Cordarone. This is one of our most important medications for the treatment of potentially life-threatening 

arrhythmias, particularly in patients who have undergone successful surgical repair of complex 

congenital heart defects. The FDA-approved label simply states 

‘‘The safety and efficacy of Cordarone Tablets in pediatric patients 

have not been established.’’ This means that the manufacturer is 

not allowed to share prospectively any data that they may have 

concerning experience with this drug in children. 

Another example, not specific to children, is a labeling of ablation 

catheters. These devices are used in performing catheterization 

procedures to cure arrhythmias. In the last 25 years, these procedures have essentially replaced open heart surgery as the best option for a curative procedure. Their labeling is limited to only certain arrhythmias. For example, the Cryocath, a cryoablation catheter manufactured by Medtronic, is only labeled for treating one 

common arrhythmia, AVNRT, despite the fact that it is ideal for 

treating other, more dangerous arrhythmias. It would be absurd to 

use a different catheter for these other arrhythmias on the basis 

of the labeling, and even more absurd if you consider open heart 

surgery. However, because of the labeling, technical support representatives of the manufacturer are not allowed to discuss other 

29 

indications directions and prospectively, despite the fact that the 

use of this catheter for these other indication sis widely agreed to 

be the standard of care. 

There is an important way in which information sharing among 

physicians may also be adversely affected. When a medical conference is directly sponsored by a manufacturer, these conferences 

do not qualify as official continuing medical education events. Consequently, physician speakers are considered to be ‘‘agents’’ of the 

manufacturer sponsoring the event, and they are also limited to 

discussing only the labeled indications. Any discussion between 

physicians regarding experiences with drugs or devices that are offlabel at such events must occur informally, rather than as part of 

the program, and thus these discussions do not benefit from the 

great potential for information sharing among physician attendees. 

The good news is that it doesn’t have to be this way. It is likely 

that there is a large amount of data maintained by manufacturers, 

which under the current rules they are not allowed to proactively 

share with clinicians. I urge the committee to explore ways to define acceptable types of real-world evidence that manufacturers 

might proactively share with medical decision makers. These types 

of data might include observational studies, pharmacokinetic studies, and information on particular sub-populations. The data must 

be truthful, presented in context, and scientifically valid. 

There is some concern that manufacturers might overwhelm physicians with data taken out of context or data that are misleading 

and skewed to present a more favorable picture than is realistic. 

However, physicians are trained to analyze data. We know how to 

evaluate the validity of studies. If regulatory restrictions provide 

guard rails to ensure that data are truthful and presented in context, physicians are fully capable of analyzing such data effectively. 

In my opinion, a reasonable regulatory paradigm lies somewhere 

between no communication and completely unrestricted communication. The current structure is not optimal for fostering the advancement of medical knowledge, and it leaves many patients and 

their physicians at an unnecessary disadvantage. Additionally, it 

seems incongruous to me that the manufacturer, the entity with 

the most robust data related to a product, cannot share information 

they hold proactively while any lay person with an internet connection can freely disseminate whatever information they like about 

that same product however biased and unreliable. 

In closing, I hope that my testimony has provided the committee 

with a real-world perspective on how the current rules often prevent physicians from receiving valuable, clinical information in a 

timely fashion. I respectfully suggest that Congress should establish ways to unlock 

data maintained by manufacturers related to off-label use of 

drugs and devices. I thank the committee for its time. The Heart 

Rhythm Society would welcome the opportunity to work with you 

on policy proposals related to this topic. Thank you. 

[The prepared statement of Dr. Van Hare follows:] 

30 


TESTIMONY OF DR. GEORGE VAN HARE, MD, FHRS, CCDS, CEPS-PC 

PRESIDENT, HEART RHYTHM SOCIETY 

Before the 

U.S. HOUSE OF REPRESENTATIVES 

ENERGY AND COMMERCE COMMITTEE 

SUBCOMMITTEE ON HEALTH 

Hearing entitled: 

"Examining Medical Product Manufacturer Communications" 

July 12,2017 

VAN HARE TESTIMONY 
31 


Chairman Burgess, Ranking Member Green, and Members of the Subcommittee: thank you for 

holding this hearing and for inviting me to testify on this important topic. My name is George 

Van Hare. I am Chief of Pediatric Cardiology at Saint Louis Children's Hospital and Professor of 

Pediatrics at Washington University School of Medicine in St. Louis, Missouri. My clinical 

practice is focused on caring for children with heart rhythm disorders, as well as adults who are 

survivors of surgery for congenital heart disease. As such, l prescribe antiarrhythmic 

medications, utilize medical devices such as catheters for cardiac ablation procedures, and 

implant pacemakers and defibrillators. This year, l have the honor of serving as the President of 

the Heart Rhythm Society. Founded in 1979, the Heart Rhythm Society is the international leader 

in science, education and advocacy for cardiac arrhythmia professionals. Its members include 

6, I 00 physicians, scientists, nurses and other allied health professionals in more than 90 

countries who specialize in electrophysiology and perform basic, clinical, and translational 

research science. Electrophysiology is a distinct subspecialty of cardiology, and adult 

clcctrophysiologists arc board certified through the American Board oflnternal Medicine. 

BACKGROUND: OFF-LABEL USE 

The Food and Drug Administration (FDA) approves drugs and medical devices for specific 

indications, which are reflected in the product's label. Off-label use refers to the utilization of an 

FDA-approved treatment or device for any use other than the one(s) listed in the approved 

labelling, or in a population not reflected in the labelling, such as children. It is important to note 

that these off-label uses are often not experimental uses. In fact, some are so common they have 

become the standard of care. Many off-label uses are well-documented in the peer-reviewed 

VAN HARE TESTIMONY 
32 


literature, are discussed widely among physicians, and are cited as standard and accepted 

treatment in medical textbooks. 

THE CURRENT REGULATORY PARADIGM IMPEDES SCIENTIFIC DISCOURSE. 

FDA prohibits any promotion by manufacturers related to off-label uses of a drug or device. The 

question then becomes: what is promotion? The current regulatory approach limits the ability of 

a manufacturer to share data not referenced in the package insert. This means that much valuable 

information may never be conveyed to clinicians and other medical decision-makers. Essentially, 

we do not get the benefit from data that has not been derived from randomized, controlled 

clinical trials. 

Sharing comprehensive, scientifically valid data is critical to the practice of medicine 

generally, and it is even more critical for particular specialties. It is sometimes claimed that the 

use of drugs or devices off-label is the result of a choice by physicians. While sometimes this is 

true, for pediatric cardiologists and electrophysiologists, this is usually not the case. This is due 

to the fact that very few of the medications for arrhythmias that are on the market are formally 

approved for usc in children. Thus, using treatments off-label is often our main method of 

treatment. Similarly, catheters that we use for catheter ablation procedures are labelled for a 

limited number of specific arrhythmias, but arc used by all elcctrophysiologists (adult and 

pediatric) for treating and curing all types of arrhythmias. 

By way of example, I will cite the example of amiodarone, brand name Cordarone. This 

is one of the most important medications for the treatment of potentially life-threatening 

arrhythmias, particularly in patients who have undergone successful surgical repair of complex 

congenital heart defects but who have dangerous arrhythmias in the aftermath of surgery. The 

VAN HARE TESTIMONY 
33 


FDA-approved label simply states "The safety and effectiveness of Cordarone Tablets in 

pediatric patients have not been established." 

There are an additional six months of exclusivity granted to manufacturers of medications 

who generate data related to pediatric populations, under the Pediatric Research Equity Act 

(PREA) but this has not been sufficient to produce the amount of shareable data we might like, 

particularly for older drugs. As such, our clinical decisions often rest on anecdotal evidence and 

informal information-sharing among physicians. This is not an ideal environment in which to 

make treatment decisions. 

Another example that I might cite, not specific to children, is labelling of ablation 

catheters. These devices are used in performing curative catheterization procedures, and these 

procedures have essentially replaced open heart surgery as the best option for a curative 

procedure for the last 25 years. Their labelling is limited to only certain arrhythmias. For 

example, the Cryocath Freexor-Xtra cryoablation catheter (manufactured by Medtronic) is only 

labelled for treating one arrhythmia, atrioventricular node reentry tachycardia (A VNRT) despite 

the fact that it is ideal for treating tachycardia due to accessory pathways located close to the 

normal conduction system without risking inadvertent atrioventricular block. It would be absurd 

to use a different catheter for this indication on the basis of the labelling, and even more absurd 

to consider open heart surgery. However, because of the labelling, technical support 

representatives of the manufacturer arc not allowed to discuss this indication directly, despite the 

fact that the usc of this catheter for this indication is widely agreed to be the standard of care. 

There is an important way in which this information-sharing among physicians may also 

be adversely affected. When a medical conference is directly sponsored by a manufacturer, these 

conferences do not qualify as continuing medical education (CME) events based on rules of the 

VAN HARE TESTI!vfONY 4 
34 


Accreditation Council on Continuing Medical Education (ACCME). Consequently, physician 

speakers arc considered to be "agents" of the manufacturer sponsoring the event, and so they are 

also limited to discussing only the labelled indications. Any discussion between physicians 

regarding experiences with drugs or devices that are off-label at such events must occur 

informally, rather than as part of the program, and thus these discussions do not benefit from the 

great potential for information sharing among physician attendees. Such discussions can occur 

formally at medical and scientific conferences not directly sponsored by industry, but this rule 

limits the opportunities for such information sharing of data related to children. 

The good news is that it doesn't have to be this way. It is likely that there is a large 

amount of data maintained by manufacturers, which, under the current regulatory structure, 

manufacturers are not allowed to proactively share with clinicians. I recommend that the 

Committee develop ways to work with FDA to unlock this data. I also would like to respectfully 

suggest a few parameters to ensure this is done in a responsible manner. 

REGULATION SHOULD DISTINGUISH BETWEEN PROMOTION AND DATASHARING. 

There is a difference, in my view, between advertising an unapproved use to the public versus 

sharing scientifically valid data with clinicians, and this difference can be reflected in the 

regulatory approach to each type of activity. There is a vast space between our current regulatory 

approach and a "Wild West" approach. In my opinion, the appropriate and responsible regulatory 

approach likely lies somewhere in the middle. 

I urge the Committee to explore ways to define acceptable real-world evidence that 

manufacturers can proactively share with medical decision-makers. These types of data may 

VAN HARE TES71MONY 
35 


include observational studies, pharmacoeconomic studies, or information on subpopulations. The 

data must be truthful, presented in context, and scientifically valid. 

There is some concern that manufacturers might overwhelm physicians with data taken 

out of context, or data that is misleading and skewed to present a more favorable picture than is 

realistic. However, physicians are trained to analyze data. We know how to evaluate the validity 

of studies. lf regulatory restrictions provide guardrails to ensure that the data is truthful and 

presented in context, physicians arc fully capable of analyzing such data effectively. 

As I noted previously, a reasonable regulatory paradigm lies somewhere between no 

communication and completely unrestricted communication. However, the current structure is 

not serving to foster the advancement of medical knowledge, and it leaves many patients and 

their physicians at an unnecessary disadvantage. Additionally, it seems incongruous that the 

manufacturer- the entity with the most robust data related to a product- cannot share the 

information they hold proactively, while any layperson with an internet connection can freely 

disseminate whatever information they like about that same product, however biased and 

unreliable. 

CLOSING 

I hope that my testimony has provided the Committee with a real-world perspective on how 

current FDA policy is preventing physicians from receiving valuable, clinical information in a 

timely fashion. In closing, I respectfully suggest that Congress should establish ways to unlock 

data maintained by manufacturers related to off-label conditions and populations. I thank the 

Committee for its time and look forward to working with you on policy proposals related to this 

topic. 

VAN HARF: TESTIMONY 6 
36 

Mr. BURGESS. The Chair thanks the gentleman for his testimony. 

Dr. Kesselheim, you are recognized for 5 minutes for your statement, please. 

STATEMENT OF AARON S. KESSELHEIM 

Dr. KESSELHEIM. Good morning, Chairman Burgess, Ranking 

Member Green, and other members of the committee, thank you for 

the opportunity to join you today. In my time I want to make four 

main points. 

First, the current restrictions on manufacturers’ ability to market their drugs for non-FDA-approved indications is not a bureaucratic or paternalistic effort to prevent manufacturers from communicating. These rules were developed in response to major public 

health problems caused by the lack of such regulation. Evidence of 

the public health dangers that arise from widespread off-label marketing can be seen in the drug paroxetine or Paxil, an 

antidepressant that was promoted off-label for use in children leading to at its peak over two million prescriptions per year for use 

in children until it was ultimately linked to self-injury and suicide 

in that population. Or, the off-label promotion of anti-psychotic 

medications to control behavioral symptoms in elderly patients 

with dementia, uses that are not only generally ineffective, but 

that also increase the risk of death by 60 to 70 percent. 

At one point, due to off-label promotion approximately one in 

seven elderly nursing home residents reportedly received these 

drugs. 

Over and over again, these episodes show us, as former Chief 

Justice William Rehnquist originally put it that ‘‘there are sufficient dangers attending [the] widespread use [of pharmaceuticals] 

that they simply may not be promoted in the same manner as hair 

creams, deodorants, and toothpaste.’’ 

Second, the dangers from off-label promotion do not come simply 

from the spread of false information about these products, although 

that does happen on occasion of course. Rather, in one study that 

I led, we found that off-label promotion most commonly involved 

presenting reports of individual cases or poorly designed studies as 

definitive evidence supporting an off-label use, while de-emphasizing data that didn’t fit the narrative the manufacturers were 

creating. In each of these particular cases, the words themselves 

may not have been false or strictly misleading, but the benefits of 

the drug overstated and the risks down played in ways that the 

physicians might have needed advanced training in epidemiology or 

access to the underlying clinical trial data to understand which 

they simply do not have. This is why we need the diligent, independent assessment of safety and efficacy provided by the FDA. 

The complexity of the assessment that is required, along with the 

high stakes of getting that assessment wrong provides the rationale for having a formal drug approval process in the first place. 

Third, the Griffith and Guthrie discussion drafts directly risk 

these outcomes. The Guthrie discussion draft, for example, defines 

scientific information that could support an off-label marketing 

claim as including preclinical data in petri dishes or in mice, and 

all it requires is a study that was conducted that the manufacturer 

anticipates could be sufficient to support FDA approval. 

37 

The Griffith draft, in creating a so-called safe harbor for scientific exchange, purports to require manufacturers to disclose appropriate contextual information for their statements, but it would 

be highly risky to give a manufacturer with a strong financial and 

intellectual stake in the product’s success free reign to determine 

what is or isn’t proper context or what is or isn’t contradictory for 

its product. At the same time, it is unrealistic to expect each individual physician to have the time and expertise to subject such 

claims to the same kind of scrutiny that the FDA would exercise 

when it reviews a drug application or a request for a new indication. 

The drafts also purport to protect the public health by attaching 

disclaimers to these off-label communications, but I led a systematic review of the evidence about the impact of such disclaimers, 

most of which currently come in the context of promotional statements for herbal remedies and dietary supplements for which Congress eliminated FDA oversight of promotion more than 20 years 

ago. Many of these products advertise health-enhancing effects despite no legitimate evidence that they work with disclaimers that 

the FDA has not evaluated the promotional claims, but the massive 

collective evidence reveals that such disclaimers fail to adequately 

inform or modify consumer behavior. So when anybody proposes a 

disclaimer, I suggest that there be a disclaimer, that disclaimers 

don’t actually work. 

Finally, I want to emphasize that the current system helps protect patients from widespread promotion of drugs and devices for 

potentially unsafe and ineffective off-label uses, while still permitting off-label prescribing at the discretion of physician and patients 

and providing well-circumscribed avenues for manufacturer communication about these issues such as in response to bona fide 

questions arising from physicians. By contrast, the Griffith and 

Guthrie discussion drafts would reduce manufacturers’ incentives 

to conduct well-controlled trials of potential off-label uses in the 

first place. Instead, as Representative Green mentioned, manufacturers would be incentivized to seek approval of drugs and devices 

for the narrowest indication possible, and then conduct ‘‘studies’’ of 

variable quality showing the utility of these products for unapproved indications that would not meet current FDA standards for 

scientific rigor. 

I strongly recommend that the committee not pursue these drafts 

and instead consider how we can give the FDA the proper resources and authorities to continue to review emerging data efficiently so that evidence that does support new uses of drugs and 

devices can be incorporated into their labels and clinical practice 

while uses that the totality of the data show are unsafe can be 

identified for the benefits of patients. Thank you very much. 

[The prepared statement of Dr. Kesselheim follows:] 

38 


PORTAL 

Program on Regulation, Therapeutics, And Law 

Division ofPharmacoepidemiology and Pharmacoeconomics 

Harvard Medical School and Brigham & Women's Hospital 

AaronS. Kesselheim, M.D., J.D., M.P.H., Director 

jerry Avorn, M.D., Co-Director 

Phone: 617-278-0930 

Fax: 617-232-8602 

www.drugepi.orgjportal 

The Public Health Risks of Expanding Off-Label Promotion 

of Prescription Drugs and Devices 

AaronS. Kesselheim, M.D., J.D., M.P.H. 

Associate Professor of Medicine, Harvard Medical School and Brigham and Women's Hospital 

Subcommittee on Health 

Committee on Energy and Commerce 

U.S. House of Representatives 

July 12, 2017 

Washington, D.C 

1620 7l·emont Street•Suite 3030 • Boston MA 02120 
39 


Summary 

The Guthrie and Griffith discussion drafts dangerously expand the permitted range of offlabel statements for manufacturers. Current rules restricting off-label promotion exist 

because of major public health problems that have arisen from lack of regulation of 

manufacturer promotional activities. 

Expanding the range of off-label communications will expose patients to drugs that may 

not work or for which the safety has not been adequately established, and potentially 

divert use from drugs that we know have benefits that outweigh their risks because they 

have passed FDA review. It will also increase health care costs by increasing use of 

inadequately tested, costly products. 

• The FDA's independent assessment of the benefits and risks of drugs and high-risk devices 

can help ensure that information is not communicated to physicians or patients that gives 

an incorrect impression of the utility of the product at issue (even if it isn't clearly "false") 

The Guthrie and Griffith discussion drafts suggest that disclaimers could help protect 

patients, but available evidence indicates that disclaimers on health-related promotional 

statements fail to adequately inform or modify consumer behavior 

Expanding off-label promotion would reduce manufacturers' incentives to conduct wellcontrolled trials of potential off-label uses in the first place, incentivizing manufacturers to 

seek approval of drugs and devices for the narrowest indication possible and then conduct 

"studies" of variable quality showing the utility of these products for unapproved 

indications that would not meet the current FDA standards for scientific rigor. 

2 
40 


Chairman Burgess, Vice-Chairman Guthrie, Ranking Member Green, and other members of 

the committee: 

My name is Aaron Kesselheim. I am an internal medicine physician, lawyer, and health 

policy researcher in the Division of Pharmatoepidemiology and Pharmacoeconomics at Brigham 

and Women's Hospital in Boston and an Associate Professor of Medicine at Harvard Medical 

School. !lead the Program On Regulation, Therapeutics, And Law (PORTAL), an interdisciplinary 

research core that studies the intersections between laws and regulations and the development, 

utilization, and affordability of drugs. We are the largest, academic-based independent group 

conducting empirical research in this area in the country. Thank you for this opportunity to 

provide my views on the communication and marketing of medical products for off-label uses and 

the discussion draft documents from Reps. Griffith and Guthrie. 

The current restrictions on manufacturers' ability to market their drugs for non-FDAapproved indications are not a bureaucratic or paternalistic effort to restrict manufacturers from 

communicating to physicians about their products. Rather, these rules were developed over the 

last century in response to major public health problems caused by the lack of regulation of 

manufacturer promotional activities. The notion that the FDA must validate a drug's or device's 

efficacy and safety was a response to public health tragedies in which patients died after taking 

products with poisonous constituents (sulfanilamide elixir, 1938), gave birth to babies with 

devastating congenital anomalies (thalidomide, 1962), or used contraceptive devices that caused 

bacterial sepsis (Dalkon Shield, 1974), all of which occurred in the context of wide manufacturer 

promotion of the safety of these products.' Even more common was the promotion of drugs to 

1 Kesselheim AS and Mello MM, Prospects for regulation of off-label drug promotion in an era of expanding commercial speech 

protection. Univ North Carolina Law Review 2014;92:1539-1604. 
41 


treat conditions for which they totally lacked efficacy. From these episodes, we learned, as former 

Chief justice William Rehnquist put it, that "there are sufficient dangers attending [the] 

widespread use [of pharmaceuticals] that they simply may not be promoted in the same manner 

as hair creams, deodorants, and toothpaste." 2 Rather, it was in the public's interest for an 

independent body of experts-the FDA-to validate that a medication or high-risk device actually 

worked before it could be sold and promoted for a particular use. 

Despite these rules, the past two decades has revealed that off-label promotion is quite 

common in the drug and medical device industries. Nearly every major drug manufacturer has 

now been investigated by government prosecutors for its off-label promotional practices. All of 

these cases also involved important risks to public health related to the off-label uses. A partial list 

of products for which inappropriate off-label marketing has led to patient morbidity and mortality 

includes: 

Rofecoxib (Vioxx), an anti-inflammatory drug linked to anywhere from 30,000 to 

over 130,000 heart attacks and sudden cardiac deaths because of inappropriate 

promotion.3 

Paroxetine (Paxil), an antidepressant promoted off-label for use in children, leading 

to 2 million prescriptions in children and adolescents in the year 2002 alone,4 that 

was linked to self-injury and suicide.s 

Numerous antipsychotic medications were prescribed to control behavioral 

symptoms in elderly patients with dementia, uses that were not only generally 

1 Virginia State Bd. of Pharmacy v. Citizens Consumer Council, 425 U.S. 748 (1976). 

' https:ffwww.financc.scnate.gov /imofmcdiafdoc/111804dgtest.pdf 4 http://www.bmj.comfcontent/351/bmj.h4629 

5 http://www.bmj.comfcontcnt/351/bmj.h4320 

4 
42 


ineffective but that also increases the risk of death by 60 to 70%. Its promotion led 

to about one in 7 elderly nursing home residents receiving these drugs. 6 

Settlements of government investigations of these off-label marketing episodes have led to 

over $15 billion in civil and criminal fines. 

In these cases, the manufacturers were not necessarily going around spreading falsehoods 

about their products to get physicians to prescribe them. (That did happen on occasion, of course.] 

Rather, manufacturers and their promotional salespeople might present anecdotal evidence of 

benefits from uncontrolled case series. Or they might show doctors the results of observational 

studies that actually had important design flaws not recognizable unless someone had advanced 

training in pharmacoepidemiology. Or they might describe the results of clinical trials strategically 

designed to show favorable outcomes. In one study of off-label marketing practices that I led, we 

found that 75% of the cases involved self-serving presentations of the literature through which 

physicians were given unbalanced study data supporting the unapproved use.' A common example 

was selective presentation of favorable studies, where dangers from the off-label uses allegedly being 

promoted were not mentioned. Other examples included presenting one drug as being superior to 

another when no head-to-head studies had been conducted and characterizing reports of individual 

cases or poorly designed studies as definitive evidence supporting an off-label use. In each of these 

particular cases, the words themselves may not have been false or strictly misleading, but physicians 

were given an incomplete picture of the use of the drug, leading to off-label prescribing and 

substantial patient harms. This is why we need the diligent, independent assessment of whether a 

drug or high-risk device is safe and effective for an intended use that is provided by the FDA, which 

6 US Office of Inspector GeneraL Medicare Atypical Antipsychotic Drug Claims for Elderly Nursing Home Residents. May 4 

2011. Available from: https:jjoig.hhs.govjoei/reportsjoci-07-08-00lSO.asp 7 Kesselheim AS, Mello MM, Studdert DM. Strategies and practices in off-label marketing of pharmaceuticals: a retrospective 

analysis ofwhistleblower complaints. PLoS Medicine 2011;8(4):e1000431. 
43 


can involve dozens of scientists poring over extensive databases of studies in animals, toxicologic 

evaluations, and clinical trials. 

However, the Griffith and Guthrie discussion drafts dangerously expand the permitted range of 

off-label statements for manufacturers. The Guthrie discussion draft defines "scientific information" 

that could support an off-label marketing claim as including "pre-clinical" data and all it requires is 

that a study was conducted that a manufacturer "anticipates could be sufficient" to support FDA 

approval and that the manufacturer "intend" that a supplemental application will be submitted at 

some undetermined time in the future. The Griffith draft, in creating a so-called "safe harbor" for 

scientific exchange, purports to require manufacturers to disclose the "appropriate contextual 

information" for their statements. But it would be highly risky to give a manufacturer with a strong 

financial and intellectual stake in the product's success free rein to determine what is or isn't proper 

context, or what is or isn't contradictory, for its product. At the same time, it is unrealistic to expect 

each physician to have the time and expertise to subject such claims to the same kind of scrutiny that 

the FDA would exercise when it reviews a drug application or a request for a new indication. In these 

situations, we need the FDA to act as a learned intermediary on behalf of prescribing physicians, who 

can then synthesize the available data and make judgments about risks and benefits for their 

patients. s The complexity of the assessment that is required, along with the high stakes of getting the 

assessment wrong, provides the rationale for having a formal drug-approval process in the first place. 

The Griffith and Guthrie drafts also purport to protect the public health by attaching 

disclaimers to their vast expansions of manufacturers' abilities to engage in off-label communication. I 

led a systematic review of the evidence about the impact of disclaimer related to health-related claims 

8 Kesselheim AS and Avorn J, Pharmaceutical promotion to physicians and First Amendment rights. New England Journal of 

Medicine 2008;358:1727-1732. 

6 
44 


of medical products.9 Most such data has been gathered in the context of promotional statements for 

herbal remedies and dietary supplements, for which Congress eliminated FDA oversight of promotion 

more than 20 years ago in the Dietary Supplement Health and Education Act of 1994. The result has 

been the proliferation of untested, ineffective, and frequently unsafe products that fill store shelves 

and patients' medicine cabinets and consume about $32 billion of health care resources in the US, 

often with no demonstrable benefit. Many of these products advertise health-enhancing effects and 

bear disclaimers that the FDA has not evaluated the promotional claims, but the mass of collected 

evidence reveals that such disclaimers generally fail to adequately inform or modify consumer 

behavior. There is no scientific basis for believing that disclaimers would function any better in this 

context. 

Expanding permitted off-label communications will expose patients to drugs that may not 

work or for which the safety has not been adequately established. It will also potentially divert use 

from drugs that we know have benefits that outweigh their risks because they have passed the usual 

FDA requirements. The result will also be increased health care costs, due to broader use of 

inadequately tested, costly products. Such effects are predictable because decades of evidence show 

that manufacturer promotion is a powerful force in shaping and directing physician prescribing and 

influencing physician knowledge in ways that favor the product being promoted, as opposed to the 

evidence-based practice. By contrast, the current system helps protect patients from widespread 

promotion of drugs and devices for potentially unsafe or ineffective off-label uses, while still 

permitting off-label prescribing at the discretion of physician and patients and providing well9 Kesselheim AS, Connolly JC, Rogers J, Avorn J. Despite mandatory disclaimers on dietary supplements, many consumers 

remain unaware or overlook the information. Health Affairs 2015:34(3):438-446. 

7 
45 


circumscribed avenues for manufacturer communication about these uses, such as in response to 

bona fide questions arising from physicians. 

Finally, the Griffith and Guthrie discussion drafts, if enacted into law, would reduce 

manufacturers' incentives to conduct well-controlled trials of potential off-label uses in the first place. 

Instead, manufacturers would be incentivized to seek approval of drugs and devices for the narrowest 

indication possible, and then conduct "studies" of variable quality showing the utility of these 

products for unapproved indications that would not meet the current FDA standards for scientific 

rigor. 10 Many studies would predictably appear to support claims of efficacy, and those that best met 

marketing aims could be selected for emphasis in promotional campaigns, with the others relegated 

to footnotes or ignored. I strongly recommend that the committee not pursue these drafts and instead 

consider how we can give FDA the proper resources and authorities to continue to review emerging 

data efficiently so that evidence that does support new uses of drugs and devices can be incorporated 

into their labels and clinical practice, while uses that the totality of data show are unsafe can be 

identified for the benefit of patients. 

1° Kcssclheim J\S, Mello MM, J\vorn J. FDA regulation of off-label drug promotion under attack.JAMA 2013;309(5):445·446. 

8 
46 

Mr. BURGESS. The Chair thanks the gentleman. 

Ms. House, you are recognized for 5 minutes for an opening 

statement, please. 

STATEMENT OF LINDA HOUSE 

Ms. HOUSE. Good morning. My name is Linda House, and I am 

the president of the Cancer Support Community. I would like to 

thank the committee for allowing us to be here and share this testimony today. 

The Cancer Support Community is an international nonprofit organization whose mission is to ensure that all people impacted by 

cancer are empowered by knowledge, strengthened by action, and 

sustained by community. Our organization sees over 100,000 patients and families each year through a network of affiliates 

around the world. We also have a Cancer Support Helpline where 

we administer through both of those properties, over $50 million of 

evidenced-based care and support each year free of charge to patients and their families. Importantly, CSC is also home to the only 

Research and Training Institute of its kind whose mission is to collect and analyze information from patients to elevate the voice of 

the patient and the caregiver as it relates to their cancer experience. 

I am here today to bring you what I feel is the most important 

voice to this conversation and that is the voice of the patient. 

The last 20 years have delivered unprecedented growth in innovation across all aspects of health care. Never before has a patient 

had so many options for diagnosis, treatment, and follow-up care 

as they do now. Patients are more educated. They are more engaged. They are more empowered consumers of health care than 

ever before. Yet, despite the emergence of patients as important 

players, and even leaders of their care teams, accessibility to comprehensive information continues to be elusive. 

We will be releasing data next week from our Cancer Experience 

Registry where we have learned that 50 percent of patients engage 

in shared treatment decision making with their healthcare professionals. Only about eight percent report allowing healthcare professionals to make decisions without their input. Yet, only 25 percent 

indicate that they feel like they are prepared to have those treatment decisions. 

Importantly, our data reflects a growing concern about inadequate collection, reporting, and label updating of endpoints that 

are meaningful to patients. In our research, 93 percent of respondents considered quality of life as very important when making 

treatment decisions. Quality of life measured higher than length of 

life, and these are people with cancer, yet product labels continue 

to focus very little on fully measuring comprehensive quality of life 

metrics. Further, product labels almost never reflect updates when 

there are findings beyond the clinical trial setting including findings about long-term effects which would be meaningful for patients. A system that does not proactively collet, publish, and share 

data poses a significant risk to patient care. 

There are a few issues I would like to raise as current limitations 

and we do support the work that the FDA does and we do support 

47 

the work of the clinical trial systems and we do support accurate, 

meaningful, nonpromotional communication. 

Preapproval information, as you know, is when clinical data is 

available on a product prior to the product having an FDA label. 

According to PhRMA, it takes an average of 10 to 15 years for a 

drug to make it to market. And during that time, much is learned 

about the way in which the drug works in the body, how the body 

works with the drug, what is the accurate dose, what is the toxic 

dose, and what are the side effects associated with that drug. Yet, 

this treasure trove of information remains out of reach from individuals other than the sponsor or potential trial investigators. 

Number two, limiting communication of information to only that 

which is reflected in the label poses a significant challenge to patients. CSC appreciates the work of the FDA and sponsors of phase 

IV studies, in particular, but recognizes that these studies do not 

capture comprehensive data for the use of the product as was mentioned in the real world. Also, it is a rare occurrence for the label 

to be updated in a manner that would allow for proactive communications of findings outside of the controlled clinical trial setting. 

And as we know, once trials go into broader, less controlled situations, they perform differently in those patients. 

Number three, data accumulated through Investigator Initiated 

Trials on diseases that would never reach the investment potential 

for registration in a label is extremely important to clinical care. 

This information may never be communicated to clinicians and will 

almost certainly not be made available to patients who may benefit 

from the findings and this is particularly important in patients 

with rare disease. 

Number four, information learned outside of the clinical trial setting and not captured in the label can also have a true impact on 

the patient experience. And as I submitted in my written testimony, this could be things like burning at the injection site, a reduction in fatigue by understanding how to better supplement the 

treatment. That information is not in the label and cannot be 

shared in a proactive way. 

Number five, there are several elements in general clinical practice that are continuing to contribute to the limitation that patients 

have to access comprehensive medical information through their 

healthcare team. And in particular, as there is an active evolution 

of the care delivery systems from volume to value, it has brought 

with it efficiency and cost containment strategies that focus on limiting treatment decisions. And I am talking about hospital-based 

formularies and clinical pathways that are currently being used in 

physician practices. 

Number six, there is an inconsistent practice and reinforcement 

of publishing clinical trial data results in scientific journals and 

other databases. This information has to be published and as mentioned in my written comments, the ratio of trials that have been 

opened, closed, and published, the compliance rate with that abysmal and there must not only be requirements, but also enforcement 

of the requirements to ensure that all results of trials be posted 

whether those results are positive or negative. 

Finally, industry interpretation of the current regulations is applied inconsistently across companies. This impacts the way in 

48 

which industry communicates with all stakeholders and most certainly the way in which industry communicates with patients and 

families forcing them only through the direct-to-consumer marketing channel. 

So in conclusion, while the comments that I have made have simply scratched the surface on what is a much broader and deeper 

issue, it is my hope that I have highlighted in your mind the perspective of patients who are living with chronic and life-threatening 

illness across the United States. 

And to summarize in specific areas where we would like to continue to work with the committee and the FDA, patients and 

healthcare providers must have access to medical research findings 

in a comprehensive and real-time manner. Product labels should be 

updated in a timely manner and include data from endpoints that 

matter most to patients and/or there must be another mechanism 

by which to capture and proactively communicate findings that are 

clinically meaningful and relevant. Scientifically sound communications about safe and effective uses of a product are essential and 

should be made available to all stakeholders. Clinical trial results, 

positive and negative, should be published by the trial sponsor in 

a period of time that is reasonable to allow full and meaningful 

data review while ensuring timely access to information. Data, 

positive and negative, collected outside of the clinical trial process, 

inclusive of real-world evidence that is collected and analyzed with 

appropriate scientific rigor should be published and made available 

to stakeholders. And finally, proactive medical communication 

should be tailored to meet the needs and literacy levels of specific 

stakeholders and should not, for any stakeholder, be limited only 

to the product label which may not yet exist or be outdated. 

Thank you for allowing us to be here. 

[The prepared statement of Ms. House follows:] 

49 


United States House of Representatives The Energy and Commerce Committee 

Hearing: Examining Medical Product Manufacturer Communications 

July 12, 2017 

Written Remarks Submitted by: Linda House, MSM, BSN, RN, 

President, Cancer Support Community 

Good morning, my name is Linda House, and l am the President of the Cancer Support 

Community (CSC) glohal headquarters. Thank you to Chairman Walden, Vice Chairman Barton, 

Ranking Member Pallone, and all of the members of the Energy and Commerce Committee for 

allowing me to join you today and offer this testimony. 

The Cancer Support Community is an international nonprofit organization whose mission is to 

ensure that all people impacted by cancer are empowered by knowledge, strengthened by action 

and sustained by community. CSC serves over I 00,000 patients and families annually through a 

network of !50 affiliate sites and satellite locations across the country as well as through the 

Cancer Support Helpline where patients and their families receive evidence-based programming 

and social and emotional support. The CSC network delivers close to $50 million in services, 

free of charge, each year. CSC is also home to the only Research and Training Institute focused 

on collecting and analyzing data to understand and elevate the patient and caregiver voices about 

the cancer experience. 

Thank you for the opportunity to speak with you this morning regarding medical product 

manufacturer communication. 

Tbe Patient Perspective 

I am here today to bring you the most important voice in this discussion regarding medical 

product manufacturer communication-that of the patient. As you may have seen, CSC joined 

seven other national organizations to submit a response to the Food and Drug Administration's 

(FDA) recent guidance on this very important issue. We appreciate the FDA's efforts to provide 

additional guidance in this area and look forward to working with the Agency in the coming 

months and years to ensure its regulations reflect the best interests of patients. 

The last twenty years have delivered unprecedented growth in innovation across all aspects of 

health care. Never bcf(,re has the patient had so many options for diagnosis, treatment, and 

follow-up care. Patients are more engaged, educated, and empowered consumers of their health 

care than ever before. Yet, despite the emergence of patients as important players-and even 

leaders--of their care teams, accessibility to comprehensive information continues to be elusive. 

The Cancer Support Community will release new survey data next week that outlines the patient 

experience with treatment decision-making among other factors associated with the cancer 

CancerSupportCommunity. org Uniting The Wellness Community and Gilda"s Club Worldwide 
50 


COMMUNITY 

A Globof Network of Education and Hope.-

Research &: Training Institute: 

4100 Chamounix Drive, Fairmount Park, Philadelphia, PA 19131 

267.295.3000 Phone 215.883.2580 Fax 

experience. In our research, we learned that nearly half of all the patients we surveyed made 

treatment decisions together with their care teams while only 8% leave their treatment decisions 

fully to their care team. Yet, the data also underscores that patients feel unprepared to make these 

choices with I in 4 reporting that they did not at all feel prepared to discuss treatment options 

with their physicians. 

The data also reflects a growing concern about inadequate collection, reporting, and label 

updating of endpoints that are meaningful to patients. In our research, 93% of respondents 

considered quality of life as "very important" when weighing treatment options. Quality of life 

measured higher than length of life (79%), yet product labels continue to focus very little on 

fully measuring comprehensive quality of life metrics. Further, product labels almost never 

reflect updates when there are findings beyond the clinical trial setting including findings about 

long-term effects that would be meaningful to patients (e.g., neuropathy with chemotherapy 

administration). A system that does not proactively collect, publish, and share data poses a 

significant risk to patient care. 

Current Limitations 

As a starting point, I would like to ground us in a set of long-standing institutional as well as 

regulatory limitations that restrict the flow of information to patients. 

At the core of the FDA's mission is the responsibility to protect the public health. We 

wholeheartedly support the FDA in this core mission and are eager to work with the agency to 

meaningfully meet this goal. However, current regulatory requirements create barriers for 

patients to secure a full complement of relevant and meaningful information on treatment options 

for their conditions. 

"Pre-approval" information is when clinical data is available on a product prior to the product 

having an FDA label. According to the Pharmaceutical Research and Manufacturers of America 

(PhRMA), it currently takes an average of I 0 to 15 years to bring a drug to market. During that 

time, much is learned about the way in which the drug works in the body, how the body responds 

to the drug, the accurate dose, the toxic dose, and the associated side effects. Yet, this treasure 

trove of information remains out of reach from individuals other than the sponsor and trial 

investigators. The proactive sharing of information learned during the development stage is 

subject to pre-approval promotion regulations of the FDA. This is problematic for many of the 

patients who are being asked to participate in the clinical development process of the 7,000 drugs 

in clinical development today. A patient's ability to learn about earlier phase information 

regarding safety or efficacy signals is severely limited. For example, just last week, I was 

approached on behalf of a patient who was asked to go on a phase II trial for a new drug for a 

certain type oflung cancer (alk +).Having my own questions about safety and efficacy in the 

earlier phases of development, including the therapeutic dose, why phase II instead of the phase 

Ill trial, I spent time searching publicly available documents. After spending well over 90 

CancerSupportCommunity.org Uniting 11te Wellness Comtmmihj and Gilda's Club Worldwide 
51 


~ 

.~\11~ ~ 

CANCER 

COMMUNITY 

A Cfobo! Network of Education and Hope 

Headquarters Office: 

734 15th Street, NW, Suite 300, Washington DC 20005 

202.659.9709 Phone 202.974.7999 fax 888.793.9355 Toll Free 

Rest>arch & Training Institute: 

4100 Chamounix Drive, Fairmount Park, Philadelphia, PA 19131 

267.295.3000 Phone 215.883.2580 Fax 

minutes searching, I, an educated consumer, could find only 2 pieces of infonnation that 

referenced safety and efficacy. The reality is that the early phase results are very promising and 

relevant to this patient, but they were not proactively shared with him at the time of the request 

to join the trial and finding them were not intuitive. I would also add that only one of the 2 pieces 

of information I found was published in a peer-reviewed forum. 

Limiting communication of information to only that which is included in the product label poses 

significant challenges to patients. Product labels reflect information collected in the controlled 

clinical trials setting with specified patient populations. It is widely observed that the 

perfonnance of a drug may be different once it is introduced into general use, which will likely 

be a broader, less-controlled population. CSC appreciates the work of the FDA and sponsors of 

phase IV studies, but also recognizes that these studies do not capture comprehensive data for the 

use of a product in the real world. Also, it is a rare occurrence for the label to be updated in a 

manner that would allow for proactive communication about findings. 

Additionally, data may be accumulated through Investigator Initiated Trials (!ITs) on diseases 

that would never reach the investment potential for registration and a label, yet the data may be 

extremely relevant for clinical care, both positive and negative. This information may never be 

communicated to clinicians and will almost certainly not be made available to patients who may 

benefit from the findings. One example of this is lupus treatments. According to the Lupus 

Foundation of America, there are 1.5 million Americans living with the disease. Yet according to 

the FDA's website, there arc only 4 drugs approved to treat lupus-Aspirin in 1948 followed by 

corticosteroids (year not listed), a drug originally used as an anti-malarial (Plaquenil) in 1955 

and, most recently, Benlysta in 20 II. The reality for patients with lupus is that there are many 

treatments being used to treat their disease in an off-label manner. The lack of proactive 

communication on the safe and effective use of these "off-label" indications is arguably a patient 

safety and well-being issue. This example only begins to illustrate the challenges for any patient 

facing a rare condition. 

Information learned outside of the clinical trial setting and not captured in the label can also have 

a true impact on the patient experience. I saw this a number of times in my role as a medical 

information administrator for a large phannaceutical company. In that role, I was charged with 

answering unsolicited medical questions about a product approved for certain cancers. There are 

two situations that I will always carry with me to illustrate this. First, I received several reports 

each week from the sales representatives stating that their customers were repeatedly saying that 

patients were complaining about burning at the injection site when the intravenous medication 

was started. Upon investigating the potential issue, I found that when reconstituted, the pH of the 

product was acidic (around 2.7 to 3.3) which caused burning when coming in contact with the 

vein wall. A simple solution to this was to place a warm compress at the injection site prior to 

turning on the infusion. Yet, because this solution was not a part of the product label, it could not 

be proactively shared with patients or clinicians. The second example dealt with fatigue 

CancerSupportCommunlty.org Uniting The Wellness Community aud Gilda's Club Worldwide 
52 


.~\HI~ ~ ~ 

CANCER 

COMMUNITY 

A Global Network ofEducotion ond Hope 

Headquarters Office: 

734 15th Street, NW, Suite 300, Washington DC 20005 

202.659,9709 Phone 202.974.7999 Fax 888.793.9355 To!! Free 

New York City Office: 

165 West 46tn Street, Suite 1002, New York, NY, 10036 

917.305.1200 Phone 212.967-8717 Fax 888.445.3248 To!! free 

experienced by patients in the immediate 24 to 48 hours post administration. There was a small, 

published study that demonstrated the administration of low-dose steroid at 8, 16, and 24 hours 

post administration significantly reduced the patient experience with fatigue. Again, this was not 

a part of the label and could never be shared proactively with patients and clinicians. Both had a 

significant impact on patient quality of life. 

There are several elements in general clinical practice that contribute to the limitations of 

patients having access to comprehensive information through their health care team. CSC 

acknowledges that these may be collateral effects versus the withholding of information, but the 

outcomes for patients are real nonetheless. The active evolution of the care delivery system from 

volume to value has brought with it efficiency and cost-containment strategies that focus 

treatment decisions on a limited selection. One example is institution or system level 

formularies where hospitals or large systems (e.g., the Veterans Administration) have a limited 

list of treatment options available for their health care providers to consider as they make 

treatment decisions for their patients. A second example is the implementation of clinical 

pathways which are based on scientific information but essentially limit treatment options for 

patient use. Even more concerning is that a clinical pathway used in one practice may be 

different than the pathway for the same disease used in another practice. The lack of 

transparency regarding the data used to make formulary and pathway decisions coupled with the 

limited patient access to comprehensive information sets is simply unacceptable as we move 

towards patient centricity as the gold standard. 

Another limitation is the inconsistent practice and reinforcement of publishing clinical trial 

results in scientific journals and other databases (e.g., clinical trials.gov). Findings secured 

through the clinical trial process, whether positive or negative, may never become a part of a 

product label, but certainly offer meaningful contributions to the overall body of scientific 

knowledge. A study by Riveros and colleagues (2013) analyzed 600 trials with results posted on 

clinicaltrials.gov. They found that 50% of the trials did not have a corresponding published 

article. Even more alarming are the results found by Anderson and colleagues (2015) which 

looked at 13,327 trials that had terminated or completed between January I, 2008 and August 31, 

2012. Of the trials, 13.4% posted summary results within 12 months after trial completion, and 

only 38.3% reported results as of September 27, 2013. The findings from these trials offer 

meaningful information for patients and providers in both clinical practice and also as 

foundational knowledge for further drug development and clinical trial participation, There must 

not only be requirements but also enforcement of requirements to ensure that all results of all 

trials be posted and/or published within a reasonable period of time. 

Finally, industry interpretation of the current regulations are applied inconsistently across 

companies. This may impact the way in which industry communicates with all stakeholders, but 

it almost universally results in industry choosing not to speak with the patient or family with the 

exception of direct-to-consumer advertising tactics. Guidance should be issued and enforced to 

CancerSupportCommunity.org Uniting The Wellness Community and Gilda's Club Worldwide 
53 


A Globof Network ofEduwtion and Hope 

New York City Office: 

165 West 46th Street, Suite 1002, New York, NY, 10036 

917.305.1200 Phone 212,967-8717 Fax 888.445.3248 ToH Free 

Rf"search & Training Institute: 

4100 Chamounix Drive, Fairmount Park, Philadelphia, PA 19131 

267.295.3000 Phone 215.883.2580 Fax 

allow patients and families to, at a minimum, secure answers to questions they may have about 

products they are taking. One very recent example was a call that I made to the medical 

infonnation line of a pharmaceutical company to inquire about transferring a topical anesthetic 

from a very large and non-travel compliant tube to a smaller, travel compliant container. The 

question was whether the transfer from the original container would impact the integrity of the 

product. The response from the pharmaceutical company was that I would have to speak with my 

physician to secure the answer. 

Recommendations 

While these comments have simply scratched the surface on a much broader and deeper issue, it 

is my hope that I have highlighted in your mind the perspective of patients living with chronic 

and life-threatening illnesses across the United States. To summarize, the specific areas where 

we would like to partner and continue to advance the work of this committee, the FDA, and trial 

sponsors include: 

I. Patients and health care providers must have access to medical research findings in a 

comprehensive and real-time manner. 

2. Product labels should be updated in a timely manner and include data from endpoints that 

matter most to patients and/or there must be another mechanism by which to capture and 

proactively communicate findings that are clinically meaningful and relevant. 

3. Scientifically sound communications about safe and effective uses of a product are 

essential and should be made available to all stakeholders. 

4. Clinical trial data results, positive and negative, should be published by the trial sponsor 

in a period of time that is reasonable to allow full and meaningful data review while 

ensuring timely access to information. 

5. Data, positive and negative, collected outside of the clinical trial process, inclusive of 

real-world evidence that is collected and analyzed with appropriate scientific rigor should 

be published and made available to stakeholders. 

6. Proactive medical communication should be tailored to meet the needs and literacy levels 

of specific stakeholders and should not, for any stakeholder, be limited to only the 

product label which may not yet exist or be outdated. This includes physicians who are 

generalists and also specialists, allied health care providers (e.g., nurses and pharmacists), 

payers, and patients. 

Thank you again for the opportunity to bring the patient voice to this important discussion. The 

Cancer Support Community along with many of our partners in the patient advocacy community 

stand ready to help improve patient and provider access to infonnation that is vital to planning 

care for and improving outcomes for patients. 

CancerSupportCommunity.org Uniting The Wellness Community and Gilda's Club Worldwide 
54 


.~\11~ ~ ~ 

CANCER SUPPORT 

COMMUNITY 

A Globa! Network ofEducmion and Hope 

References: 

Headquarte-rs Office: 

734 15th Street, NW, Suite 300, Washington DC 20005 

202.659.9709 Phone 202.974.7999 Fax 888.793.9355 To!! free 

New York City Office: 

165 West 46~n Street, Suite 1002, New York, NY, 10036 

917.305.1200 Phone 212,967-8717 Fax 888.445.3248 Toll Free 

Research & Training Institute: 

4100 Chamounlx Drive, Fairmount Park, Philadelphia, PA 19131 

267.295.3000 Phone 215.883.2580 Fax 

Anderson, M. L., Chiswell, K., Peterson, E. D., Tasneem, A., Topping, J., & Califf; R. M. 

(20 15). Compliance with results reporting at clinicaltrials.gov. The New England Journal 

of Medicine, 372, 1031-1039. DOl: 10.1056/NEJMsal409364. 

Lupus Foundation of America. (n.d.). Facts and statistics. Retrieved from 

http://www.resources.lupus.org/entry/facts-and-statistics 

Pharmaceutical Research and Manufacturers of America. (2016). 2016 profile. 

Biopharmaceutical research industry. Retrieved from http://phrmadocs.phrma.org/sites/default/files/pdf/biopharmaceutical-industry-profile.pdf 

Riveros, C., Dechartres, A., Perrodeau, E., Haneef, R., Boutron, 1., & Ravaud, P. (2013). Timing 

and completeness of trial results posted at clinicaltrials.gov and published in journals. 

PLOSMedicine, 10(12), 1-12. DOl: 10.1371/journal.pmed.I001566. 

United States Food and Drug Administration. (2017). Lupus therapies continue to evolve. 

Retrieved from https://www.fda.gov/forconsumers/consumerupdates/ucm398682.htm 

CancerSupportCommunity.org Uttiti11g T1ze Wellness Community and Gilda's Club Worldwide 
55 

Mr. BURGESS. Thank you. Thank you for your testimony. 

Ms. Khachatourian, you are recognized for 5 minutes, please. 

STATEMENT OF KATHERINE WOLF KHACHATOURIAN 

Ms. KHACHATOURIAN. Thank you to Chairman Burgess, Ranking 

Member Green, and members of the Subcommittee on Health for 

providing me the opportunity to speak before you today. 

I am Katherine Khachatourian, a pharmacist working in Medicare health insurance and a member of the AMCP Professional 

Practice Committee. 

Imagine a world where you are required by Federal and State 

laws to determine a budget and coverage criteria for all drugs 8 to 

12 months in advance of the coverage year using limited available 

information while knowing there is information that could help you 

make more accurate and informed decisions. You just don’t have 

the key to unlock the consistent release of that information. This 

is the world we live in as payers and population health decision 

makers. 

The limitations on information we are able to obtain results in 

a hindrance to patience access to novel and emerging therapies, 

limits our ability to accurately forecast, plan, and budget for anticipated expenditures, and it precludes our ability to contract on 

value rather than volume. This is the reason I am here before you 

today, to demonstrate the need for a legislative framework in support of House Bill 2026 which will provide the key to unlock additional information needed for us to make informed benefit decisions 

for better patient access to treatment. These concepts have been 

discussed in depth with a diverse group of stakeholders including 

payers, manufacturers, clinicians, and patient advocacy groups who 

provide consensus recommendations for how, who, and what information should be exchanged prior to FDA approval. This information should be limited to a narrow audience inclusive of payers and 

population health decision makers. This scope does not include 

manufacturer communications with patients or prescribers prior to 

FDA approval. 

Let me share a few personal examples where lack of information 

has decreased patients’ timely access to treatment. In December of 

2013 and October of 2014, the FDA-approved breakthrough treatments for the treatment of hepatitis C. These drugs had novel 

mechanisms of action which changed the landscape for patients 

with this diagnosis. Note, these approval dates were several 

months after we had already—one of the payers had already analyzed costs and planned benefit. Had we been able to discuss in advance of the approval of these treatments, we would have had a 

better understanding of the landscape, timing of approval of multiple products, the relevant patients for each treatment, and any 

clinical information that would help us to make better decisions 

and ultimately been able to treat more patients in a more effective 

manner without the subsequent criteria revisions that proceeded 

after the approval of these products. 

More importantly, the lack of needed information can impede patient access as seen in the new treatments for Duchenne’s Muscular Dystrophy. In this instance, the level of evidence required to 

deem products safe and effective met the requirements for FDA apVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00059 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
56 

proval. However, due to the inability of payers and manufacturers 

to openly discuss the level of evidence required for coverage, payers 

are not covering these therapies at this time. This is why the bidirectional information exchange is important to understand the 

level of evidence available and necessary for coverage. This example has left patients in a situation where they cannot access therapy. Had payers been able to convey the level of evidence required 

for coverage, could we have avoided this situation? Perhaps. 

Another patient access issue was one I experienced in the past 

year for a request for oncology. On September 21, 2016, we received a coverage request for a treatment of a patient diagnosed 

with inoperable lip cancer that had recently spread to their tongue. 

The FDA granted accelerated approval to expand the indications of 

an existing chemotherapy treatment on August 5, 2016 to include 

head and neck cancer. However, when we received the request for 

coverage, the labeled indications and data supporting the expanded 

indication were not publicly available. In this situation, had I had 

the ability to discuss the data in advance with the manufacturer, 

I could have been better prepared to discuss the requested treatment with the provider, rather than scrambling through 

clinicaltrials.gov and requesting a copy of the clinical trial from the 

manufacturer while the insured patient awaited my coverage decision. 

Because we can only estimate when therapies will be approved, 

if we receive a coverage request shortly after FDA approval, the 

landscape still remains one of chaos and special requests to manufacturers until the data is published, compendia and guidelines are 

updated, and coverage criteria reflect these new and novel treatments. 

I have demonstrated in the previous examples each of these 

breakthrough therapies represent innovations and the potential to 

change a patient’s life, if they are able to gain access to treatment. 

The barrier to access to novel therapies is a population health decision maker’s ability to have sufficient data and sophisticated discussions with those most informed about the utility of the products 

in a timely enough fashion to budget, plan and forecast it for the 

therapies coming to market. 

In conclusion, this is an issue of great importance for patient access to emerging therapies where a diverse group of stakeholders 

have come together to develop consensus recommendations. This 

includes a very narrow audience and scope of exchange between 

manufacturers and payers only. We need your legislative support 

to better care for our patients. Thank you. 

[The prepared statement of Ms. Khachatourian follows:] 

57 


Academy of 

Managed Care 

Pharmacy® 

Written Statement for the Record 

Energy & Commerce Committee, Subcommittee on Health 

"Examining Medical Product Manufacturer Communications" 

July 12,2017 

Katherine ("Kat") Wolf Khachatourian, PharmD, MBA 

Vice President of Pharmacy Services, Strategy, and Delegation Oversight 

Qualchoice Health Plan Services, Inc. 

& 

Member of the Professional Practice Committee 

Academy of Managed Care Pharmacy (AMCP) 
58 


Summary of Statement 

Existing Jaws and regulations hinder the ability ofbiopharmaceutical manufacturers to share information 

proactively on emerging therapies with population health decision makers, who have indicated that 

waiting until FDA approval is often too late for the critical planning, budgeting, and forecasting 

associated with health benefit design, especially given the recent influx of high-cost medications and 

focus on value-based payment models, and that they need access to information about emerging 

therapies at least 12-18 months prior to FDA approval. Therefore, in September 2016, a diverse group of 

stakeholders came together to develop consensus recommendations on how to enable preapproval 

communications, while still maintaining appropriate safeguards to prevent this information from 

reaching unintended entities. 

In January 2017, the FDA released a draft guidance document explaining how "FDA does not intend to 

object" to certain types of information being shared prior to approval. However, the draft guidance 

remains non-binding and does not provide the level of certainty needed to truly operationalize 

Pharmaceutical Information Exchange (PIE). Therefore, there is a need for Congress to engage in this 

topic to create a legislative safe harbor for PIE so that it is clear that the proactive dissemination of 

certain information does not violate the prohibitions against preapproval promotion and does not run 

afoul of the labeling, misbranding, and intended use provisions of the Federal Food, Drug, and Cosmetic 

Act and its implementing regulations. HR. 2026- The Pharmaceutical information Exchange (PIE) Act 

of 2017 incorporates the consensus recommendations developed by the multi-stakeholder group, creates 

a very narrow safe harbor for a very specific purpose, and will improve patient access to emerging 

medication therapies. 
59 


Statement 

As the U.S. health care system evolves from a historical payment system based upon quantity and 

process to a modernized system rewarding quality and improved patient outcomes, the need for timely 

communication between biopharmaceutical manufacturers and population health decision makers (e.g. 

payors, provider sponsored health plans, pharmacy benefit managers, accountable care organizations, 

and integrated delivery networks) about emerging therapies is critical for the successful shift to a valuedriven system. The current pipeline of therapies awaiting Food and Drug Administration (FDA) 

approval offer promising, but often costly, treatments or cures for chronic diseases that previously had 

few options for long-term management. However, existing laws and regulations hinder the ability of 

biopharmaceutical manufacturers to share information proactively on emerging therapies with 

population health decision makers. Allowing for proactive Pharmaceutical Information Exchange (PIE) 

on these pipeline therapies will help population health decision makers to identify cost offsets for other 

medical interventions that impact patient costs. 

Three Main Imperatives Driving the Need for Communications Prior to FDA Approval 

A. Planning, Budgeting, and Forecasting for Benefit Design -As a result of federal laws and state 

mandates, population health decision makers are required to evaluate their plan designs, formularies, 

and rates 12-18 months in advance to meet submission deadlines 6-9 months before the beginning of 

the intended plan year. For example, for the 2016 coverage year, population health decision makers 

analyzed 2014 data to submit their 2016 rates by spring 2015. The budget impact of new therapies 

that were approved hy the FDA after spring 2015 could not be integrated into the 2016 rates. 
60 


As detailed in Appendix I, a recent prime example of the need for population health decision makers 

to account for new medications entering the marketplace was the introduction of novel treatments for 

hepatitis C infection in 2013. Population health decision makers were not properly prepared for the 

impact of these new therapies and the inaccuracies in budgeting and forecasting resulted in limited 

patient access to these medications. I lad PIE been available during this timeframe, population health 

decision makers would have had better knowledge of the impact of the new hepatitis C medications, 

would have been able to better plan, budget, and forecast, and would have been able to minimize 

disruptions to patient access to these medications. 

Therefore, accurate forecasting and rate setting is critical to ensure patients have continued access to 

affordable coverage for their health care needs. With rates being filed over a year in advance, proper 

planning, budgeting, and forecasting are integral for population health decision makers to accurately 

account for the impact of new therapies that will enter the market. 

B. Value-Based Payment Models- There is an increased focus on value-based payment models as 

evidenced by the Medicare Shared Savings Program and a range of initiatives launched and 

proposed by the Center for Medicare and Medicaid Innovation (CMMI). Successful implementation 

of value-based payment models requires understanding the overall value of a therapy, including how 

pharmacy spending can offset medical costs and vice versa. In addition, it requires downstream 

planning for population health decision makers to change plan design, formularies, and necessary 

contracts in advance of submitting rates at least a year in advance of the intended coverage year. 

Therefore, to increase the utilization of value-based payment models, it is important for 

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61 


biophannaceutical manufacturers and population health decision makers to be able to share 

information prior to FDA approval about emerging therapies to provide sufficient time to implement 

these models in a timely and effective manner upon FDA approval. 

C. Patient Access to Breakthrough Therapies - The Food and Drug Administration Safety and 

Innovation Act of 2012 (FDASIA) created an expedited approval pathway allowing the FDA to grant 

priority review if preliminary clinical trials indicate a therapy may offer substantial treatment 

advantages over existing options for patients with serious or life-threatening diseases. Under the 

expedited approval pathway, therapies may be approved by the FDA before clinical trial data is 

published and made publicly available, thereby making it very difficult for population health 

decision makers to determine whether a therapy is appropriate for a patient if they receive a coverage 

request prior to publication ofthe data. Guidelines and peer-reviewed compendia sources are even 

further delayed in providing population health decision makers with reputable reference material for 

making sound clinical judgements when published clinical data is not available. 

In 2016, of the 22 new molecular entities approved by the FDA, 32% received breakthrough therapy 

designation. This percentage is expected to increase in the future as a result of provisions included in 

the 21'" Century Cures Act to advance medical product innovation and ensure that patients get access 

to treatments as quickly as possible. 

As detailed in Appendix I, l personally experienced a situation where we received a coverage request 

for pembrolizumab, a medication approved by the FDA under the breakthrough therapy designation 

to treat head and neck squamous cell carcinoma. The medication was approved by the FDA on 

August 5, 2016. l Iowever, three weeks later when we received our first patient coverage request, 

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62 


clinical trial data was still not published and not available. We had no information available to us to 

determine whether the medication was appropriate for our patient and that resulted in an undue delay 

in her care. Had we been able to communicate with the manufacturer leading up to FDA approval of 

the medication, we would have had access to the data available at the time of FDA approval and 

been able to make a coverage decision for our patient, minimizing delays in her care. 

In these situations, enabling communications prior to FDA approval is critical to ensuring population 

health decision makers are aware of the information available to date on emerging therapies granted 

breakthrough designation by the FDA so they are prepared to make coverage decisions for patients 

immediately upon FDA approval. 

Multi-stakeholder Group Develops Consensus Recommendations for Enabling Communications 

Prior to FDA Approval 

In September 20 !6, the Academy of Managed Care Pharmacy (AMCP) convened a Partnership Forum 

with a diverse group of stakeholders representing population health decision makers, biopharmaceutical 

manufacturers, patient advocacy groups, health care providers, health economists, and others. As a 

participant in the Partnership Forum, I worked alongside the key professionals and entities affected by 

the current restrictions on the sharing of preapproval information to develop consensus 

recommendations on how to improve patient access to emerging medication therapies by clarifying the 

scope of permitted health care economic and scientific information communications between 

biopharmaceutical manufacturers and population health decision makers, while still maintaining 

appropriate safeguards to prevent this information from reaching unintended entities. The full 

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63 


recommendations from the Partnership Forum were published in the January 2017 issue of the Journal 

of Managed Care & Specialty Pharmacy and are also included as Attachment A. 1 The consensus 

recommendations from the Partnership Forum included the following provisional recommendations: 

Create a safe harbor to allow biopharmaceutical manufacturers to share truthful and nonmisleading clinical and economic information about medications in the pipeline with population 

health decision makers proactively at least 12-18 months prior to FDA approval during the 

forecasting and rate setting process. 

o Forum participants agreed that a safe harbor for PIE was necessary to confirm that the 

proactive dissemination of certain information does not violate the prohibitions against 

prcapproval promotion and does not run afoul of the labeling, misbranding, and intended 

use provisions of the Federal Food, Drug, and Cosmetic Act and its implementing 

regulations. 

o Forum participants agreed that information shared under PIE should meet the competent 

and reliable scientific evidence standard as defined by a prior AMCP Partnership Forum2 

to be "truthful and non-misleading tests, analyses, research, studies, models, or other 

evidence. Such evidence would be based on the expertise of professionals in the relevant 

area and be derived using methods that arc transparent, disclosed, reproducible, accurate, 

and valid." 

o Forum participants agreed that the specific format or process for sharing PIE should not 

be prescribed in legislation but should be developed collaboratively between the 

1 Enabling the Exchange of Clinical and Economic Information Pre-FDA ApprovaL Journal of Managed Care & Specialty 

Pharmacy2017 23:1, 105-112 2 AMCP Partnership Forum: FDAMA Section 114-Improving the Exchange of Health Care Economic Data. Journal of 

Managed Care & Specialty Pharmacy 2016 22:7. 826- 831 

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64 


biopharmaceutical manufacturers and population health decision makers who would be 

exchanging this information. 

Limit exchange to narrow audience: biopharmaceutical manufacturers and population health 

decision makers (e.g. payors, provider sponsored health plans, pharmacy benefit managers, 

A COs, and lDNs) only. 

o Forum participants debated the scope of preapproval communications and also 

considered whether providers and patients should be considered within scope. After much 

debate, forum participants agreed that given that information shared under PIE is prior to 

a product being deemed safe and effective by the FDA, information should only be 

shared proactively with those entities that have accountability for forecasting costs to 

ensure patient access and coverage. In addition, PIE should be limited to a sophisticated 

audience who has the education, training, and expertise to critically analyze and evaluate 

health care economic information for credibility. Therefore, PIE should be limited to a 

narrow audience and should only be permissible for biopharmaceutical manufacturers 

and population health decision makers. 

Limit exchange to new molecules and expanded indications with an intent to file only. 

o Forum participants debated whether PIE should be limited to new molecular entities only, 

or should also include expanded indications. During the debate, population health 

decision makers articulated that expanded indications can have a major impact on 

budgeting, forecasting, and rate setting if the expanded indication increases the patient 

population eligible to receive the product significantly. For example, if the indication for 

PCSK9 inhibitors were expanded to include generalized hypercholesterolemia, it would 

result in a major increase in the eligible population and corresponding costs associated 

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65 


with the treatment of hypercholesterolemia. llowever, population health decision makers 

also noted that while they want to receive information about expanded indications 

preapproval, they do not want to receive information about all off-label uses of a product. 

In addition, they wanted to ensure that incentives were still in place to encourage 

biopharmaceutical manufacturers to file for an expanded indication as FDA approval 

remains the gold standard for formulary placement for most classes of medications. 

Therefore, forum participants recommended that PIE should be applicable to both new 

molecular entities and expanded indications with an intent to file. An intent to file would 

be demonstrated by submission of a Supplemental New Drug Application (sNDA) or 

other similar steps. However, forum participants also noted that in certain situations, 

especially for rare diseases, a financial incentive to file for an expanded indication may 

not be viable and therefore an avenue should be available for PIE to be applicable absent 

a regulatory filing in certain circumstances. 

Allow for bidirectional exchange of infonnation that does not necessarily have to be clinical or 

scientific evidence. 

o Forum participants agreed that bidirectional exchange of information was a key element 

of PIE to encourage a continuous and ongoing dialogue between biopharmaceutical 

manufacturers and population health decision makers throughout a product's preapproval 

lifecycle. The bidirectional communication would also allow population health decision 

makers to share with manufacturers what they are looking for in clinical endpoints and 

level of evidence to make coverage decisions for patients. This notion has become 

increasingly important recently with the approval of new therapies for Duchenne's 

Muscular Dystrophy. These products were approved by the FDA as safe and effective, 

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66 


but population health decision makers are hesitant to cover the products as the level of 

evidence docs not meet their needs to make a coverage decision, resulting in patients 

being unable to access these products. Had PIE been permissible during the development 

phase of these products, population health decision makers could have shared their 

expectations for the level of evidence generated from clinical trials and perhaps avoided 

the gap in patient access that exists today. 

o Forum participants debated whether PIE should be limited to "evidence" or 

"information." After much debate, it was agreed that "information" was the more 

appropriate term as some elements shared under PIE would always amount to 

information and not evidence, such as anticipated indications, place in therapy, routes of 

administration, and budget impact. It was also discussed that economic models cannot be 

considered evidence and limiting the standards to "evidence" may cause legal concern 

and be interpreted as requiring a level of research or replicability for all information 

disclosed, which might be unattainable at certain stages of the product's development. 

o Forum participants discussed the need to establish a minimum set of standards that 

information shared under PIE should meet, including the need for a dynamic standard 

that would support the evolution of information to evidence as a biopharmaceutical 

product approaches FDA approval. Forum participants suggested that an independent 

objective entity comprised of a multi-stakeholder collaborative of representatives from 

various organizations could be responsible for developing consensus recommendations 

regarding good research practices for information shared under PIE. The independent 

objective body would also be responsible for continually updating the established good 

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67 


research practices to reflect updates in scientific rigor and other advances in evidentiary 

standards. 

o Forum participants also emphasized that because the information about a product could 

change and augment over time, information shared under PIE should include appropriate 

disclosures including transparency regarding the methods and results with appropriate 

disclosures of uncertainty and limitations inherent in such information. 

FDA Releases Draft Guidance and Shares Its Current Thinking on Preapproval Communications 

In January 2017, the FDA released a draft guidance document 3 outlining its current thinking on 

manufacturer and payor communications. The draft guidance took a helpful first step in creating a safe 

harbor for manufacturer communications to payors regarding investigational products, but did not 

include expanded indications. While population health decision makers were pleased to see that the 

FDA draft guidance allows the proactive communication of certain information by biopharmaceutical 

manufacturers to payors prior to FDA approval, the draft guidance remains non-binding and these 

provisions must be codified by law. Therefore, there is a need for Congress to engage in this topic to 

create a legislative safe harbor for PIE so that it is clear that the proactive dissemination of certain 

information docs not violate the prohibitions against preapproval promotion and docs not run afoul of 

the labeling, misbranding, and intended use provisions of the Federal Food, Drug, and Cosmetic Act and 

its implementing regulations. 

3 FDA Draft Guidance- Drug and Device Manufacturer Communications With Payors, Formulary Committees, and Similar 

Entities~Questions and Answers [FDA-2016-D-1307]" as published in the Federal Register on January 19, 2017. Available 

at: https:i !www. fda.govldown loadsiDrugs/GuidanccC:ompl ianceRegulatorvl nformation/Guidances/UCM53 734 7 .pdf. 

Accessed July 10,2017. 

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H.R. 2026- The Pharmaceutical Information Exchange (PIE) Act of 2017 is Introduced 

In April2017, Representative Brett Guthrie (R-KY) championed this issue by introducing H.R. 2026-

The Pharmaceuticalll?formation Exchange (PI~) Act of 2017 to improve patient access to emerging 

medication therapies by clarifying the scope of permitted health care economic and scientific 

information communications between biopharmaceutical manufacturers and population health decision 

makers. The bill, as amended, incorporates the consensus recommendations developed by the multistakeholder group and creates a very narrow safe harbor to allow for biopharmaceutical manufacturers to 

share proactively health care economic or scientific information with population health decision makers. 

The bill also solidities the current thinking of the FDA and includes expanded indications, an area that 

the FDA did not include in their draft guidance, but an area that the multi-stakeholder group felt was 

integral to improving the ability of population health decision makers to properly plan, budget, and 

forecast for the impact of an expanded indication. The bill also requires that information provided under 

PIE must include a conspicuous and prominent statement describing any material differences between 

the information provided and the FDA-approved product labeling. 

There is a Need for Congress to Engage in This Topic 

PIE is an acute issue that a broad group of stakeholders came together and agreed needs clarification. 

While the FDA draft guidance took a helpful first step in creating a safe harbor for manufacturer 

communications to population health decision makers regarding investigational products, the draft 

guidance remains non-binding and does not provide the level of certainty needed to truly operationalize 

PIE. Absent a legislative safe harbor, PIE will likely not be utilized to its full potential by 

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69 


biopharmaceutical manufacturers and population health decision makers for fear of enforcement, and 

unfortunately patients will not realize the benefits of PIE. 

Therefore, there is a need for Congress to engage in this topic to create a legislative safe harbor for PIE 

so that it is clear that the proactive dissemination of certain information does not violate the prohibitions 

against preapproval promotion and does not run afoul of the labeling, misbranding, and intended use 

provisions of the Federal Food, Drug, and Cosmetic Act and its implementing regulations. 

Congressional action is needed to create a safe harbor for PIE to improve patient access to emerging 

medication therapies. 

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Appendix I 

In practice, the importance of the need for PIE and where access to PIE would have improved patient 

access to care is demonstrated in the following scenarios. The answer to improving access here is having 

necessary information 12-18 months ahead of FDA approval, and having legislative support that not 

only grants access, but provides the necessary framework and safe harbor enabling a sophisticated 

audience the ability to have a bidirectional dialogue concerning this information. 

(I) Scenario Ia- Hepatitis-C: All Medicare bids for 2014 benefit offerings use the 2012 experience to 

structure benefits offered to patients ('members'); all clinical, actuarial and cost analyses due to 

submit to CMS for approval 5/31/2013, including our formulary covering at least 2 drugs in every 

therapeutic category 

Sovaldi: groundbreaking treatment for Hepatitis C, approved by FDA 12/6/2013 with novel 

mechanism; changing the landscape for an estimated 3,2 million people known to the CDC as 

diagnosed with Hepatitis-C (note, 7 months after we've already analyzed our costs and planned 

our 2014 benefits) 

111114-12/31/14: Drugs to treat Hepatitis C accounted for $500k (1/2 million dollars) for 4 

patients in our plan. Two additional patients opted not to pick-up their medications, which would 

have accounted for another $!60k in spend. For that time-period, we had another 16,000 people 

to take care of, and cancer was the only category with higher spend. 

(2) Scenario lb. Hepatitis-C 2014: bids for 2015 benefits due 6/2/2014 based on base period of2013 

drug use trends, Harvoni approved I 0110/20 14; 2015 benefit year saw I 0 I claims for 32 of our 

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22,500 patients accounted for I 0% of our spend, while only caring for 0.14% of our member 

patients. 

In the first two scenarios, had we been able to discuss proactively with Gilead their emerging evidence, 

treatment options, and had a better grasp on understanding their pricing strategy for a 'cure', the 

restrictive coverage criteria and multiple iterations of coverage criteria revisions might not have 

occurred over the ensuing years. 

(3) Scenario II Oncology: 

Key time line: follow the time line presented previously - bids for 2016 were submitted 6/2015 & 

bids for 2017 submitted 6/2016- we are always playing a game of catchup for planning and 

communication of benefits to our members 

Let me introduce you to a patient, one of our enrolled members- a 67 year old diagnosed with 

inoperable lip cancer which has spread to tongue, clinically called 'squamous cell carcinoma': 

Patient is eligible for a low-income subsidy based on annual income (annual single income 

5135% FPL ($16,278) 

Provider tells patient about a new treatment the FDA granted accelerated approval 8/5/2016 for 

pembrolizumab (Keytruda) to treat head and neck squamous cell carcinoma due to overall risk 

reduction of 16% seen in clinical trials; 

200mg/dose every 3 weeks plan pay $7,178 (pt pay $1 ,830)/dose x 8 visits ~ $57,424 (pt pay 

$14,640)/treatment course until $6,500 Maximum-Out-of-Pocket (MOOP) Limit 

Out of pocket limits update annually, so potential for full patient liability since treatment crosses 

2016-2017. 

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Without being a head and neck cancer specialist, how can I have an informed discussion with my 

provider regarding the level of evidence showing 16% overall response rate when clinical trial 

evidence is not yet publicly available without a specific data request to the manufacturer? 

In this scenario if we were able to talk with the manufacturer, in this case Merck, about their 

pipeline and treatments ahead of time, or better yet have a portal for secure login and review the 

information available, thus understand their value statement and clinical data; I could better plan 

for this treatment and have an open dialogue with my provider once the product is approved, 

rather than scrambling to review the evidence and appropriateness of care on 9/I!I6 when I 

received the request for coverage of the product and the patient already scheduled to receive 

treatment on 9/2/l6. 

Reflecting on historical 'what if scenarios can only be made more impactful if we look at what is ahead: 

(4) Scenario III Future State: In the next 12-18 months there are approximately 60 new products that 

have filed for, or are anticipated to file for, approval within categories including diabetes, antiinfective agents, dermatologic, inflammatory conditions, multiple sclerosis, cancer, and others. 

As a reminder, we submitted our 2018 Medicare bids for formulary and coverage criteria on June 

5, 2017, and will submit our 2019 benefits and formularies the first week of June, 2018; thus 

each of these potential new treatments represent coverage uncertainty for payors, providers, and 

ultimately a patient who is at the receiving end of coverage decisions. 

Because we can only estimate when therapies will be approved, if we receive a coverage request 

shortly after FDA approval, the landscape still remains one of chaos and requires special requests 

16 
73 


to biopharmaceutical companies to access the data until the data is published, compendia and 

treatment guidelines are updated, and coverage criteria reflect new and novel treatments. 

These new drug application estimates do not include expanded label indications- which adds 

additional importance for continued communication as the label of products evolve over time as 

new indications are studied. 

As demonstrated in my previous scenarios, each of these breakthrough therapies represent innovation 

and the potential to change a patient's life IF they can gain access to therapy. The barrier to access to 

novel therapies is a population health decision maker's ability to have sufficient data and sophisticated 

discussions with those most informed about the utility of the products in a timely enough fashion to 

plan, budget, and forecast for the therapies coming to market. Payors represent an extremely 

sophisticated audience who has the education, training, and expertise to critically analyze and evaluate 

health care economic information for credibility. These individuals are trained to review evidence and 

understand clinical endpoints resulting in better information applied to patient access 

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Attachments 

Attachment A: Enabling the Exchange of Clinical and Economic Information Pre-FDA Approval. 

Journal of Managed Care & Specialty Pharmacy 2017 23:1, 105-112 

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75 


AMCP Partnership Forum: Enabling the Exchange of Clinical 

and Economic Information Pre-FDA Approval 

SUMMARY 

Gurrentfederallawsand FOAregulationshavesignilicantlyrestrictedthe 

sharingolclinicalandhealtheconomicinformationonbiopharmaceutica!s 

thathaveyettoreceiveFOAapprova!. Overthepastsevera!years, organizationsthatmakehealthcarecoveragedecisions, including those that set 

copayments, premiums, and formulary placement, have expressed a need 

forreceivingthisinformationbeforeapproval,aslongasappropriatesafeguardsexisttopreventthisinformationfromreachingunintendedentities. 

Populationhealthdecislonmakershaveindlcatedthatwaitinguntll FDA 

approvalisoftentoolateforthecritica!planning, budgeting, andforecastingassociatedwithhealthbenefitdesign,especial!ygiventherecentinf!ux 

ofhigh-costmedicationsandscrutinyforbetterevaluationandpreparation. Recognizingthatsecuritieslawsrestrictthedisclosureofnonpub!ic 

information and may need to be amended, permissible early dissemination 

woulda!!owpopulationhealthdecisionmakerstoincorporatec!inicaland 

economicinformationforpipel!nedrugsorexpandedindicationsintofinancialforecastingforthefollowingyear'splan.Accesstothisinformationis 

needed 12-18monthsbeforeFDAapprovalwhenorganizationsaredeciding 

ontermsofcoverageandbudgetaryassumptionsforstatehea!thinsuranceratefilings,MedicareandMedicaidbids,contractswithhea!thcare 

purchasers,andotherfinancialarrangements. 

The needforexchangeofclinica!economicinformation before FDA 

approval was first introduced at a previous Academy of Managed Care 

(AMCP) forum in March 2016, which addressed section 114 of the Food 

and Drug Administration Modernization Act and the communication of such 

information after FDA approvaL To address preapproval information specifically, AMCP convened a Partnership Forum on September 13~14, 2016. 

This forum included a diverse groupo! stakeholders representing managed 

care,thebiopharmaceuticalindustry,providers,patients,hea!theconomists,academia,andothers. Themu!tistakeholdergrouprepresentedthe 

keyprolessionalsandentitiesaffectedbythefederaJiawsand FDAregulatioosthatrestrictthesharingofpreapprovalin1ormationandtheco!lective 

credibilitynecessaryforproposingthisnewcommunicationprocess. 

Forum participants primarily focused on 6 items of discussion: (1} creat* 

ing and defining new terms for how biopharmaceutical manufacturers may 

provide clinical and economic information 12-18 months before FDA approval; 

(2)definingthecllnica!andscientificstandardsthatthisinformationshould 

meet; (3) determining which entitles should have access to this information 

and the value to each; (4) the format and process by which this infOrmation 

shouldbedisseminated;(5}developingdefinitions1orexistingtermsreferenced in current laws, regulations, or guidance documents that would need 

to be modernized to align with the identified new term; and (6) providing 

safeguardstopreventthisintormationfromreachingunintendedentities. 

Forumparticipantsselected"preapprovalinformationexchange"(P!E) 

asthecorrecttermtodescribethisproposednewcommunicationprocess 

andtobeinc!usiveofdatafrompivota!phasell!clinicaltrials,pharmacoeconomicdata,andpatient-reportedoutcomes,aswe!lasotherre!evant 

items, including anticipated indications, placeintherapy,androutesof 

administration.StakeholdersagreedthatPIEshouldbetruthful,nonmisleading,andincludeabroadrangeofinformationtomeettheneedsof 

popu!ationhealthdecisionmakersandhealthcaretechno!ogyevolution. 

Recipients of PIE would be limited to population health decision makers who 

needthisinlormationforcoveragedecisions.TheformatandprocessforPIE 

disseminated should allow for a bidirectional exchange between manufacturersandpopulationhea!thdecisionmakersbutshouldnotbeproscribed 

integislation.Furthermore,new!egis!ativelanguagemaybebeneficial, 

since PIE is a novel category of information. New legislation could provide a 

safeharborandclaritythatPIEdoesnotviolate preapproval promotion and 

the Federal Food, Drug, and Cosmetic Act and its regulations. 

J Manag Care Spec Pharm. 2017;23(1):105-12 

Copyright©2017, Academy of Managed Care Pharmacy. AI! rights reserved. 

l JMCP Journal of Managed Care & Specialty Pharmacy 105 
76 


FIGURE 1 

~ Avalere Ttming Challenges with Emergence Qf lllustrattve Novel Drug 

October January Apnl July October January Aprd July October 

October January Apn! July October January Apnl July October 

Hi A - 1l<d,>gl< II< n"'' App!•wtwn, C:VfS -· t '~nlcr< fm 

~·lA "-:.kd''"'e Advanluge. ,\"J),\ ,;)\;n, D"BE Appb:urwn 

106 Journal of Managed Care & Specialty Pharmacy JMCP jJnuJr; 
77 


exchange (PIE) is critical to ensuring that population health 

decisiOn makers are aware of the information available to date 

granted breakthrough by 

the prepared to make coverage 

for patients immediately upon FDA approval 

Restricting Information Dissemination 

Current federal laws and FDA regulations have 

restncted communications betw·een b>O!Dharm>>eeu.tical 

health decision makers for 

extst, the interpretation is unclear, and enforcement invoh·es 

vanous entities with approaches (i.e., Health and 

Human Services Office of the Federal Trade 

CommlsslOn, Department of justtce, and state governments).8 

l The term that would be used to describe the abihty of bio~ 

pharmaceutical rnanufaCLurers w proactively share clinical 

and economic information about medications in the 

line with other entities before 

2 The 

3. Stakeholders who access to clinical and eco~ 

nomic information before FDA approval and the value of 

this mformation to each of these entitles or mdtviduals. 

4 The format and by wh1ch eligible entities 

information from 

J•mttary20l7 Vol 23,t><o! )MCP JournalofManagedCare&SpecialtyPharmacy 107 
78 


public health protccuons that should b~ constdercd to U:m Terminology to Describe the Sharing of Preapproval 

prevent the Jt:.setlttnation of clintca! ;.1nd CC\)non\tc lnf,mn<t- Clinical and Economic Information 

uon to unintended entitles beiorr FD1\ approval 

A\1C:P hdd a 

2016 to 

mformation (HCFO 

;..Jarch forum d1scussed \ h<: and 

swn Llf Secuon of the Food and Drug 

:Vhxlerntzanon Act (FD,-\MA) tL) nbtain consrnsus recommendal tons on how mfonnallO!:l. related to thts statute should br the method of conversation should be deemed an exchange or 

ms;.em•nat,on. · \1/hlle recommendations from the \larch mfortn.'<tton shanng 

108 Journal of Managed Care & Specialty Pharmacy }MCP 

Preapproval 

The 
79 


wlth securities and trade secrets laws that restnct the 

drg,"mination of matena! non public information, which could 

mclude pncmg, as well as cenam clinical tnul data 

Information Versus Evidence 

the term ''scienuftc mfonnatton'' \vas 

agreed that thts term may be m<>mlemt<eted 

to research stud1es 

the 

(e g., 

encomp;::~ssmg te-rm thal !Tl3Y not have as 

much \Vetght m the scienuflc community 

mat ion vers\lS ev1dence is d1scussed m more detad 

this proceedings document 

Exchange Versus Information Sharing 

The third area of discussion focused on the terms '·exchange'' 

versus ·'tnformauonsharing." Supporters of the term "exchange" 

felt that the usc of thts term wuu!J btdtrecuonal 

enuties as evolves into evidence throughOlH drug development Furthermore, stakeholders 

biocohacmctccutical manufacturers who mtend to file for a new 

(new molecules and new indications), 

mg the risk for off-label 

mtent of a biooharmc<eeu.tlcal 

to be 

ddmmon, wnh a few proposed excepnons· 

''Information" should be either added to the definition or 

should replace "evidence" 

A minimum set of standards should be set for this inforblo1Jhacmacceutkal product approaches 

would become stronger and 

wtth appmprwte cl!sdosures 

inherent m such in!ormation, and 

be reproducible-not the results) 

Some stakeholders expressed that all-inclusive information 

sharing, wtth ulumate!y no restnctions, allow too much 

lenience, white bemg too 

a Entities and Individuals Who 

Should Receive Preapprovallnformation 

that th1s preapprova! commumcation only applles to "health care decision makers beyond 

'""":mcpNg )Jmi,\1'}·20P Yol 2>.:->:n 1 ]MCP JournalofManagedCare&SpecialtyPharmacv 109 
80 


asked to consider these same entltJeS for preapproval purposes, 

m addttton to and therapeutiC commlltees, manaccountable 

eties (e.g., lnternauonal SoC1ety for Pharm;:~coeconmmcs and 

Outcomes Research), actuanes, contract spccbhsts, and others 

A.H stakeholders agreed that population hea!th deosion 

makers such as and 

ticals would also be 

twn. These popu!anon deCision makers \Vere included 

because enttties and mdn·tduals wnhm these organizations 

need to receive thts inlormatton m ad\·ance of FDA approval for 

budgeting, and dects!On 

Forum other entitles that arc "mf!uenccrs," such as groups that develop value 

be mcluded 

and coverage, \VhKh 1s not 

\VhHe preapproval mformauon sharmg with lnfluencers and 

PAGs was considered, there was .consensus that the 

approval information most valuable tll mfluencers PAGs 

was dlmcal in nature, not prelimmary economic or financw! data. Furthermore, cnmies such as inOuencers or PAGs 

could receive this mformation through the usual channel of 

unsobntcd Therefore, the majonty of stakeholders 

that enuties who manage a population's health 

recewe preapproval mformation 

110 Journal of Managed Care & Specialty Pharmacy }MCP J~nu~r)· 2017 

vcrsations between manufacturers and decision makers" 

~1ore imponantly, manufacturers and decision makers 

would have the option to choose the type and frequency of 

Vol 21.:-:o 1 'I.WWJn>cpori( 
81 


AMCP Partnership Forum: Enabling the Exchange of Clinical and Economic Information Pre-FDA Approval ·-~ """""'"- ·- - - . ~. ..~--~----~------·-----

their individual needs, and 

to use a repository or another process for 

exchanging th1s mformation 

D. Definitions for Existing Terms in Current 

laws. Regulations, or Guidance Documents 

own harbor, in a manner consistent with existing taw. 

B Public Health Protections to Prevent the 

Dissemination of Preapprovallnformation 

as in place to 

mation from reaching unintended entities recommenda~ 

non from this Partnership Forum ts for Congress to establish 

a safe harbor for information between 

biojohaccmaceut.ical manulKtctces and population deci~ 

better decision makmg, without 

ln the biophannaceuucal and 

]anuary20l7 

forum Partfc1pants 

! JMCP Journal of Managed Care & Specially Pharmacy 111 
82 


AMCP Partnership Forum: Enabling the Exchange of Clinical and Economic Information Pre· FDA Approval ~·~ ·---- ------ ·----~---- ------ ____ _._, ____ --------- ·---~ __ , __ _ 

H. 21st Cemury Cures Ac\. HR. 6. ll4th Congress (201 '5-2016) lw~llbhle 

Arcessed 

112 Journal of Managed Care & SpecialtyPharmacv ]MCP ]amwy 20!7 \'o1 
83 

Mr. BURGESS. I thank you for your testimony. I want to thank 

all of our witnesses. It has certainly been compelling testimony this 

morning. People will note that I allowed the clock to run over because you had important information to provide us. I guess we will 

underscore that I will not be so generous with Members, so try to 

confine your time to the 5 minutes allotted to these products that 

have not been evaluated by the FDA. This product is not intended 

to diagnose or prevent any condition, just to get through the appropriate label disclaimer. 

Let me begin the questioning and I will recognize myself for 5 

minutes. And Ms. House and Ms. Khachatourian, thank you so 

much for your testimony. 

Ms. House, while you were talking and I actually wrote down a 

note to myself about when you mentioned about clinical trials and 

I was going to ask you about the utility of getting the information 

off of clinicaltrials.gov and then Ms. Khachatourian actually referenced that as well. So this is a real-world phenomenon where 

payer decisions are unable to be made, but the data is sort of accumulating on the data side of the docket, but it is not coming up 

to the payer’s side. So it sounds like both of you have dealt with 

that. 

And Ms. Khachatourian, I thank you for bringing up the issue 

with the new hepatitis C drugs, because we were sitting on these 

panels in 2012 and 2013. And I would suggest it is not just an 

issue of commercial payers. Our State Medicaid directors, our State 

prison directors, our Federal prison directors were going to have to 

deal with this information in very short order and they did not 

have it available to them. 

And I would be happy to listen to what both of you have to say, 

particularly on the clinicaltrials.gov. Are we doing a good enough 

job getting that information out there in a usable way so that you 

can actually begin the process of what are we going to have to do 

as far as on the payer’s side? 

Ms. House, we will start with you, and then I would like to hear 

Ms. Khachatourian’s thoughts on that. 

Ms. HOUSE. Thank you, but I didn’t share my comments that I 

have in my written testimony. I included two studies that were 

done on the clinicaltrials.gov database where there was a random 

sampling of 600 trials originally. And 50 percent of those trials did 

not have a corresponding article. The second study was even more 

alarming in that there was a look at 13,327 trials and 1-year postdata closure, only 13 percent of those has posted clinical trials information. And even when they gave a bit of a grace period and extended that for another couple of years, only 38 percent had clinical 

trials posted there. So not only is the system extremely difficult to 

sort of use and find and especially as we are moving into the age 

of personalized medicine to get to trials that are relevant for me, 

the data results aren’t there. 

And I will give you an example that happened to me just last 

week, is that a patient of ours reached out and he has a certain 

type of lung cancer, ALK positive lung, in which there are a number of solutions and options available for him. His physician wanted to put him on a phase 2 trial with a new product and he said, 

‘‘What do you think about this?’’ And so I went online to try to find 

84 

information because I was trying to decide why would they put him 

on a phase 2 trial instead of the phase 3 trial, and I am an educated consumer and I have worked in clinical trials for a long time. 

After about an hour and a half, I could find two sources online to 

your point. One of them was with a reputable medical society and 

the other was an opinion piece on the way in which this product 

worked. 

They are in a phase 3 setting already, so there is a lot of evidence on this particular drug and not available to even educated 

consumers. 

Mr. BURGESS. OK. Ms. Khachatourian. 

Ms. KHACHATOURIAN. Thank you, Mr. Burgess. I actually pulled 

some dates more relevant to some recently approved therapies. In 

the hepatitis space, the products Zepatier and Epclusa were approved January 28, 2016, and June 28, 2016, per the FDA website. 

However, results on clinicaltrials.gov were not published until September 27, 2016 and April 26, 2017 respectively. So just to give 

perspective regarding when data is available and results are published, those are key dates that I was able to glean. I have some 

oncology examples as well, but I think that proves the point regarding the delay in access to information that is necessary for coverage decisions. 

Mr. BURGESS. Dr. Van Hare, you referenced the rich data sets 

that would be available by a drug or device manufacturer, but that 

data is sort of locked away from the clinician. I guess you have to 

go the bar to have those discussions? You can’t have those discussions in the hearing room or the continuing education room? You 

have to go offsite? 

Dr. VAN HARE. On the stairwell. 

Mr. BURGESS. On the stairwell, OK. Very well. And you see what 

we are talking about today as a way of unlocking those data sets 

being available to the clinicians? 

Dr. VAN HARE. I think so. I think it is really pretty simple for 

allowing off-label use. A physician who prescribes something offlabel is responsible for ensuring that they have evaluated the most 

appropriate clinical data before they make a decision about prescribing something off-label and some of that data is actually held 

by the manufacturers. 

They are allowed, as I understand it, to provide it to us privately 

and in response to an unsolicited request, but you know, there is 

300 of me in the country, the pediatric cardiologists who do what 

I do in the country. Every single one of us has to independently call 

up the drug company to get the information. It is not particularly 

efficient. 

Mr. BURGESS. No. I think my time is expired. I want to be respectful of everyone’s time. 

Mr. Green, you are recognized for 5 minutes for questions, 

please. 

Mr. GREEN. Thank you, Mr. Chairman. Long ago, Congress recognized the importance of requiring manufacturers to provide evidence demonstrating the safety and efficiency of the product. In 

marketing under current law, drug and medical device manufacturers can disseminate certain medical and scientific information 

85 

about unapproved uses of approved or cleared products to health 

care professionals and other entities. 

Recent court cases cited as a source of uncertainty around the 

types of communication about these unapproved uses are permissible. 

Ms. Charo, in your written testimony, you said if the First 

Amendment means that the off-label promotion must be permitted, 

then the promotion of entirely untested, unproved drugs should 

also garner the same protection. Is that true? 

Ms. CHARO. I fear that the logic would be the same in both cases. 

Now it is true that for things that have been approved at least 

once, one does have some, at least, early information that the drug 

is not highly toxic because that is what we are going to get from 

the early Phase 1 or 2 trials. But the reality is over time, both the 

drugs that have never been approved before or the off-label indications for things that have been approved turn out to fail which 

means that one begins with a presumption that any unapproved 

use or any unapproved drug is probably not safe or not effective 

until it is proven to be so. 

Mr. GREEN. Well, this is an issue that this subcommittee and our 

committee has wrestled with for a number of years. Can you help 

us understand what restrictions the Constitution does and does not 

allow? Does the First Amendment prohibit the FDA from restricting promotion of unapproved uses? 

Ms. CHARO. No, there are a number of Federal cases that have 

upheld the FDA’s authority to do just that. There is constitutional 

protection for commercial speech and there are standards for that 

protection and in the area of commercial speech it is a fair amount 

of protection although not the same degree of protection as you 

would get for political speech or other forms of speech. And those 

restrictions on commercial speech are permitted when there is a 

substantial public interest in doing so. In this case, by restricting 

off-label promotion, one is able to create both a stick and a carrot 

that drives the pharmaceutical industry toward the research needed to actually figure out which things are safe and which things 

are effective. If one is able to simply promote without restriction 

and gets no market advantage by going in and investing in the research, one loses that system entirely and we really do risk having 

an absence of information for people like Dr. Van Hare to solicit 

or to develop on his own, let alone to share with his colleagues. 

Mr. GREEN. Ms. House, I note in your focus on your testimony 

the fact that so much clinical trial data is unpublished. One thing 

that concerns me is the bias in what is published. Multiple studies 

have shown that positive trial results are more likely to be published than negative results. And in particular, industry sponsorship has been demonstrated to be a factor contributing to the biased publication. Industry has no incentive to publish or promote 

negative findings. 

My question is if industry is more likely to publish positive than 

negative results, do you also worry that positive results will be promoted more than negative results, even if there is a particular research being communicated is truthful and not misleading? Doesn’t 

selected provocation create a distorted view of the safety and effectiveness of the unproven use? 

86 

Ms. HOUSE. I am going to answer this very carefully because I 

have not seen the data that you re referencing that would suggest 

that there is more positive data than negative data. What I would 

say is that our position is is that both positive and negative data 

needs to be published in an equal manner and should be available 

for communication because we do know that there are patient 

harms as well as benefits. 

Mr. GREEN. And I think that is what we want to get to. If I am 

a pharmaceutical or if I am advertising anything else, I am going 

to talk about how great it is. If we are running for office, I am not 

going to talk about our bad side. We are going to talk about the 

good side. So we need to have it, but we need some agency to be 

able to say this is what you are doing and the FDA is what we 

have. That is my frustration, I guess. 

Dr. Van Hare, in your testimony you note that Pediatric Research Equity Act has not been sufficient in producing the amount 

of shareable data we might like particularly in the older drugs and 

clinical decisions are often made. I think you raised an important 

point about the need for the robust data to allow clinicians to make 

the best decisions they can. My concern is there is nothing in this 

legislation we are talking about today would actually encourage 

drug companies to conduct those clinical trials that could answer 

important questions for pediatric populations. And again, our subcommittee for decades has wrestled around what may be appropriate for an adult is just not appropriate for children and we need 

to do a lot more work on that to make sure that we don’t leave out 

the pediatric population. 

Mr. Chairman, I know I am over time, so I yield back my time, 

unless you want to give it Dr. Van Hare? 

Mr. BURGESS. Dr. Van Hare, did you want to comment? 

Dr. VAN HARE. I think that legislation has actually helped children in terms of getting a lot more information about drugs. And 

certainly in the pediatric world, originally for some companies or 

actually enticed some companies to actually do some trials. For the 

most part though companies are not really interested in the pediatric market. We are very, very small market and sort of thinking 

about the carrot and stick sort of approach, none of the carrots are 

really going to help us in pediatrics because it is a fairly small 

market. So we are left in a situation where no one is going to do 

the type of clinical trial that was actually going to allow labeling 

for pediatric application for a lot of the things that we actually use. 

Despite that, we are talking care of our children, and we need 

the best available data to make those decisions. 

Mr. BURGESS. Thank you. The Chair recognizes the gentleman 

from Illinois, Mr. Shimkus, 5 minutes for questions, please. 

Mr. SHIMKUS. Well, thank you. I am going to follow up with Dr. 

Van Hare first of all saying for my colleagues that the Washington 

University School of Medicine is one of the preeminent institutions 

in our country. And VJC which they are affiliated with, that is the 

go-to for major deals. So welcome. 

Dr. VAN HARE. Thank you. 

Mr. SHIMKUS. And I know that because—please extend my hello 

to Dr. Braverman and Dr. Damiano, who I know personally from 

personal medical stuff. I am a Homer for these folks and I have 

87 

great confidence in your testimony and your word. But I would like 

to follow up on the question in that how often do you assess the 

various information to try to treat kids? I mean so we are talking 

about FDA approval, but you have given testimony about outside 

information to make sure you can best care for kids. How often do 

you go and search outside information to try to bring the best medical care to the kids in the cardiology aspects? 

Dr. VAN HARE. It really depends on what the condition is that 

we are actually trying to treat. I would say that we do have the 

process of developing consensus documents that actually summarize the medical evidence, the clinical trials and things like that 

that actually sort of express and certainly our society, the Heart 

Rhythm Society does this all the time to create these consensus 

documents to give physicians guidance. But you know, I guess pediatrics and also really sub-specialty medicine in general, we take 

care of a lot of very unusual types of conditions that don’t really 

fall under the labels and the recommended uses. And so I guess for 

those less common, more unusual types of situations, we are often 

looking to our colleagues. We are calling around. We are finding 

what has your experience been with this? What has your experience been with that? 

Interestingly, I am a real proponent of the concept of partnership 

between industry and physicians. We often work elbow to elbow 

when we put pacemakers in and when we do different kinds of procedures. They have a lot of information just from their experience 

and it is an important source for us. 

Mr. SHIMKUS. Great. Thank you. Let me go to Ms. Klasmeier. In 

your testimony you talked about, and I quote, ‘‘strict scrutiny’’ the 

test. What does that mean, strict scrutiny in a test in court? 

Ms. KLASMEIER. As a practical matter, Congressman, it means 

the goverment loses. So strict scrutiny is a bit of a legal fiction that 

we indulgence. It reflects the notion that when you examine Government regulation that affects core speech such as political 

speech, it is very, very hard for the Government to sustain its burden of justifying that speech regulatory provision against First 

Amendment is solvent. So as a practical matter, if the court concludes the applicable standard is strict scrutiny, the Government 

loses. 

Mr. SHIMKUS. Maybe my colleague, Mr. Griffith, will follow up on 

that. He is our legal mind here on the committee and does a good 

job. 

Let me finish with Dr. Kesselheim. I am somewhat confused in 

your testimony because you used numerous times the term promotion over and over again in your testimony. But on page 2 of the 

Griffith draft, it explicitly excludes promotional communications. 

Am I missing something? 

Dr. KESSELHEIM. Well, no. I mean I think this is part of an example of how the Griffith draft actually makes something that is 

fairly clear a lot less clear because, you know, if the pharmaceutical company defines something as promotion determines 

whether or not they fall into this safe harbor. 

Mr. SHIMKUS. What do you mean by promotion? You used it numerous times. 

88 

Dr. KESSELHEIM. Sure. When a pharmaceutical company promotes a drug, it goes out and it tells people about the use of 

the—— 

Mr. SHIMKUS. For their ability to sell it? 

Dr. KESSELHEIM. Yes. It goes out and it tells physicians about 

how to use the product and it sort of promotes the use of the drug 

through one of the various advertising—— 

Mr. SHIMKUS. I am reclaiming my time. I will let Congressman 

Griffith kind of hash this out more, but again, on page 2, it is pretty clear. It says communication is not advertising or otherwise promotional in nature. So I just had a concern with your statements 

in your opening statement because you said it over and over again. 

I think it gives the wrong indication of what my colleague is trying 

to do. With that, I yield back my time. 

Mr. BURGESS. The Chair thanks the gentleman. The gentleman 

yields back. The Chair recognizes the gentlelady from Illinois, Ms. 

Schakowsky, 5 minutes for questions, please. 

Ms. SCHAKOWSKY. Thank you. I think it is really important that 

we step back and remember that the FDA approval process really 

is the gold standard, the universal gold standard to determine safety and efficacy. And efforts to undermine that standard are very 

worrisome to me and I think that is what happens in these drafts. 

I think that Ms. Charo put it best in her testimony when she stated ‘‘for complex products like drugs, the marketplace of ideas cannot work properly with unvetted information from a self-interested 

source.’’ 

I mean I think that often this committee is inclined to say whatever PhRMA wants, PhRMA gets. But I want to ask Dr. 

Kesselheim, we have heard compelling testimony, I think, about access for patients to drugs. And so it is very important, I think, for 

you to explain what—-does access trump safety or does it have to 

by having these kind of off-label procedures? It seems to me that 

safety ought to come first, but are there ways to guarantee that 

safety without the process of approval by the FDA? 

Dr. KESSELHEIM. Well, I mean so sure and I think that part of 

some of the testimony that we heard was a little bit disingenuous 

because the access to the products was not defined necessarily by 

the communications that occurred. The access in the case of the 

hepatitis C drugs, the effectiveness of the hepatitis C drugs is not 

a secret. Everybody knew how well they worked. Access to them 

was determined by the high cost of the product, not the evaluation, 

not whether or not there could have been communication in the few 

months before the drug was approved. So I mean I think the issue 

is really about getting high quality evidence or high quality communications out to help inform the market so that patients can 

make well-informed decisions based on the highest quality information that is out there possible. And the way to do that is to make 

sure that a neutral, third party body of experts like the FDA is 

able to vet the information. And I think what we should be doing 

is talking about how to make sure that more information is published, more trials are published, more trials are available, open access, and that the FDA has more power and more authority to review information so that they can make those kinds of determinations so patients can benefit. 

89 

Ms. SCHAKOWSKY. Is there a way for the FDA to move more 

quickly? We heard about 9, 10 years, or whatever? 

Dr. KESSELHEIM. I think if the FDA had more resources, it would 

be able to move more quickly. There are plenty of examples where 

the FDA has gone out and has been concerned about new safety 

issues that emerge, about off-label uses and ultimately goes 

through the process of revising the label to try to integrate those 

kinds of changes. If the FDA had more resources added and more 

people doing that kind of post-market surveillance, label updating 

kind of work, then I think we would get that information out to patients and vetted information out to patients more efficiently and 

more quickly. 

Ms. SCHAKOWSKY. Ms. Charo, one of the most compelling things 

I heard from you saying that, in fact, when you look at these drugs, 

the majority of them, in fact, would probably not meet the test. Am 

I hearing you right? 

Ms. CHARO. You are hearing me correctly, and I believe, in fact, 

it was Ranking Member Green who referenced some of those studies in his opening comments. 

You know, scientific research is often somewhat equivocal for a 

very long time. I think what we are discussing here is really what 

to do in that interim period where the evidence is shifting around. 

Do we presume everything is going to work and therefore everything people want to say is likely to be true and should be allowed 

or are we going to presume that it probably isn’t going to work out 

and we should restrain the speech until we have actually proved 

it will. 

From my perspective, given that the risk of incorrect information 

is that people will actually be harmed, or they won’t go for the effective treatment, they will go for the ineffective one, we need to 

err on the side of caution here and protect the larger population. 

That said, there are certainly going to be some occasions in 

which it turns out that something does work and it would have 

been wonderful if we could have seen it earlier and talked about 

it earlier, but those incidents will be fewer than those in which it 

would be damaging. 

Ms. SCHAKOWSKY. In the last 30 seconds, Dr. Kesselheim, what 

does history tell us about off-label promotion? Are there some 

things we should be recognizing here? 

Dr. KESSELHEIM. Sure, I mean over and over and over again 

throughout history and you don’t even have to go back to the 

thalidomides 50 years ago, more recent history tells us that offlabel promotion drives physician practices in ways that favor the 

drug being promoted, not in ways that favor the overall state of the 

evidence and the overall state of practice. I think that we need to 

be very wary about efforts to try to expand that promotion when 

it covers nonevidenced based—potentially nonevidenced based communications. 

Ms. SCHAKOWSKY. I think we need to, when it comes to patient 

access, discuss more about the cost. Thank you. 

Mr. BURGESS. The gentlelady yields back. The Chair thanks the 

gentlelady. The Chair recognizes the gentleman from New Jersey, 

Mr. Lance, 5 minutes for questions, please. 

90 

Mr. LANCE. Thank you, Mr. Chairman. Let me state that I don’t 

believe any of the testimony has been disingenuous, in my judgment. This is a very difficult issue, and we are trying to balance 

the equities on this committee, and I am pleased that every member of the panel is here, and I do not question the integrity of any 

member of the panel. 

Counselor Klasmeier, do you believe that the standard will be 

strict scrutiny, or will it be rational basis, or will it be some intermediate standard, based upon your professional judgment as a distinguished member of the bar? 

Ms. KLASMEIER. Congressman, my judgment is that the standard 

will be some variation of intermediate scrutiny. 

Mr. LANCE. Intermediate scrutiny, yes. 

Ms. KLASMEIER. And it will be most likely the Central Hudson 

standard with a garnish of heightened scrutiny as a result of the 

Supreme Court’s decision in Sorrell in 2011. 

Mr. LANCE. Yes, that is my judgment as well, and I think that 

there is a history of decisions in this regard that would indicate 

that that is probably where we would be eventually as a matter of 

legal analysis. Thank you. 

Dr. Van Hare, we have all heard that some off-label uses are well 

established in clinical practice, and supported by high-quality evidence, and are the standard of cure for many conditions. From your 

perspective, based upon your distinguished history, how does the 

pieces of legislation before this committee stand to improve care for 

patients? 

Dr. VAN HARE. Well, to the extent that the legislation proposed 

by Congressman Griffith allows or improves the efficiency of sharing data that the device companies and pharmaceutical companies 

actually have, for physicians who are prescribing off-label, I think 

it will actually help. 

Mr. LANCE. Thank you, and other members of the panel are certainly welcome to comment. 

Ds. Khachatourian, what are the odds that if we pass legislation 

we are considering today, sophisticated population health decision 

makers like payers, provider sponsored health plans, pharmacybenefit managers, and other organizations would be misled by unscrupulous drug and device manufacturers who make unfounded 

claims about their products? 

Ms. KHACHATOURIAN. So first let me acknowledge my testimony 

by no means disingenuous. 

Mr. LANCE. I am sure and that is why I raised it. And if I might 

interrupt you, I try to lead by example in the Congress, both on 

the floor and in committee, and I enjoy the testimony of every witness who comes before us. Those who know me know that disingenuous is not a word that I find attractive in vocabulary here on Capitol Hill. Yes, please continue. 

Ms. KHACHATOURIAN. Thank you. So population health decision 

makers and clinicians that we are discussing here are well trained 

to look at things with scrutiny and to determine what level of evidence is acceptable. And during the multi-stakeholder discussions 

that we have had, we did address the need to determine a level of 

evidence and to have an agreement on what is acceptable and nonmisleading. And as evidence continues to evolve and as new theraVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00094 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
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pies continue to emerge, that is the goal, is to develop strict criteria 

that will be used to apply to any level of evidence in order to ensure that it is high level and with the patient’s best interest in 

mind. 

Mr. LANCE. Certainly, and that is what we are attempting to get 

to a place where we can make sure that always there is the greatest standard of care. It is the jurisdiction of the subcommittee and 

ultimately of the full committee to promote the better health of the 

American Nation, and we recognize this is a difficult issue and I 

certainly commend my colleagues, including the gentleman to my 

immediate right, the distinguished Member from Virginia, as we 

undertake an analysis of how best to protect the American people 

recognizing that that is the goal of this subcommittee in a bipartisan nature. I yield back 22 seconds, Mr. Chairman. 

Mr. BURGESS. The Chair thanks the gentleman. The Chair recognizes the gentlelady from California, 5 minutes for questions, 

please, Ms. Matsui. 

Ms. MATSUI. Thank you very much, Mr. Chairman. This committee recognizes the important role that FDA plays to ensure public health and safety as evidenced by the bipartisan User Fee Reauthorization that we intend to pass out of the House this afternoon. 

Now we can’t tolerate efforts to jeopardize that role as patients 

across America who take drugs to treat or cure conditions rely 

upon the FDA to monitor the safety of these drugs and devices. 

I am really glad that we are holding this hearing today to examine issues that arise around information sharing, particularly for 

those so-called off-label use and what could be done to alleviate 

those issues without detracting from FDA’s ability to regulate safety. 

I am particularly interested in the situation that many rare disease and cancer patients find themselves in. As many as one in five 

prescriptions are written for drugs off-label, meaning that they are 

prescribed for a condition or population that has not been FDA-approved as safe and effective. Oftentimes, off-label drugs are the 

only treatment available and even the standard of care for rare disease patients with limited options. 

Ms. House, thank you very much for your advocacy on behalf of 

cancer patients. Can you please discuss prevalence of off-label use 

in cancer patients? 

Ms. HOUSE. So there was a physician posted by the Friends of 

Cancer Research just yesterday that indicated that the use in cancer off-label was close to 80 percent. And part of—one of the problems that I just wanted to raise is I was looking at some other discussion is I am going to give you an example. It is an older example, but it really talks about how the current labels are out of date. 

There was a time around 2000 where this is the time prior to personalized medicine, so it was still in the era of poisons for cancer, 

that there was a combination being used off-label as standard of 

care for the treatment of lung cancer. That particular combination 

failed at that time 13 Phase 3 trials which is the gold standard for 

the evaluation for the FDA, yet it continued to be used standard 

of care for many, many, many years beyond that. 

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This morning, I went on the FDA website and pulled up the label 

for the lead drug in that and today in 2017, still has not been updated to reflect the use of that combination which is a problem. 

Ms. MATSUI. It is a problem, right. Now, you know when a family 

gets a cancer diagnosis, I think the world stops. And you are sort 

of grasping at what can we do? And I think we all go to the internet. That is where we go right now. 

What types of information is generally available to patients and 

their providers when a drug is used off-label and even when you 

are an educated consumer, you really kind of hit a brick wall. What 

kinds of solutions might you recommend to address these challenges? 

Ms. HOUSE. I think creating solutions that again are tailored to 

the stakeholder, to their literacy level, to their educational level. 

There is really no reason why we can’t create forums that would 

be peer reviewed, scientifically sound analysis, and presentation of 

clinical data. What it does prevent then is people going to the internet and getting into a chat room that may be facilitated out of another country or by somebody who has absolutely no medical background. And we see that happening all the time. And furthermore, 

if a patient calls a pharmaceutical company and says I am a patient, can you give me information about XYZ, the response will almost uniformly be, I cannot answer your question. You will have 

to go speak with your doctor. 

Ms. MATSUI. Thank you very much. Ms. Charo, I know you have 

concerns about the legislation that we are discussing today. Are 

there ways that we can refine the legislation to reach our shared 

goal of promoting public safety by increasing patient access to safe 

and effective drugs? I think there is information out there and you 

know, we are in a time now where there is much more research 

and innovation and I would hate to just have a hard and fast rule 

regarding this. 

Ms. CHARO. Thank you. I completely agree with you that there 

are other avenues that need to be explored. For one thing, it may 

make sense to try to distinguish those areas where off-label use 

really is a necessary and important part of medical care as we just 

heard in the area of cancer, and some other areas there it really 

is not as prevalent and is not as needed. And I would suggest that 

pediatrics may be another good example. 

And the Congress has made great strides in trying to create new 

systems for both incentives and even possibly rewards for continuing the necessary research to find what really is safe and effective, for example, in the pediatric population. Working on making 

sure that there is a proper incentive and reward to fill in the gaps 

in those areas would be a good step forward and might accomplish 

many of these goals without some of the risks that are intended 

upon some of the ambiguities and what constitutes promotional 

marketing or what constitutes accurate information. 

Ms. MATSUI. Thank you. I have run out of time. I yield back. 

Mr. BURGESS. The Chair thanks the gentlelady. The gentlelady 

yields back. The Chair recognizes the gentleman from Indiana, Dr. 

Bucshon, for 5 minutes for questions, please. 

Mr. BUCSHON. Thank you, Mr. Chairman. I was a practicing 

cardiothoracic surgeon prior to coming to Congress and I just have 

93 

a comment, not a question, but the medical community is relatively 

small and I think Dr. Van Hare said there is 300 pediatric cardiologists. There is about 4,500 to 5,000 cardiac surgeons. Information 

travels quickly. Physicians are always looking for better ways or effective ways to treat their patients whether it is on label or offlabel and information passes quickly. 

Frustration with labeling can be really high amongst different 

physician communities because of the delay in updating what may 

or may not be FDA-approved. Patients are desperate and are getting information potentially from incorrect sources including the 

internet as has been pointed out and so I would suggest that we 

definitely need reform so that patients have the opportunity to get 

more accurate information. 

With that, I am going to yield the remainder of my time to Mr. 

Griffith. 

Mr. GRIFFITH. Thank you very much. I appreciate it greatly. Let 

me first say that I appreciate everybody being here today and appreciate all of your testimony. I am open to continue to work on 

the language to make sure that we get it right. So that is something that I would invite you all, if you have issues with the language that we currently have, please get those suggestions to us 

because we want to try to do this in the best way that we can. We 

do believe that we need to do something on a legislative side. 

Also, Mr. Chairman, I have some letters in support of the bill 

and a draft language, and, if I could have unanimous consent to 

enter those into the record, I would appreciate it. 

Mr. BURGESS. If the gentleman will share those with us, I will 

seek unanimous consent in a moment. 

Mr. GRIFFITH. I also want to make sure that we are all working 

on the language that we currently have. And so what the bill says 

is, when we are talking about communication, if you look on page 

2 it says, ‘‘(a) the communication is not advertising or otherwise 

promotional in nature; (b) the communication is supported by competent and reliable scientific evidence.’’ And then (c) and this was 

to address some of the concerns that have been raised here today, 

we put this language in: ‘‘The communication clearly discloses appropriate contextual information about the data presented including information about limitations.’’ And I probably should put numbers in front of these. ‘‘(1) Limitations of the data; (2) the scientific 

and analytical methodologies used; and (3)’’—and I think very importantly—‘‘any contradictory data or information known to the 

manufacturer or sponsor.’’ 

We are never going to solve all of the problems if somebody is 

not doing what they are supposed to do, but our intent is to try to 

make sure that both sides are presented. I think somebody mentioned that earlier in their testimony, that both sides are presented 

and that the negative evidence is out there as well. 

And then we talk about situations related to the rare diseases. 

Cancer has been mentioned today and the children because one of 

the problems you have in those situations and Dr. Van Hare, you 

touched on this is that there may not be a sufficient number of patients to actually warrant doing a clinical study. Nothing compared 

to what you deal with your families Dr. Van Hare, but my son who 

is now 11 had 2⁄3 of his body covered with eczema when he was 

94 

about 3 months old. I kept telling my wife because of the history 

in the family we have allergy problems, honey. We got him to an 

allergist. Between the cream that worked for me that my pharmacist knew, between the steroid creams, between the antihistamines that they gave him, we were able to control that situation. 

We still have issues there. But for a child under the age of 2, there 

were no—some of that might have been on-label, but most of that 

treatment was off-label, so I appreciated Ms. Charo saying that we 

ought to take a look at that, because I think those are the two hotbutton areas. But that doesn’t mean we should exclude others. 

I was very curious, too, about this whole agent concept that is 

going on where you can’t go and tell the 300 other doctors, Dr. Van 

Hare. Could you speak on that briefly, and I have only got a 

minute left of this time period. 

Dr. VAN HARE. Yes. It has to do with how CME or Continuing 

Medical Education is defined. CME is actually a safe harbor. If I 

am speaking at a conference that is sponsored by an accredited 

CME provider, like the Heart Rhythm Society or the American College of Cardiology or some other group, I can say whatever I want 

and I can talk about off-label indications as much as I want. If I 

am actually speaking at a conference that is actually sponsored by 

the pharmaceutical company or the manufacturer, then I basically 

am an agent, or considered an agent. 

Mr. GRIFFITH. So if on the podium somebody asks you about a 

catheter to be used in a child that might be off-label, you could 

then be deemed and the company could be deemed that you are 

their agent and then be in trouble under the current rules of the 

FDA. Is that correct? 

Dr. VAN HARE. That is my understanding. 

Mr. GRIFFITH. That is my understanding also. All right, Ms. 

Klasmeier, my friend and colleague from New Jersey, Mr. Lance, 

did a great job of going through the intellectual. Let us translate 

that into human regular English. That means that if you bring 

that example to the courts, FDA is most likely going to lose, 

wouldn’t you agree? 

Ms. KLASMEIER. I would agree and I would go one further. FDA 

did lose that case. That was the Washington Legal Foundation decision in 1998 and the upshot of that is that the court found it unconstitutional for the Government to purport to restrict the identity 

of the speakers that could participate in those kinds of continuing 

education events that Dr. Van Hare described. 

Mr. GRIFFITH. Thank you very much. I yield back to my colleague. Thank you. 

Mr. BUCSHON. I yield back. 

Mr. BURGESS. The gentleman had a unanimous consent request 

and I sought counsel from the other side of the dais, so without objection, so ordered if that unanimous consent request still stands. 

[The information appears at the conclusion of the hearing.] 

Mr. GRIFFITH. It does, and I apologize. I just saw my time taken 

away. 

Mr. BURGESS. Very well. The Chair recognizes the gentlelady 

from Florida, Ms. Castor, for 5 minutes for questions. 

Ms. CASTOR. Well, thank you very much, Mr. Chairman, for calling this hearing. I think allowing drug companies and manufacturVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00098 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
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ers to market their drugs and devices for unapproved uses would 

be very dangerous for American families, American consumers. It 

would reduce the incentive for them to go through FDA’s approval 

process and reduce the incentive to go through clinical trials that 

really just test whether or not a product is safe and it is effective. 

FDA’s approval process right now is the gold standard for safety 

and efficacy. 

The FDA Commissioner, Dr. Gottlieb, has said the most important incentive to developing useful information remains the ability 

for companies to market drugs based on what can be proven scientifically. Now this is not a hard and fast rule because I have 

learned today and reviewing your testimony, there are safe harbors, but nevertheless, Professor Charo, some contend that we 

must revisit this regulation of off-label promotion because the trend 

in the courts is that restrictions on off-label promotion run afoul of 

the First Amendment. I think this is a stretch. Does the First 

Amendment limit FDA’s responsibility for scientific review? Does it 

limit FDA from restricting promotion of unapproved uses? If not, 

what avenues do medical product manufacturers have to communicate about such uses? 

Ms. CHARO. Well, we have seen some cases that have touched on 

these things from the fringes, but you don’t actually get cases that 

touch on it directly. For example, in one case that is frequently 

cited for the suggestion that the Constitution prevents the FDA 

from restricting truthful speech, at issue at the time was not truthful speech, but simply off-label speech and the FDA premised its 

entire case on the fact that the speaker had been discussing an offlabel use and never really talked to the issue about whether or not 

the speaker’s comments had been true. 

The problem here has simply been that it is really and I hope 

that Mr. Griffith’s staff is still around for this, the problem is that 

no company is going to have all the information about all the studies that are being done at that time including those that have negative results because of various rules about confidentiality of information. The FDA may be in possession of all the information, but 

not necessarily every company. So even with the best of intentions 

to be conveying what they believe to be truthful and contextualized 

information, there is the risk that that actually is missing large 

areas of data that would suggest that the studies they are discussing are not, in fact, going to be indicative of a truly safe and 

effective drug at the end of the day. This is why there really is a 

substantial public interest which is one of the key elements in the 

restriction of speech to the current system. 

And the alternatives that have been presented, unfortunately, I 

believe offer risks to public health that dwarf their benefits which 

is why the second rung, the second prong of these tests which have 

to do with whether or not the Government can find an alternative 

way of achieving its goals I think show that really the current system is probably the best way, tweaking, yes, but the removal of 

many of these restrictions, I don’t believe is necessary in order to 

meet the Constitution test. 

Ms. CASTOR. And there seems to be debate on whetherthe Griffith proposal would restrict scientific exchange under the safe harbor. What is your view of this and the Griffith discussion draft? 

96 

Ms. CHARO. You know, I think that the text does attempt does 

attempt to isolate what is nonpromotional and protect that while 

continuing the prohibit promotional language. I think that the difficulty here is that the very notion of what is promotional is actually somewhat ambiguous. We now know, for example, that it is 

possible to tweak how various results come up on the internet, 

whether or not it is the first, second, or third thing you see on the 

page. If there is a tweaking algorithm, does that constitute promotional if all it does is raise your particular data to the front of 

the page? These are the kinds of subtle questions that can both 

make the language ambiguous despite our efforts and also from my 

perspective, suggest that it is better to have the flexible tools of 

guidances that can be negotiated over time with the constantly 

changing nature of communication rather than the somewhat more 

rigid tools of regulation and legislation, let alone having courts do 

it 17 years after the fact and leave everybody uncertain for that 

long period in between. 

Ms. CASTOR. Dr. Kesselheim, do you have a comment on this 

topic as well? 

Dr. KESSELHEIM. I mean I also agree that the way that this discussion draft is written provides substantial leeway for companies 

to interpret these various provisions in ways that are favorable to 

their particular advertising strategy. 

Ms. CASTOR. And at the cost to public safety. 

Dr. KESSELHEIM. And at the cost to public safety. 

Ms. CASTOR. Thank you. I yield back. I am out of time. 

Mr. BURGESS. The gentleman yields back. The Chair thanks the 

gentlelady. The Chair recognizes the gentleman from Georgia, Mr. 

Carter, 5 minutes for questions, please. 

Mr. CARTER. Thank you, Mr. Chairman. And thank all of you for 

being here. Certainly, an important subject. 

Dr. Khachatourian, you are a pharmacist, as am I. And I can tell 

you that after 30 years of practicing pharmacy, certainly side effects are—we call them side effects. And you know, it has always 

been interesting to me why we call them side effects because essentially they are effects of the drug, but they are not what we want 

it to do, so we kind of label them as side effects. 

I noticed in your statement, in your testimony, in your written 

testimony that you feel like the Pharmaceutical Information Exchange would be helpful and useful and there is some debate on 

whether it should be evidenced based or whether it should be information based. And I noticed that you said that it should be based 

on information only, well, not only, but basically. Can you kind of 

elaborate on that? 

Ms. KHACHATOURIAN. Absolutely, thank you. So when we think 

about evidence, there are established criteria for evidence as far as 

what constitutes a clinical trial and the acceptable level of evidence 

for FDA approval. When I talk about information, information may 

include financial models, may include other information that does 

not quite meet the level of evidence that one might traditionally 

think. So when we talk about information, if I am able to discuss 

with my clinical colleagues at a manufacturer what models might 

be available, what sub-populations were studied and what level of 

97 

information might be available that can help me to make more effective decisions, that is what I mean by information. 

And again, I will reference the multi-stakeholder forum where 

we discuss developing criteria that will set the foundation for what 

that information might entail and what level of quality of information could be deemed acceptable. 

Mr. CARTER. You also mentioned in your testimony that a very 

proactive pharmaceutical information exchange would lead cost 

savings. It could lead to cost savings for patients. So in that respect, how can we assure that the cost savings are going to be 

passed on to the patients if we don’t have transparency within the 

prescription benefit managers and the other middle men that are 

included so often in these scenarios? 

Ms. KHACHATOURIAN. Sure. While cost is an aspect of evolving 

and emerging therapies and treatments that are coming, cost is an 

aspect that needs to be discussed. However, with the exchange of 

information it makes us more effective in the use of the funds that 

we have available to make benefit decisions. So when we are structuring a benefit based on value, that is what value will be conveyed 

to both us as the payer as well as the patient. So ultimately from 

a cost discussion, that is, in turn, outside of the transparency 

which is a little bit of a different discussion. 

Mr. CARTER. I am not sure I understand how it can be a little 

bit of a different discussion. Because I believe truly that it can 

have cost savings to the patient if we have transparency within the 

system and I don’t see how it can be if we don’t have transparency. 

Ms. KHACHATOURIAN. So I absolutely acknowledge transparency 

is an important factor. However, the information exchange between 

a payer, as well as the manufacturer, will help us to make better 

decisions and with a limited pool of money that we are able to allocate to benefit design. We try to make the most cost-effective decisions on behalf of those patients that we serve, so in turn, the cost 

savings are passed to the patient as the ultimate user of our benefit design. 

Mr. CARTER. OK. I will move on. Dr. Van Hare—and thank you 

very much for being here, Dr. Khachatourian. 

Dr. Van Hare, I have seen in my practice over the years, particularly with prescription drugs, a lot of off-label uses, if you will, in 

pediatric patients. And I just want to get your feeling on the value 

of that? Because I have seen it first hand that it has been very valuable. 

Dr. VAN HARE. Yes, well, so I would say it is essential, in fact, 

for most of what we do, particularly in the pediatric cardiology 

area. But I mean I do think we have reservations about it. When 

people make decisions based on information they get from like one 

other colleague who used it once on some patient, that is very, very 

sort of limited. But I would say that certainly we have to do it. We 

have no choice but to do off-label prescribing in a lot of situations. 

And we would prefer to have the best possible information. 

We also use what is known about the use of these medications 

in other age groups, particularly adults, or other particular conditions and basically extend to these particular populations. That 

may or may not be valid as some other members of the panel here 

98 

have talked about. But absent better data, it is all we actually 

have. 

Mr. CARTER. Great. Thank you all very much for your participation here today. A very important subject I can tell you. Many 

years of practice in pharmacy, we have used many drugs that were 

not indicated or at least not approved for certain therapies that 

have been very, very beneficial to patients. 

Thank you, Mr. Chairman. I yield back. 

Mr. BURGESS. The Chair thanks the gentleman, the gentleman 

yields back. The chair recognizes the gentlelady from California, 

Ms. Eshoo, 5 minutes for questions, please. 

Ms. ESHOO. Thank you, Mr. Chairman. And thank you to all of 

the witnesses. I also want to thank our colleagues who are offering 

the drafts and to Mr. Griffith, I especially appreciate your openness 

to suggestions and I think that that is very important. 

Over all the years I have been in Congress, this is my 25th year, 

and have worked with medical device manufacturers, worked with 

the biotechnology industry, done legislation that has reformed how 

medical devices are approved, passed legislation signed into law, 

but I can’t remember which President relative to pediatric medications, and improved that system for children. This issue, the issues 

that are being discussed here today, no one has ever raised with 

me. So this is the first time I am hearing about it. But it is good. 

It is a discussion, but it still says something to me that no one has 

contacted me about this. So I don’t think it is exactly a burning 

issue. 

Number two, it is my understanding that what is being offered 

by our two colleagues today were supposed to be a part of the overall approval for the FDA, but were pulled because they were controversial. I can hear today where the controversy is coming from. 

That is legitimate and I am glad that it wasn’t in the larger bill, 

because they really didn’t belong there. This cake has not been 

baked yet. 

Now it is my understanding that in one of the discussion drafts, 

that there is no clear list of what qualifies as scientific information. 

Now that is foundational to me, scientific information. Not who is 

gabbing and saying what from a given industry. That is always interesting and those discussions take place. But we are dealing with 

over 200 million people in our country and these words are going 

to walk into their life. This is a huge responsibility. They don’t 

know that we are here today. They don’t know any of our names, 

but we have the public interest in the safety and the efficacy of 

what takes place on their behalf. 

To Ms. House, I am not sure, are you in favor of the two discussion drafts? Yes or no? 

Ms. HOUSE. We have not taken a formal position on either. 

Ms. ESHOO. That is fine. 

Ms. HOUSE. Neither of them are perfect. 

Ms. ESHOO. Yes, well, but I couldn’t tell from your testimony 

whether you were for or against or where you were. 

Ms. Charo, thank you for your testimony. I think that you have 

set down the importance of where the information comes from and 

that it can’t be haphazard. There has to be a final kind of resting 

99 

place that has all of the information for people in our country that 

can be used. 

I don’t think anyone has really made the case here to take it outside of the FDA. Maybe I am missing something, but I haven’t 

heard that. 

To Ms. Khachatourian—I love the I–A 09N; I share either your 

husband’s heritage or yours—when you spoke about hep C, how 

many patients were excluded from treatment? 

Ms. KHACHATOURIAN. So while I can’t speak for all payers and 

all—— 

Ms. ESHOO. No, but you used that as an example, hep C. So we 

know, it is a company I am very familiar with in my district. I have 

worked with them. They have presented a cure which we are not 

accustomed to. It is expensive. But who was left out, according to 

your testimony? 

Ms. KHACHATOURIAN. Sure. So in the initial approval, we approved treatments according to the label. So for the first time in 

hepatitis C, we saw the criteria, the approval criteria change multiple times. So initially it excluded patients that might have cirrhosis. It initially excluded patients that according to the FDA 

label—— 

Ms. ESHOO. How do these drafts fix that? 

Ms. KHACHATOURIAN. So with the drafts, we could understand 

that there would be evidence published that would add additional 

clinical evidence to indicate effectiveness of treatment in those subpopulations although at the time of the initial approval, that evidence was not available for decision making. 

So in my medical space—— 

Ms. ESHOO. You are saying people were excluded, but you don’t 

know how many? 

Ms. KHACHATOURIAN. I can’t speak to the exact number globally. 

However, within our population, Medicare is who defines our coverage criteria. So when we submit our criteria to CMS for approval, 

it has to be according to the Part D coverage, what is listed in the 

FDA-approved label. So we cannot cover off-label unless it is within 

the oncology space. When we are talking about a Part D indication. 

Ms. ESHOO. I still don’t know who has been injured in this according to your testimony. That is why I am asking you, and I still 

don’t know. But I appreciate your trying. 

Thank you, Mr. Chairman. 

Ms. KHACHATOURIAN. If we expand the discussion to commercial 

payer outside of Part D, the additional patients that were denied 

treatment. 

Ms. ESHOO. But you don’t know how many. 

Ms. KHACHATOURIAN. I don’t coverage commercial insurance, 

however, that is something I would be happy to look into for you. 

Ms. ESHOO. Thank you. 

Mr. BURGESS. The gentlelady yields back. The Chair thanks the 

gentleman. The Chair recognizes the gentleman from Virginia, Mr. 

Griffith, 5 minutes for questions, please. 

Mr. GRIFFITH. Thank you very much. I appreciate it. Ms. 

Klasmeier, we have had some discussions and I know this is not 

the Judiciary Committee, but this is where the law touches everything. And so as we consider legislation in this area, just so the 

100 

committee knows as a whole and that I am better educated, what 

points should we be taking away from the various judicial cases in 

considering First Amendment challenges to the FDA’s regulations? 

And what should we be looking out for? So that is Part A and Part 

B. What should we be looking out for to make sure that we get it 

right and that we do it where it is constitutional as we draft this? 

Ms. KLASMEIER. Thank you very much for the question, Congressman. I think a very important take away from the case law 

is the need for clarity and that point arises out of the intersection 

of the Fifth Amendment case law and the First Amendment case 

law. I think there is a lot of discussion about the First Amendment, 

but the due process laws requires clarity and precision, requires 

rules that give regulated entities clear notice on an a priori basis 

of what conduct is prohibited versus permitted. 

Mr. GRIFFITH. And let me, I don’t want to cut the rest of the answer off, but let me interrupt up there because that is one of my 

pet peeves. So many times people think that means we have to define every word in the bill, but if there is no definition in the bill, 

then the courts use the normal usage of the English language or 

if it is a term of art, the term of art in this case from the medical 

community. Is that not correct? 

Ms. KLASMEIER. It is absolutely correct, sir. And just to augment 

your observation, there was a conversation earlier this morning 

about the definition of claim and promotion and where do we draw 

the line. And I understand why there may be some misunderstanding around that, but I have to say as a practitioner in this 

area—and I also have to say I suffer from a little bit of an existential crisis because the news that this is not a hot-button issue or 

something that needs to be resolved makes me question what I 

have spent the last 20 years of my life doing. But that is an aside. 

Mr. GRIFFITH. No worry, her phones will be lit up before the day 

is done, I am sure. 

Ms. KHACHATOURIAN. But there is among those of us who practice in this area day in and day out a very well-understood line between promotional speech and nonpromotional speech. So I think 

the legislative measures that we have been talking about this 

morning would just under foundational interpretive principles be 

examined against those background legal norms. So there is a very 

rich body of administrative precedent from FDA in addition to case 

law and the statutory foundation of the measures that you are 

talking about. We know what these words mean. So I agree to the 

extent that you are saying we ought not to feel overly anxious 

about those two or three words. I think folks who are battle tested 

in this area know the difference between promotional speech and 

nonpromotional speech and can advise clients accordingly. 

Mr. GRIFFITH. And I kind of got you off track there for a second. 

You were talking about the First and the Fifth. I am going to let 

you go back to is there anything else on that you wanted to touch 

base on that I distracted—— 

Ms. KHACHATOURIAN. Many things, but I will try to limit it to a 

big-ticket item, which is it is increasingly obvious from the case 

law, which goes back to at least to 1976, that it is very hard for 

the Government to defend any speech regulation that affects accurate communication regarding lawful activity. I think we tend to 

101 

get hung up on the kind of Central Hudson test and prongs and 

that sort of thing. But just to sort of bring it down to its essence, 

if the Government wants to restrain accurate speech about conduct 

that is permitted—and off-label use is not only permitted in almost 

all cases, it is by Federal law, it is also the standard of care in 

many instances—it has really got an uphill battle. 

I think there is probably a way for all of these very challenging 

and complex policy considerations to be balanced in a smart way 

that takes account of the First Amendment backdrop, and I think 

the measures that we are talking about today have done an admirable job of strengthening that balance. But there is a little bit of 

a thumb on the scale, if you like, as a result of years and years 

of case law going back to at least 1976 against anything that would 

purport to prohibit accurate speech about lawful activity. 

Mr. GRIFFITH. And while I wasn’t as concerned about the freedom of speech, per se, although it is very important to me, when 

I put in that clause that they have to put in the contradictory information, as well, and the contextual information, that actually 

shores that up from a free speech standpoint as well, because we 

are saying you have to present—if you are going to present—you 

have to present both sides of the data. Isn’t that accurate? 

Ms. KHACHATOURIAN. Absolutely accurate, yes, sir. 

Mr. GRIFFITH. I appreciate that. And it does make me worry and 

I know it is not their field of expertise either, but you indicated 

there was a late ’90s case that clarified some of this. I think the 

bill clarifies it more, but I am just curious why the FDA keeps 

going down this pathway when they have lost a number of cases 

over the years, if not in this circle of the three-ring circus, in another circle of that same circus under the same tent. 

Ms. KHACHATOURIAN. Yes, well, it is concerning because you 

have not only the cases that we have been talking about here, 

Caronia and Amarin and Pacira, but also on the dietary supplement side of the house, a great many cases from the DC Circuit, 

a lot of other sources of precedent that draw into question the constitutionality of the current scheme. That said, I think there are a 

lot of undeveloped arguments that we have been, in industry, waiting with bated breath for FDA to articulate and there was a memoranda that FDA lodged in one of its administrative dockets in January, right before the inauguration that purported to explain for all 

the world to see how the agency thought through these constitutional issues and it was a little more than a defense of the status 

quo. 

I think there is a lot of room for optimism in the coming months, 

particularly with the involvement of this subcommittee and the 

Congress, generally, that FDA will do a better job of explaining and 

including stakeholders in a conversation about the constitutionality 

and constitutional issues associated with this current regulatory 

scheme. 

Mr. GRIFFITH. I appreciate it and yield back. Thank you, Mr. 

Chairman. 

Mr. BURGESS. The Chair thanks the gentleman. The Chair 

thanks Ms. Khachatourian for her optimism. We always welcome 

optimism on this subcommittee. 

102 

The Chair now recognizes the gentleman from Maryland, Mr. 

Sarbanes, 5 minutes for questions. 

Mr. SARBANES. Thank you, Mr. Chairman. I want to thank the 

panel. This is a really complicated issue, I am finding. I sat here 

through the entire testimony. And certainly the ability and the 

internet is kind of at the center of this now for people to get hold 

of information about beneficial off-label use of drugs and medical 

devices much more readily than obviously they ever could before, 

is creating some pressure to figure out a way to make that opportunity more available to people. The fast distribution of information 

can also allow for the fast distribution of bad information and lead 

to poor decision making. But I understand that Congressmen Griffith, Guthrie, and others are trying to respond to pressure and 

often it comes from patients that are seeking a solution. 

What I am concerned about is that you could solve the way they 

are proposing for this pressure, or you could solve perhaps by 

building more capacity inside the FDA. So what I am interested in 

hearing about, I don’t want us to take a shortcut. I don’t want the 

reason we are reaching for the proposed solution here to be that 

we have overlooked the opportunity to build more capacity in FDA 

as a way of solving for this, and perhaps solving for in a way that 

protects public safety better than taking the alternative route. 

So I wonder, Ms. Charo, maybe you could begin here. Speak to 

that issue. How do we explore fully the opportunity to build capacity in FDA to respond to the pressure we are talking about? Can 

that be done? If so, what are the ways in which it can be done, et 

cetera? 

Ms. CHARO. Well, first, I am going to second what has been said 

by others here which is that FDA, just in terms of sure personnel, 

would certainly benefit from having more people able to act on data 

as it is coming in and everything would move more rapidly with 

no question. But we shouldn’t restrict ourselves only to FDA. I 

mean one of the things we have been struggling with here is that 

there are areas in which the incentive systems that currently exist 

are inadequate for driving the research that we all agree would be 

ideal to figure out what really works and what does not. Pediatrics, 

rare diseases are two very good examples. 

Now we have some new tools. Congress have given things like 

priority reviews and extended patent periods as incentives, but we 

have yet to completely explore the full range of tools. Antibiotics 

is another example where the Infectious Disease Society of America 

has been pointing out for years we could use rewards, milestone rewards. We have not talked about NIHI funding for direction of 

studies that would look at things like off-label uses that are hinted 

at already and that need to be confirmed. 

In other words, we need not restrict ourselves to only one tool 

which is to pull the industry slowly to do the research under the 

threat of not being able to market. But we could bring to bear a 

combination of tools to get the information developed more rapidly. 

And ideally, then everybody would benefit because we would have 

a wider range of applications, but we would have more confidence 

that they have been tested in a way that is comprehensive and objective and has been vetted by independent eyes. 

103 

Mr. SARBANES. I appreciate that. I mean, I worry a little bit that 

I don’t completely trust the industries we are talking about here 

to restrain themselves if they get—if there is an avenue for aggressively pursuing a particular product’s appeal out there in ways that 

may compromise public safety, and I worry about a bunch of camels starting to get their noses under the tent. So I understand the 

desire to try to accommodate people’s interest in pursuing this, but 

if there are other ways we can respond to that, without sacrificing 

some of these concerns about public safety, then I think that we 

ought to pursue those and explore some of the additional tools that 

you have suggested, perhaps. With that, I yield back. Thank you. 

Mr. BURGESS. The gentleman yields back. The Chair thanks the 

gentleman. The Chair recognizes the gentleman from Florida, Mr. 

Bilirakis, 5 minutes for questions. 

Mr. BILIRAKIS. Thank you, Mr. Chairman. I thank the panel as 

well. I have a question for Ms. House. Again, thank you for your 

testimony. Throughout my time on the Energy and Commerce 

Committee, I have been involved with the rare disease community. 

There are about 30 million Americans—and there are 7,000 rare 

diseases—30 million Americans have a rare disease, which includes 

pediatric cancers. And I understand there are about 500 FDA-approved treatments. Correct me if I am wrong. 

Do you think that many of these 30 million Americans are taking 

medications off-label? For Ms. House, please. 

Ms. HOUSE. Yes. Yes, I do. I do. In my written comments, I have 

referenced in particular lupus, and if you look at the FDA site right 

now, there are only four drugs that are approved for lupus. And the 

approvals of those go back into the mid-1900s. So when you look 

at the drugs, aspirin was approved first in 1948, followed by 

steroids, and there was no drug listed. There was an antimalarial 

that was approved in 1955. And finally, a new drug approved in 

2011. So if you are a patient living with lupus, you are likely not 

getting aspirin as a therapeutic option for your particular disease. 

And certainly when you look at cancer, there is a reason why there 

is such a high rate of pediatrics in cancer clinical trials, and it is 

because they don’t have a lot of other options available to them. 

Mr. BILIRAKIS. Thank you, so there are other examples out there. 

So a large percentage of the 30 million are taking medication offlabel. 

Ms. HOUSE. Arthritis is another good sample. If you look at the 

label of methotrexate, for example, you will see that the label 

doesn’t reflect the broad use of that particular product and you can 

probably speak to that better than I could. 

Mr. BILIRAKIS. Thank you. I am here with a young Floridian 

from the Miami area who told me about how she came down with 

ITP, a condition where her body destroyed her platelets. And I 

have conversed with her over a long period of time on these particular issues. I have sponsored the Open Act and we are working 

together. 

She had to become an expert. She became an expert on ITP, and 

she really became her own doctor and found a treatment, really extraordinary. She was able to find a drug that could treat her condition. The drug was FDA-approved for non-Hodgkin’s lymphoma and 

rheumatoid arthritis, but not for ITP. 

104 

After a long conversation with her physician, we were able to 

pursue that course, the off-label treatment, and it was very successful. She comes to DC on a regular basis as an advocate for 

cures and treatments for rare diseases. 

Ms. House, does it make sense to withhold information from physicians and not share truthful medical information that could say 

a person’s life? And who should be in charge of a patient’s treatment? The patient working with her physician or again, a bureaucrat? If you could answer that question, I would appreciate that. 

Ms. HOUSE. Well, you know, we have spent 35 years trying to assist patients to become equal participants and empower participants in their care, so I am going to answer that as the patient 

needs to be quarterback of their care, working with their particular 

physician. 

I will say that it is incredibly important though that the information that is provided, both to patients and to physicians, is fair balanced. I worked in the pharmaceutical industry for a period of 

time, so I also understand the bright white lines between what is 

promotional and what is nonpromotional and we are not talking 

about shipping patients or physicians glossy pieces of information 

on off-label uses or other additional information, but we have to 

provide for them and whether that is, I do agree that there are alternative solutions, whether it is through the FDA, whether it is 

through a professional society, whether it is through a third party 

peer reviewed entity, we have to get to a point where we are providing that data set to people who are making decisions, including 

patients who are making more and more of their care decisions as 

you have referenced. 

Mr. BILIRAKIS. Thank you. Agreed. Dr. Van Hare, in your practice, you deal with children and adults who suffer from a heart condition such as the congenital heart and some are congenital heart 

in nature. I sponsored a bill to reauthorize a congenital heart program and it went through this committee and hopefully on the 

floor as soon as possible. 

If you have a child who comes to the hospital with a heart condition, you might need to do a surgical procedure. How common is 

it for medical devices to be approved for use in children? 

Mr. BILIRAKIS. Well, as I understand, most medical devices, at 

least that I use in the cardiology sphere are not specific to children 

or adults. They are more specific to actual specific arrhythmias. 

And as I talked about in my oral testimony, a lot of what we take 

care of, the devices, in fact, are not labeled for those particular sort 

of conditions. 

I will say that you sort of raise the issue of surgery for congenital 

heart disease. We often think about surgery as basically correcting 

a problem. But those patients need to have a cardiologist for the 

rest of their life and one of the biggest problems if they develop 

heart rhythm issues and those heart rhythm issues are often very, 

very difficult to take care of and so we are reaching for whatever 

we can find to treat those things most effectively. And we use technology and we use devices that have been approved for other indications for this particular situation. 

I just want to emphasize that we keep talking about pediatrics 

as sort of being an important issue and I am a proud pediatrician 

105 

and I believe that. But I think pediatrics is a special case of a larger issue which is there are a lot of patients that devices and drugs 

have been developed for other indications. We have to find a way 

to take care of our patients. I think pediatric diseases, but also rare 

diseases, and anything that is kind of on a cutting edge of what 

we are doing medically to treat things are going to fall into this 

discussion. 

Mr. BILIRAKIS. Thank you very much. I yield back, Mr. Chairman. 

Mr. BURGESS. The Chair thanks the gentleman. The gentleman 

yields back. The Chair recognizes the gentleman from New York, 

Mr. Engel, 5 minutes for questions, please. 

Mr. ENGEL. Thank you very much, Mr. Chairman. I have long 

been an advocate for those suffering from rare diseases. I was an 

author of the ALS Registry Act and the two most recent Muscular 

Dystrophy Care Act reauthorizations and I know how much relief 

and encouragement new therapies can bring to rare disease patients. And I think I speak for everyone on this subcommittee when 

I say that all of us want to do what we can to bring effective and 

potentially life-saving treatments to patients as quickly as possible, 

but it is absolutely critical that we ensure our actions do not compromise patient safety. 

Efficiency is a worthwhile goal that we all share, but as we strive 

to hasten the delivery of new treatments, safety and effectiveness 

must always be paramount and that is why this hearing is so important. Any action by this committee needs to take into account 

the input of expert witnesses who can speak to the potential implications of our actions. And that is what we have, Mr. Chairman, 

in our panel. And so I want to thank today’s witnesses for being 

here and sharing your insights. 

Let me start with Ms. Charo. During your testimony, you noted 

that ‘‘approval of a drug for labeled’’—I am quoting you—‘‘indication does not mean it will be safe and effective for off-label uses.’’ 

And that ‘‘additional studies are needed to explore them.’’ 

Now it would seem to me that if a manufacturer wished to communicate about an off-label use for a product that manufacturer 

must already have reason to believe that this product is safe and 

effective for the given off-label use. So if there is already evidence 

supporting an off-label use, can you explain why additional studies 

would be necessary? 

Ms. CHARO. Of course. And I think other people on this panel are 

even more expert than I in research trial design, but the reality is 

that evidence comes in many forms and often it is based on small 

numbers of people with very homogenous kinds of situations. But 

in the real world, you need larger numbers of people with a wider 

variety of background conditions and complexities in order to detect 

both the areas in which it will or will not be effective. It might depend upon co-morbidity, and also to detect some of the less common 

kinds of side effects or adverse events. 

And those things are relevant to deciding whether or not the 

benefit that some people get will be sufficient to outweigh the kinds 

of risks or failures to work for other people. 

So initial evidence often can look extremely promising. Preclinical evidence, particularly we have cured cancer in mice countVerDate Mar 15 2010 10:40 Nov 14, 2018 Jkt 037690 PO 00000 Frm 00109 Fmt 6633 Sfmt 6633 I:\115THCONGRESS\115X44MEDCOMMASKOK102218\115X44MEDCOMMPDFMADE W
106 

less times, but also early human evidence is often very, very promising and then when we move into larger trials with more complicated and more diverse populations we discover that, unfortunately, it was misleading. And it is just a matter of basic statistics 

as well as medicine. That is why there is such an emphasis on 

properly controlled trials of sufficient size and statistical power and 

the ability, too, to look at the possibility of inherent biases and how 

you structure the trials. It is very easy to structure trials in a way 

that subtly lead to one conclusion or another without even intending to do so. That is the value of the independent expert eyes that 

the agency brings. 

Mr. ENGEL. Thank you very much. Dr. Kesselheim, you also 

touched on the need for additional studies in your testimony. So I 

would like to ask you the same question. If there is already evidence supporting an off-label use, can you explain why additional 

studies would be necessary? 

Dr. KESSELHEIM. Sure. I mean if there is evidence supporting an 

off-label use and there are certainly plenty of ways that that evidence can already be communicated under the current rules. I 

think the rules are fairly clear about what types of communications 

are, where there are opportunities to communicate that information. And if there are additional studies and again, I think the importance is what is the nature of that evidence. How is that evidence defined? What are the statistical methods that were used in 

testing? How is the population defined? And these are details that, 

you know, average physicians don’t know a lot, don’t have a lot of 

training in and don’t know a lot about it and these are the details 

that the FDA has expertise in. And so if there are nuances that 

might not be caught in initial examination of the information, additional studies that are necessary, then the numerous dozens of experts at the FDA with training in various different fields can identify that and pick up on that and determine whether or not what 

might initially be seen in the data, turns out to be legitimate. 

Mr. ENGEL. Thank you. Ms. Charo, I have one final question for 

you. It is my understanding that in January the FDA released 

draft guidance regarding which manufacturer communications are 

consistent with the FDA required labeling in which are not. And 

I understand also that this guidance has not yet been finalized. 

So do you feel that draft guidance strikes the right balance between enabling potentially helpful communications to take place 

and protecting patient safety and why shouldn’t we legislate in this 

space to provide even greater clarity for manufacturers? 

Ms. CHARO. I do think the FDA is moving in the right direction. 

I agree that draft guidances would be better off if they were finalized guidances, although it is worth noting that a tremendous 

amount is already done through draft guidances at the FDA without any Fifth Amendment due process questions being raised about 

it. 

The thing that I think is most important about what the FDA 

has been doing is its insistence that actual knowledge about how 

your product is being used can be in some instances considered to 

be evidence that you actually intended for the product to be used 

that way. I think a lot of the debate has been around that phenomenon. But we have seen that phenomenon in other contexts. 

107 

We have seen it in areas having to do with constructive knowledge 

in tort law where if you know something is about to happen and 

you actually go ahead and do all the things that are necessary for 

it to come about, you are actually going to be considered to have 

intended that to happen in many cases. 

On the other hand, we have seen in the area of gun law, a lot 

of resistance to the idea that actual knowledge constitute intent. I 

do think that is an area where we have to have some more discussion to clarify, but I also think that it is risky to simply allow for 

an expansion of communication while simultaneously saying but 

now that I have communicated more, the fact that I know that it 

is having an effect doesn’t mean that I intended that particular 

outcome. I think to have both of those things at once I think is particularly risky. Choosing one or the other at least would be the 

right direction. 

Mr. ENGEL. Thank you very much. Thank you, Mr. Chairman. 

Mr. BURGESS. The gentleman yields back. The Chair thanks the 

gentleman. Does the gentleman from Texas have a unanimous consent request? 

Mr. GREEN. Yes, Mr. Chairman, I have a consent request. 

Mr. BURGESS. I will yield for a unanimous consent request. 

Mr. GREEN. I move that we have statements in the record from 

the American Health Insurance Plans, the Campaign for Sustainable Drug Pricing, and also Public Citizen Action be placed into the 

record. 

Mr. BURGESS. Without objection, so ordered. Seeing no other 

Members wishing to ask questions, I once again want to thank our 

witnesses for being here today. 

[The information appears at the conclusion of the hearing.] 

Mr. BURGESS. Pursuant to committee rules, I remind Members 

they have 10 business days to submit additional questions for the 

record. I ask the witnesses to submit their responses within 10 

business days upon receipt of those questions. And without objection, the subcommittee stands adjourned. 

[Whereupon, at 12:37 p.m., the subcommittee was adjourned.] 

[Material submitted for inclusion in the record follows:] 

108 


G:\P\15\H\FDA \INFO-EXCHANGE_O l.XML [Discussion Draft] 

l SEC. FACILITATING EXCHANGE OF INFORMATION 

2 PRIOR TO APPROVAL. 

3 Section 502(a) of the Federal Food, Dmg, and Cos4 metic Act (21 U.S.C. 352(a)) is amended5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 

18 

19 

20 

21 

22 

23 

24 

g:\VHLC\062817\062817.293.xml 

June 28, 2017 (4:13p.m.) 

(1) in paragTaph (1)-

(A) by striking "formulary committee" and 

inserting "formulary or technology review committce"; 

(B) by striking "drug·s for coverage" and 

inserting "drugs or devices for coverage"; 

(C) by striking "approved under section 

505 or under seetion 351(a) of the Publie 

Health Service Act for sueh drug" and inserting "approved, elcarcd, or licensed pursuant to 

scetion 505, fi10(k), fi13, or 515 of this Act or 

pursuant to section 351 of the Public Health 

Service Act for such drug or dev-ice"; 

(D) by striking "approved for the drug 

under section 505 or under section 351 of the 

Public Health Service 1\et" and inserting "approved for the drug or device pursuant to section 505, 510(k), 513, or 515 of this Act or 

pursuant to section 351 of the Public Health 

Sen-ice Act"; and 

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0:\P\ 15\H\FDA \INFO-EXCHANGE_O l.XML [Discussion Draft] 

2 

(E) by striking "The requirements set 

2 forth in section 505(a) or in subsections (a) and 

3 (k) of section 351 of the Public Health Service 

4 Aet" and inserting '"fhe requirements set forth 

5 in section 505(a), 510(k), 513, or 515 of this 

6 Act or section :351 of the Public Health Service 

7 Act"; 

8 (2) by redesignating subparagraph (2) as sub9 paragraph (3); 

10 (3) by inserting after subparagraph (1) the fol11 lowing: 

12 "(2)(A) Health care economic information or sc1-

13 entific information provided to a payor, formulary or tech14 nology review committee, or other similar entity with 

15 knowledge and expertise in the area of health care eco16 nomic analysis carr;ving out its responsibilities for the se17 leetion of drugs or devices for coverage, reimbursement, 

18 or other population-based health care management, shall 

19 not be eonsi<lered false or misleading or any other form 

20 of misbranding uHder this paragraph, or a violation of sec21 tion 505, 510(k), 513, or 515 of this Act or section 851 

22 of the Public Health Service Aet, if it is based on com23 petent and reliable scientific evidence and relates to an 

24 investigational use of a drug or clc\iee. 

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G:\P\15\H\FDA \INFO-EXCHANGE_O l.XML [Discussion Draft] 

3 

"(B) In order for information relating to an inves2 tigational use of an approved, cleared, or licensed drug 

3 or device to be provided pursuant to this subparagraph4 "(i) the study or studies the sponsor anticipates 

5 could be sufficient to support the approval, clear6 ancc, or licensing of such usc must have been con7 ducted; 

8 "(ii) the sponsor must intend that a supple9 mental application will be submitted to the Secretary 

10 for approval, clearance, or licensing of the nsc; and 

11 "(iii) the information must include, 'Where appli12 cable, a conspicuous ancl prominent statement de13 scribing any material differences between the infor14 mation provided and the labeling· approved pursuant 

15 to section 505, 510(k), 513, or 515 of this Act or 

16 pursuant to section 351 of the Public Health Service 

17 Ad .. 

I 8 " (C) I<' or purposes of this subparagTaph, scientific in19 formation ineludes clinical and pre-clinical data and re20 suits relating· to a produet or usc that has not been ap21 proved, eleared, or licensed and is being investigated or 

22 developed."; 

23 

24 

25 

g :\ VHLC\062817\062817 .293 .xml 

June 28.2017 (4:13p.m.) 

( 4) in subparagraph ( 3), as redesignated-

( A) by striking "(A)"; 

(B) by striking elausc (B); and 

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G :\P\ I 5\H\FDA \INFO-EXCHANGE_Ol.XML [Discussion Draft] 

4 

1 (C) by striking· "drug" each place it ap2 pears and inserting "drug or device"; and 

3 (5) by adding at the end the following: 

4 "(4) Xothing in this paragraph shall be construed to 

5 limit the ability of manufacturers or sponsors of drugs or 

6 devices to engage in communications or activities not spec7 ificd in subparagraph (2) or (8) that arc otherwise perm:is8 siblc.". 

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G:\P\15\H\FDA \COMMUNICA TIONS_OI.XMI[Discussion Draft] 

SEC. . . .. COMMUNICATIONS REGARDING INTENDED USES 

2 OF DRUGS AND DEVICES; SCIENTIFIC EX3 CHANGE. 

4 The Federal Food, Drng, and Cosmetic Act is amend5 eel by inserting after section 201 of such Act (21 U.S.C. 

6 321) the following: 

7 "SEC. 201A. INTENDED USES OF DRUGS AND DEVICES. 

8 "(a) l:\'TEI\DED UsE.-F1or purposes of this Act, in9 eluding· sections iW1(d), 502(f)(l), 505, 510, 513, and 

10 515, and for purposes of section :351 of the Public Health 

11 Serviee Act, the intended nse of a drug or device shall 

12 not be determined by reference to13 "(1) aetual or eoustruetive lnw"·ledge of the 

14 manufacturer or sponsor that such dmg or device 

15 \\"ill be used in a manner that varies from the use 

16 approved, cleared, or licensed for marketing under 

17 section 505, 510, 513, or 515 of this Act or section 

18 351 of the Public Health Serviec Aet; 

19 "(2) non-public statements about the drug or 

20 dc\iec that arc not rcf1cetccl in any elaim, pro21 motional statement or material, or eireumstances 

22 surrounding the distribution of the ch·ug· or device 

23 that invoh·e interactions \\ith third parties; or 

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G:\P\15\H\FDA\COMMUN!CA TIONS_O l.XM![Discussion Draft] 

2 

1 "(8) communieations meeting the criteria under 

2 subsection (b) to be considered scientific exchange 

3 safe harbor communications. 

4 "(b) SCIEXTIFIC EXCHA:'\01~ SAPE HAHBOR5 "(1) I:\' GE:\'ERAI~.-A communieation by a 

6 manufacturer or sponsor, or a person aeting on be7 half of a manufaeturer or sponsor, about informa8 tion that is not ineluded in the drug or deviee label9 ing required by this Act, constitutes a seientific ex10 change safe harbor communication if11 "(A) the co1mnunication is not advertising 

12 or othenvise promotional in nature; 

13 "(B) the connmmieation is supported by 

14 competent and reliable seientifie evidence; 

15 "(C) the communication elcarly discloses 

16 appropriate contextual information about the 

17 data presented, ineluding information about 

18 limitations of the data, the scientific and ana19 lytical methodologies used, and any eontradic20 tory data or information known to the manufac21 tl1rcr or sponsor; 

22 "(D) the communication includes a con23 spieuous and prominent statement about sneh 

24 information not being contained in the drug or 

25 deYiee labeling required by this Act; and 

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June 28, 2017 (4:14p.m.) 

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G:\P\15\H\FDA \COMMUNICA TIONS_O l.XMJ(Discussion Draft] 

2 

3 

4 

5 

6 

7 

8 

"(E) if the communication relates to a usc 

of a drug or dcYiee that has not been approYcd 

or cleared for marketing under section 505, 

510, 513, or 515 of this Act or section 351 of 

the Publie Health Service Act, the manufactnrer or sponsor, or person acting on behalf of 

the manufacturer or sponsor, makes no representation that such usc has been dem9 onstrated to be safe or effective. 

10 "(2) RTTLE OF CO:'\STHTTTIO"'.-~othing Ill 

11 this subsection shall be eonstrued12 "(A) to authorize the Seeretary to require 

13 that a manufaeturer or sponsor submit an ap14 plieation, certifieation, or other such submis15 sion, or to seek the Secretary's revww or ap16 proval, before, during', or subsequent to engag17 ing ill scientifie exehange; or 

18 "(B) to limit the ability of a manufaeturer 

19 or sponsor to engage in communieation:-; or ac20 tivities not specified in this subsection, but that 

21 are otherwise permissible.". 

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June 28, 2017 (4:14p.m.) 

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115 


July 10.2017 

The Honorable Brett Guthrie 

Vice-Chairman, Subcommittee on Health 

Energy and Commerce Committee 

2434 Rayburn House Office Building 

Washington, DC 20515 

Re: H.R. 2026 The Pharmaceutical Information Exchange (PIE) Act of 2017 

Dear Vice-Chairman Guthrie, 

The undersigned organizations commend you for your leadership in introducing HR. 2026- The 

Pharmaceutical lnjimnation Exchange (PIE) Act ol2017 which will improve patient access to emerging 

medication therapies and devices by codifying a safe harbor for certain health care economic and 

scientific information communications between biopharmaceutical and medical device manufacturers 

and population health decision makers. Collectively, our organizations represent population health 

decision makers (e.g. payers, provider sponsored health plans, pharmacy benefit managers, accountable 

care organizations, and integrated delivery networks). biophannaccutical and medical device 

manufacturers. patient advocacy groups, health care providers. health economists, and others. 

We suppot1 the need lor timelier and more proactive sharing ofprcapproval health care economic 

information (HCEI) between biopharmaceutical and medical device manufacturers and population 

health decision makers to enable the implementation of value-based contracts, aid in forecasting and 

budgeting. and expedite coverage decisions fl.lr emerging therapies, including those granted 

breakthrough designation. The need for this proactive communication is especially important now as 

the United States health care system evolves from a fee-for-service payment system to a modernized 

system rewarding quality, improved patient outcomes, and value. 

We support ll.R. 2026 because it will: 

Create a legislative safe harbor to allow hiopharmaceulical and medical device manufacturers to 

share proactively with population health decision makers truthful and not misleading clinical 

and economic information about medications and devices in the pipeline, as welt as new uses of 

approved products. prior to FDA approval during the forecasting and rate setting process. A 

legislative safe harbor for PIE will confirm that the proactive dissemination of certain 

inl(mnation does not violate the prohibitions against preapproval promotion and docs not run 

afoul of the labeling, misbranding, and intended use provisions of the Federal Food, Drug, and 

Cosmetic Act and its implementing regulations. 

1! 
116 


Facilitate communication from biopharmaceutical and medical device manufacturers to 

an appropriate audience of population health decision makers who need this information 

for financial forecasting and planning purposes only. 

Extend PIE to investigational products not approved/cleared for any use and investigational uses 

of approved/cleared products for which there is an intent to file a supplement. The rationale for 

PIE applies equally to both. Factors such as product information, indication sought, clinical 

data, anticipated approval time line, pricing information, targeting/marketing strategies and 

product related programs or services are unique to each indication. Anticipating a new 

indication and properly planning for the impact on budget and expansion of patient populations 

eligible to receive such medication or device arc vital for population health decision makers. 

Allow for bidirectional exchange of information and sharing of health care economic or 

scientific information. Such information would include data from pivotal clinical trials, 

pharmacoeconomic data, as well as data relating to patient centered outcomes (health related 

quality of life, treatment satisfaction, etc.), and could also include other material items, such as 

anticipated indications, place in therapy, and routes of administration. 

In summary, our organizations believe that furthering communications between biopharmaceutical and 

medical device manufacturers and population health decision makers prior to FDA approval/clearance 

will help to shift the United States health care system to a focus on value and promote good outcomes 

for patients. Thank you for championing this very important issue and please use our organizations as a 

resource as you continue to lead this initiative forward. 

Sincerely, 

Academy of Managed Care Pharmacy (AMCP) 

Amgen 

Blue Cross and Blue Shield Association (BCBSA) 

Bristol-Myers Squibb 

Center for the Evaluation of Value and Risk in Health, Tufts Medical Center 

Cigna 

Dymaxium, Inc. 

Genentech, Inc. 

Gilead Sciences 

Harvard Pilgrim Health Care 

Humana 

International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 

Mayo Clinic 

Pharmaceutical Research and Manufacturers of America (PhRMA) 

Precision for Value 

Qualchoice Health Plan Services, a division of Catholic Health Initiatives 

Sanofi 

Takeda 

University of Utah College of Pharmacy, Pharmacotherapy Outcomes Research Center 

Xcenda 

21Page 
117 


T" Alliance 

" f of Specialty 

Medicine 

May 2, 2017 

The Honorable Morgan Griffith 

2202 Rayburn House Office Building 

Washington, D.C. 20515 

RE: Support for the 11Medical Product Communications Act of 2017" (H.R. 1703) 

Dear Congressman Griffith: 

The Alliance of Specialty Medicine (the "Alliance") represents more than 100,000 specialty physicians. The 

Alliance is deeply committed to improving access to specialty medical care through the advancement of sound 

health policy. 

The undersigned members of the Alliance are writing to thank you for your introduction of H.R. 1703, the 

Medical Product Communications Act of 2017. The current regulatory paradigm to determine a product's 

"intended use" by the Food and Drug Administration {FDA) has created uncertainty among manufacturers, which 

in turn hampers the free exchange of information, 

For some specialties, a so-called "off-label" use- or use of a medicine or device for an indication not approved 

by FDA- is the standard of care, As such, the free flow of data on such off-label uses is critical to advancement 

of the practice of medicine, Unfortunately, the current way FDA determines the "intended use" has a negative 

impact on such scientific exchange, 

Your legislation would establish clear parameters on what constitutes a "scientific exchange" by which a 

manufacturer could, within defined limitations, share data related to an unapproved indication, We believe that 

H,R, 1703 strikes the right balance between placing reasonable and sound limits on manufacturers and allowing 

a productive, scientific exchange of data that will benefit patients. 

In closing, we thank you for your commitment to this important issue and stand ready to help you advance the 

Medica! Product Communications Act of 2017. Please do not hesitate to contact us should you have any 

questions or require additional information. 

Sincerely, 

American Association of Neurological Surgeons 

American College of Mohs Surgery 

American College of Osteopathic Surgeons 

American Gastroenterological Association 

American Society for Dermatologic Surgery Association 

American Society of Cataract and Refractive Surgery 

American Society of Echocardiography 

American Society of Plastic Surgeons 

American Urological Association 

Coalition of State Rheumatology Organizations 

Congress of Neurological Surgeons 
118 


May 16,2017 

The Honorable Morgan Griffith 

2202 Rayburn House Office Building 

Washington, DC 20515 

because the cost of doing nothing is too great 

RE: Support for HR. 1703, the "Medical Product Communications Act of2017" 

Dear Congressman Griffith, 

The Dystrophic Epidermolysis Bullosa Research Association of America (debra of America) is 

the only U.S. nonprofit providing all-inclusive support to the Epidermolysis Bullosa (EB) 

community by engaging in two initiatives in parallel. We fund innovative research for a 

treatment and a cure and provide free programs and services for those with EB. We call EB "the 

worst disease you've never heard of'-it is a rare connective tissue disorder with many genetic 

and symptomatic variations that affects l out of every 20,000 births in the U.S. 

We, and other members of the Rare Disease community, often find ourselves with few, if any, 

treatment options. In fact, of the more than 7,000 rare diseases, very few have FDA approved 

treatment options. According to Global Genes, a leading rare disease patient and organizational 

advocacy group, only five percent of rare diseases have a FDA approved treatment. While we 

would like nothing more than to see that landscape change, now most rare disease patients, 

including those with EB, are receiving off-label treatments out of necessity-if they are lucky. 

With I in I 0 Americans suffering from a rare disease, H.R. 1703 has the potential to improve 

treatment options for a large number of patients. We want to thank you for your leadership on 

this issue and introducing H.R. 1703. 

Off-label use is often considered the standard of care for many rare diseases and their respective 

patients; therefore, it is imperative that more comprehensive information pertaining to off-label 

usc be shared in a way that can best benefit patients, potentially providing more treatment 

options. This sharing of this comprehensive information would potentially provide more 

treatment options from off-label usage. Currently, the FDA's determination of"intended use" 

negatively impacts scientific exchange of information that could be beneficial or even potentially 

life-changing to patients. We believe H.R. 1703 appropriately balances patient safety while 

providing patients and their physicians access to appropriate, evidence-based information used to 

make informed treatment choices. 

Dystrophic Epidermolysis Bullosa Research Association of America, Inc. 

BOARD OF DIRECTORS 

Richard Gallagher, Chair • Andrew Tavani, Vice Chair • J Alec Alexander, Treasurer • Daniel Siegel, M.D., Secretary • Leslie Rader, Chair Emeritus 

Angela Christiano, Ph.D. • WHiiam Cornman • faith Daniels • Thomas Gillespie 

Frank Kacmarsky • John Lee • Robert Meirowitz, M.D. • Rob Ray! • Robert Ryan, Ph.D. 

Jeanne Rohm • Jouni Uitto, M.D., Ph.D. • James Wetrich 

Brett Kopelan, M.A, Executive Director 

WE ARE A SOI(c)(l) TAX-EXEMPT NONPROFIT 

debra of America t 75 Broad Street, Suite 300 + New York, NY ! 0004 t (P) 212,868-1573 t (F) 212-868-9296 + debra.org 
119 


because !he cost ot doing nothing is too great 

The undersigned organizations thank you for your commitment to this issue and stand ready to 

help you advance the Medical Product Communications Act of2017. 

Sincerely, 

Association for Creatine Deficiencies 

Bridge the Gap-SYNGAP Education and Research Foundation 

Choroidermia Research Foundation 

Dystrophic Epidermolysis Bullosa Research Association of America, Inc. 

Foundation for Sarcoidosis Research 

Gastroparesis Patient Association for Cures and Treatments, Inc. 

Global Genes-Allies in Rare Disease 

Fibrous Dysplasia Foundation 

Jonah's Just Begun-Foundation to Cure Sanfilippo, Inc. 

Little Miss Hannah Foundation 

Lymphangiomatosis & Gorham's Disease Alliance (LGDA) 

MLD Foundation 

Neuromuscular Disease Foundation 

NGLYl 

Noah's Hope 

Pathways for Rare and Orphan Studies 

Phelan-McDermid Syndrome Foundation 

RASopathies Network 

United Leukodystrophy Foundation 

Dystrophic Epidermolysis Bullosa Research Association of America, Inc. 

BOARD OF DIRECTORS 

Richard Gallagher, Chair • Andrew Tavani, Vice Chair • j Alec Alexander, Treasurer • Daniel Siegel. M.D., Secretary • Leslie Rader, Chair Emeritus 

Angela Christiano, Ph.D. • Wi!liam Cornman • Faith Daniels • Thomas Gillespie 

Frank Kacmarsky • John Lee • Robert Meirowitz, M.D. • Rob Rayl • Robert Ryan, Ph.D. 

Jeanne Rohm • Jouni Uitto, M.D., Ph.D. • james Wetrich 

Brett Kopelan, M.A., Executive Director 

WE ARE A 501(c)(3) TAX-EXEMPT NONPROFIT 

debra of America + 75 Broad Street, Suite 300 • New York, NY 10004 + {P) 212·868- 1573 • (F) 2! 2-868-9296 + debra.org 
120 


May 5, 2017 

The Honorable Greg Walden 

Chairman 

Committee on Energy and Commerce 

Washington D.C. 20515 

The Honorable Michael C. Burgess, M.D. 

Chairman 

Subcommittee on Health 

Committee on Energy and Commerce 

Washington D.C. 20515 

Dear Chairmen and Ranking Members: 

The Honorable Frank Pallone 

Ranking Member 

Committee on Energy and Commerce 

Washington D.C. 20515 

The Honorable Gene Green 

Ranking Member 

Subcommittee on Health 

Committee on Energy and Commerce 

Washington D.C. 20515 

The members of the Healthcare Leadership Council (HLC) strongly support H. R. 1703, the 

"Medical Product Communications Act." We urge the Energy and Commerce Committee to take 

up this bill for consideration and approve it. HLC members, through our broad, multisector 

National Dialogue for Healthcare Innovation (NDHI) have emphasized the need to increase 

flexibility to share scientific and healthcare economic information with healthcare decisionmakers in order to drive the use of the highest-value treatment option. 

HLC is a coalition of chief executives from all disciplines within American healthcare. It is the 

exclusive forum for the nation's healthcare leaders to jointly develop policies, plans, and 

programs to achieve their vision of a 21st century health system that makes affordable, highquality care accessible to all Americans. Members of HLC-hospitals, academic health centers, 

health plans, pharmaceutical companies, medical device manufacturers, biotech firms, health 

product distributors, pharmacies, post-acute care providers, and information technology 

companies-believe that the issue of healthcare costs should be addressed through competition 

in a transparent, consumer-oriented healthcare marketplace. 

HLC believes that biopharmaceutical manufacturers can and should partner with payers and 

providers in efforts to communicate about and optimize the clinical benefits of prescribed 

treatments. The push for value-based payment is accelerating demands by payers and 

providers for a growing range of information about the clinical and economic outcomes of 

biopharmaceutical products. Biopharmaceutical companies routinely develop data describing 

the cost-effectiveness of various treatment options, data based on post-market use of these 

medicines, as well as safety and efficacy information. Application of these data can enhance 

patient care and the efficiency of the healthcare system, but companies are not currently 

permitted to share such information proactively with healthcare professionals or payers. 
121 


As leaders from the full spectrum of American healthcare, we have long maintained that driving 

high-value healthcare must be a priority. Doctors should have the most up-to-date information 

when caring for their patients and, when done responsibly and in an appropriate context, 

manufacturers should be able to provide it. Meaningful, fact-based discussions between 

healthcare product manufacturers and the purchasers of their products will help drive the 

adoption of better and safer patient care. 

We applaud your leadership in reviewing important legislation to further these goals. Please 

feel free to contact HLC's SVP for Policy, Tina Grande (tgrande@hlc.org or 202-449-3433), with 

any questions. 

Mary R. Grealy 

President 
122 


1600 20th Street. NW • Washington, D.C. 20009 • 202/588-1000 • www.citizen.org 

July II, 2017 

The Honorable Michael Burgess 

Chairman, Health Subcommittee 

and 

The Honorable Gene Green 

Ranking Member, Health Subcommittee 

Committee on Energy and Commerce 

U.S. House of Representatives 

2125 Rayburn l louse OfJice Building 

Washington, D.C. 20515 

Dear Chairman Burgess and Ranking Member Green: 

Public Citizen, a consumer advocacy organization with more than 400,000 members and 

supporters nationwide, respectfully submits the following comments for the record for your 

subcommittee's July 12 hearing, Examining Medical Product Manufacturer Communications, 

which will include a discussion of draft legislation titled "Communications Regarding Intended 

Uses of Drugs and Devices; Scientific Exchange" and ''Facilitating Exchange of Information 

Prior to Approval." 

We urge your subcommittee to oppose both pieces of draft legislation because they include 

provisions that, would significantly expand marketing for unapproved uses of drugs and medical 

devices that have been approved or cleared by the Food and Drug Administration (FDA) for at 

least one use. These bills would threaten patient health and safety by undermining the current 

regulatory regimes for ensuring that drugs and medical devices are safe and effective for each 

intended use. Similar legislation was considered by Congress during the drafting of the 21st 

Century Cures Act but was wisely rejected because of its controversial nature. 

As the FDA recently articulated, the existing regulatory restrictions on manufacturer 

communications regarding unapproved uses of approved or cleared medical products are 

overwhelmingly justified by the substantial government interest in protecting patient health and 

safety. These restrictions advance health and safety by: 

motivating the development of robust scientific data on safety and effectiveness for each 

new use of a medical product; 

• maintaining the prcmarket review process for safety and effectiveness of each intended 

use in order to prevent harm; protect against fraud, misrepresentation, and bias; and 

prevent the diversion of health care resources to ineffective treatments; 

• ensuring that required product labeling is accurate and informative; 

• protecting the integrity and reliability of promotional information regarding medical 

product uses; 
123 


Public Citizen July 11, 2017 Letter to the Health Subcommittee 

of the House Committee on Energy and Commerce 

• protecting human subjects who are receiving experimental treatments, ensuring informed 

consent, and maintaining incentives for clinical trial participation; 

• protecting innovation incentives, including statutory grants of exclusivity; and 

• promoting the development of products for underserved patients. 1 

Together, these interests support the FDA's overarching mission of protecting and promoting 

public health. That interest outweighs any purported public health benefit of allowing 

manufacturer communications regarding unapproved uses of medical products. 

Dangers of Promotion for Unapproved Uses 

Although the FDA approves new drugs and some medical devices before they are marketed, itand the public-maintains a strong interest in evaluating the products' safety and effectiveness 

for any additional uses that were not evaluated at the time of initial approval. For example, a 

drug that poses a serious risk to the patient's immune system may merit approval to treat cancer 

but not to treat a headache. Thus, the FDA does not evaluate safety in a vacuum: For each 

proposed use, the agency balances the drug's risk of harm against its potential for benefit. 

Furthermore, the government has a powerful interest in ensuring that a drug is not only safe for 

each use for which a manufacturer markets it, but also effective. Marketing for a safe but 

ineffective use can have detrimental health effects if it diverts patients from effective treatment.2 

Moreover, a drug's safety for a second use is not established once a drug has been approved (and 

thus deemed safe and effective) for a first use. To the contrary, a drug that is safe for one use can 

be life-threatening for another. 

Although prescribing drugs and devices for unapproved uses is common, scientific evidence 

supporting most such uses often is lacking. For example, a recent study conducted in Canada 

found that the vast majority of off-label uses-81 percent-lacked strong scientific evidence of 

effectiveness. 3 Patients who received a prescription for an off-label use lacking strong evidence 

of effectiveness were 54 percent more likely to experience an adverse drug reaction that resulted 

in stopping usc of the drug than were those who were prescribed a drug for an approved use. The 

increased risk of serious adverse events when drugs are prescribed for otT-label uses, combined 

with the lack of strong evidence of benefit, demonstrates that a favorable risk-benefit 

relationship has not been established for most off-label uses of drugs and further supports strong 

restrictions against promotion of unapproved uses. 

1 FDA. Memorandum: Public health interests and first amendment considerations related to manufacturer 

communications regarding unapproved uses of approved or cleared medical products. January 2017. Available at 

https://www.regu lations. gov/contentStreamcr?documentld~ FDA-20 16-N-ll49-

0040&attachmentNumber~ I &contentType~pdf. Accessed May 30, 2017. At 3-16. 2 Wash. Legal Found. v. Friedman, 13 F. Supp. 2d 51, 69 (D.D.C. 1998) (noting evidence that off-label use of 

calcium channel blockers deprived patients of more effective treatments). 

'Eguale T, Buckeridge DL, Verma A, et al. Association of off-label drug use and adverse drug events in an adult 

population. JAA4A Intern Me d. 2016; 176(1 ):55-63. 

2 
124 


Public Citizen July 11, 2017 letter to the Health Subcommittee 

of the House Committee on Energy and Commerce 

Even Relying on Peer-Reviewed Scientific Journal Articles Can be Dangerous 

Subsection (b) (Scientific Exchange Safe Harbor) of proposed Section 201A in the draft 

legislation titled "Communications Regarding Intended Uses of Drugs and Devices; Scientific 

Exchange'' is particularly troubling because it would allow pharmaceutical and medical device 

manufacturers to disseminate a broad range of information related to unapproved uses in both the 

scientific and lay media. In this way, the bill would radically extend the types of information that 

can be disseminated by manufacturers beyond what is currently permitted under the FDA's 

January 2009 guidance for industry on good reprint practices4 and its more expansive February 

2014 draft guidance on distributing scientific and medical publications concerning unapproved 

new uses. 5 

It is important to recognize that the FDA's current policy of allowing distribution of peerreviewed journal articles about unapproved uses already allows companies to market drugs based 

on unreliable and in some cases deceptive evidence of safety and effectiveness. First, published 

peer-reviewed articles represent a partial, and often biased, sample of all medical evidence 

regarding the safety and effectiveness of medical products. For example, a 2008 study of 

antidepressant drug clinical trials submitted to the FDA found that 97 percent of all trials with 

positive results had been published, but only 39 percent of the trials deemed by the FDA to have 

negative or "questionable" results had been published.6 

Second, even among the most respected journals, the peer-review process suffers from 

shortcomings that can permit fraudulent or otherwise misleading articles to find their way into 

publication and then, via drug salespeople, into doctors' hands. Unlike the rigorous FDA review 

process for drugs and high-risk medical devices, the peer-review process for scientific and 

medical journals generally is not well equipped to uncover the wide range of problems that can 

undermine the integrity of clinical trial data, including outright fraud, flawed study design, 

failure to adhere to protocol-specified procedures, poorly conducted statistical analyses, and 

incomplete reporting of key data. Conflicts of interest resulting from financial relationships 

between authors of peer-reviewed journal articles and manufacturers can increase the likelihood 

of such problems. And most busy physicians and other health care providers arc even less 

equipped than journal peer reviewers to assess the validity and reliability of data presented in 

journal articles that are distributed by manufacturers. 

4 fDA. Good reprint practices for the distribution of medical journal articles and medical or scientific reference 

publications on unapproved new uses of approved drugs and approved or cleared medical devices: Guidance for 

industry. January 2009. http://www.fda.gov/Regulatorylnformation/Guidances/ucm 125126.htm. Accessed May 30, 

2017. 

5 FDA. Revised draft guidance for industry: Distributing scientific and medical publications on unapproved new 

uses-recommended practices. Feb 2014. 

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm387652.pdf. 

Accessed May 30, 20 17. 6 Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on 

apparent efficacy. /V' Eng/ J Med. 2008;358(3):252-260. 

3 
125 


Public Citizen July 11, 2017 Letter to the Health Subcommittee 

of the House Committee on Energy and Commerce 

To underscore the limitations of relying on peer-reviewed scientific and medical journals, the 

FDA recently explained the following: 

Although some of the assurances from independent review for a particular study can be 

obtained by review by non-governmental entities (such as peer review coordinated by a 

scientific or medical journal), the standards governing FDA review provide an assurance 

of data completeness, scientific rigor, and a thoroughness of evaluation that are not met 

by the more narrow examination of the peer review process, given the limited data 

typically available to and reviewed by peer reviewers, the more limited number of peer 

reviewers (and thus more limited areas of expertise), and the scope of a journal article7 

Relying on articles published in peer-reviewed journals without digging deeper into the 

underlying data- as occurs when FDA scientists review new drug applications, medical device 

pre-market approval applications, and some 51 O(k) device pre-market clearance applicationscan lead to the rapid adoption of ineffective or unsafe unapproved uses of drugs and medical 

devices and, thus, put patients in harm's way. And reliance on other types of"scientific" 

information, such as letters to the editor and information published in the lay media, would be 

even more dangerous. 

Enclosed arc more detailed comments on this topic that we submitted to the FDA on April 19, 

2017. 

Critique of Subsection (b) (Scientific Exchange Safe Harbor) of Proposed Section 201A 

under the Draft Legislation, "Communications Regarding Intended Uses of Drugs and 

Devices; Scientific Exchange" 

One factor that would define the boundaries of the scientific exchange safe harbor under 

subsection (b) of proposed Section 20 I A is that "the communication is not advertising or 

otherwise promotional in nature." A second factor is that "if the communication relates to a use 

of a drug or device that has not been approved or cleared for marketing ... , the manufacturer or 

sponsor, or person acting on behalf of the manufacturer or sponsor, makes no representation that 

such usc has been demonstrated to be safe or effective." Yet Congress needs to understand that 

the primary reason drug and device company representatives distribute scientific and medical 

intormation regarding unapproved uses is, indisputably, to promote those uses to physicians and 

other health care providers in the hope of increasing prescribing of the companies' products. By 

their very nature, these communications are promotional. 

A third factor that would define the boundaries of the scientific exchange safe harbor is that "the 

communication is supported by competent and reliable scientific evidence." The meaning of 

"competent and reliable scientific evidence" here is unclear. Moreover, for the reasons discussed 

above, evidence from articles published in peer-reviewed journals that may appear to be 

competent and reliable may be seriously flawed. 

7 FDA Memorandum, supra note 1, at 9. 

4 
126 


Public Citizen July 11, 2017 Letter to the Health Subcommittee 

of the House Committee on Energy and Commerce 

Finally, for a scientific exchange communication to qualify for the safe harbor under subsection 

(b) of proposed Section 201A, it would have to clearly disclose "appropriate contextual 

information about the data presented, including information about limitations of the data, the 

scientific and analytical methodologies used, and any contradictory data or information known to 

the manufacturer or sponsor." However, limitations of scientific data can easily go unrecognized 

or be disregarded, and the lack of contradictory infom1ation may reflect a failure to conduct 

appropriate additional research or rigorously search for such information. 

Conclusion 

History shows that after-the-fact enforcement of safety and efficacy standards for marketing of 

drugs and devices is inadequate to protect patient safety. Rather, when an unproven assertion of 

safety and effectiveness is relied on to market a medical product, the resulting harm may be 

severe-even life-threatening. 

Public Citizen urges you to oppose the draft legislation that is to be discussed at your 

subcommittee's hearing tomorrow arid any similar controversial legislation that is introduced in 

the future. 

Thank you for the opportunity to submit these comment for the record on these important public 

health matters. 

Sincerely, 

Michael Carome, M.D. 

Director 

Public Citizen's Health Research Group 

Enclosure 

cc; Members of the Health Subcommittee, Committee on Energy and Commerce 

5 
127 


1600 20th Street. NW • Washington, D.C. 20009 • 202/588-1000 • www.citizen.org 

April19, 2017 

Division of Dockets Management 

Food and Drug Administration 

Department of Health and Human Services 

5630 Fishers Lane, Room I 061 

Rockville, MD 20852 

COMMENTS ON 

MANUFACTURER COMMUNICATIONS REGARDING UNAPPROVED USES 

OF APPROVED OR CLEARED MEDICAL PRODUCTS 

Docket No. FDA-2016-N-1149 

Public Citizen, a consumer organization with members and supporters nationwide, 

submits these comments in response to the request for comment on "Manufacturer 

Communications Regarding Unapproved Uses of Approved or Cleared Medical Products," 

published in the Federal Register by the Food and Drug Administration (FDA) on September 1, 

2016. Primarily through its Health Research Group, Public Citizen has long been an advocate for 

strong regulation of drugs and medical devices for the protection of patients. Public Citizen 

appreciates the agency's attention to this important public health issue and the opportunity to 

provide these comments. 

At least since the 1990s. pharmaceutical and medical device companies have been 

pushing back against FDA restrictions on marketing drugs and medical devices for uses not 

approved by the agency. After only limited initial success, the industry recently stepped up its 

efforts to roll back these restrictions. At its heart, the industry push challenges two central tenets 

of the FDA regulatory scheme: (I) objective scientific evaluation of evidence concerning each 

proposed use of a drug or device is needed to protect consumers and (2) selling drugs and 

devices for therapeutic uses in the absence of validation by such evaluation is false or 

misleading. The development of appropriate policy in this area requires an understanding of the 

development of the FDA's regulatory authority. Accordingly, we begin with a short historical 

summary. We then discuss the risks to patients when manufacturers promote their products for 

unapproved uses and the unreliability of journal articles as a basis for physicians' 

decisionmaking. Finally, we explain that the First Amendment does not support the industry call 

for relaxation of the restrictions on promoting products for uses that the FDA has not approved 

as safe and effective for patients. 

BACKGROUND, FDA'S RESPONSIBILITY, AND SUBSTANTIAL GOVERNMENT 

INTERESTS 

The current regulatory regimes for drugs and medical devices developed in response to 

real-world situations that highlighted the need for an objective dccisionmaker to assess the safety 
128 


Public Citizen April 19, 2017 

Comments on FDA Draft Guidance 

Docket No. FDA-2016-D-1149 

and effectiveness of a drug or device before it is sold to patients. Congress took the first step in 

1906, passing the Pure Food and Drugs Act, partially in response to cure-all claims for worthless 

and dangerous medicines. 1 The law prohibited the sale of misbranded or adulterated drugs but 

required no premarketing review and no prior testing or showing of safety. And to force a drug 

off the market, the government bore the burden of proving that the product's labeling was false 

and mislcading.2 

Then, in 1937, I 05 people died from taking Elixir Sulfanilamide, a liquid form of the first 

sulfa antibiotic. The elixir was marketed without toxicity testing of the ingredients, which 

included the toxic chemical diethylene glycol. 3 This incident prompted passage of the 1938 

Food, Drug, and Cosmetic Act (FDCA), which required manufacturers to submit premarket 

notitlcations demonstrating the safety of each new drug before marketing. Specifically, the law 

required the manufacturer of a "new drug"-that is, a drug "not generally recognized, among 

experts ... as safe and effective for use"-to submit to the FDA, in advance of marketing a new 

product, a "new drug application" (NDA) demonstrating "adequate testing" showing that the 

drug is safe for "use under the conditions prescribed" in its labeling.4 The law thus prohibited, 

for the first time, marketing a new drug for any use not approved by the FDA. 

A near miss in 1960 prompted another important improvement in drug regulation. The 

FDA considered but ultimately refused to approve thalidomide. The drug was marketed in 

Europe and elsewhere for insomnia and morning sickness in pregnant women, and subsequently 

was found to cause severe human birth defects.5 The tragedy sparked congressional hearings, 

which revealed that drug companies were making effectiveness claims that were unsupported or 

based on shoddy scientific evidence. 6 In 1962, Congress responded by strengthening the drug 

approval process to require not onl~ proof of safety, but also "substantial evidence" of 

effectiveness for a drug's intended use. This evidence must be supported by "adequate and wellcontrolled investigations."8 Moreover, because a drug may be safe and effective for one use but 

unsafe or ineffective for another, the law requires a manufacturer of a drug that has already been 

approved through an NDA to submit a supplemental NDA demonstrating the drug's safety and 

effectiveness for any additional use before labeling or marketing the drug for that new use. 9 The 

1 Janssen W. Outline of the History of U.S. Drug Regulation & Labeling. Food Drug Cosm. L.J. 1981;36:420, 422. 2 21 U.S.C. § 352(a): Richard A. Merrill, The Architecture ofGov 't Regulation ofMed Prods., 82 Va. L. Rev. 1753, 

1761 (1996). 3 Wax P. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 

1995;122:456-46!. 

4 21 U.S.C. §§ 321(p), 355(a), (b). (d). 5 Avorn J. Learning about the safety of drugs-a half-century of evolution. New Eng! J Afed. 2011:365:2151-2153. 6 FDA. Promoting Safe and Effective Drugs for 100 Years. Available at http://www.fda.gov/AboutFDA! 

WhatWeDo/History/CcntennialofFDA/Centennia!EditionofFDAConsumerlucm093787.htm. 

7 21 U.S.C. §§ 321(p), 355(a), (b), (d). 8 !d.§ 355(d). 9 See 21 C.F.R. § 314.70. 

2 
129 


Public Citizen April 19, 201 7 

Comments on FDA Draft Guidance 

Docket No. FDA-2016-D-1149 

requirement of adequate and well-controlled studies was "revolutionary" and invaluable in 

advancing pharmaceutical safety and cffectiveness. 10 

The 1938 and 1962 laws protect patients by mandating a review process that enables the 

FDA to detect unsafe or ineffective medicines before they reach consumers and cause harm. The 

resulting premarket approval process is a cornerstone of modern drug safety regulation, serving 

the separate but complementary goals of protecting the public from dangerous drugs and 

preventing false and misleading claims. 11 Indeed, "[t]here are few, if any, more important 

functions performed by any regulatory agency than ... ensuring that when a citizen takes a 

prescription drug, that individual has absolute assurance that the product is safe and effective for 

the condition for which his physician has prescribed it." 12 The premarket review process is a 

crucial bulwark against the sorts of pseudo-scientific claims that characterized fraudulent 

medicine before federal regulation. 

As the FDA recognizes, existing restrictions on manufacturer communications regarding 

unapproved uses of approved or cleared medical products are overwhelmingly justified by 

"substantial government interests related to health and safety," including, in particular, the 

following: 

• motivating the development of robust scientific data on safety and effectiveness 

for each new use of a medical product; 

• maintaining the prcmarket review process for safety and effectiveness of each 

intended use in order to prevent harm; protect against fraud, misrepresentation, 

and bias; and prevent the diversion of health care resources to ineffective 

treatments; 

• ensuring required product labeling is accurate and informative; 

• protecting the integrity and reliability of promotional information regarding 

medical product uses; 

• protecting human subjects who are receiving experimental treatments, ensuring 

informed consent, and maintaining incentives for clinical trial participation; 

• protecting innovation incentives, including statutory grants of exclusivity; and 

• promoting the development of products for underserved patients. 13 

10 Promoting safe and effective drugs for 100 years. FDA Consumer Magazine. Jan-Feb 2006. Available at 

www. fda. gov I AboutFD A/What W eDoiHistory /Centcnnialoff'D NCentennia!Editiono !FDA Consumer/ ucm093 78 7. 

htm. [Last accessed Mar. 9, 20 17] 11 See Abigail Alliance for Better Access to Dev 'I Drugs v. von Eschenbach, 495 F.3d 695, 703 (D.C. Cir. 2007) (en 

bane). 

12 See Wash. Legal Found v. Friedman, l3 F. Supp. 2d 51, 69 (D.D.C. 1998), vacated on other grounds, TVash. 

Legal Found v. Henney, 202 F.3d 331 (D.C. Cir. 2000). 13 FDA. Memorandum: Public health interests and first amendment considerations related to manufacturer 

communications regarding unapproved uses of approved or cleared medical products. Jan 2017. Available at 

https:l/www.regulations.gov/contentStreamer?documentld=FDA ·20 16-N-1149-0040&attachmentNumber= 

I &contentType=pdf. [Last accessed Feb. 28, 20 17] at 3-16. 

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Together, these interests support the FDA's overarching mission of protecting and promoting 

public health. That interest outweighs any purported public health benefit of allowing 

manufacturer communications regarding unapproved uses of medical products. 

DANGERS OF PROMOTION FOR UNAPPROVED USES 

Although the FDA today approves new drugs and some medical devices before they are 

marketed, it-and the public-maintains a strong interest in evaluating the products' safety and 

effectiveness for any additional uses that were not evaluated at the time of initial approval. For 

example, a drug that poses a serious risk to the patient's immune system may merit approval to 

treat cancer but not to treat a headache. Thus, the FDA does not evaluate safety in a vacuum: For 

each proposed use, the agency balances the drug's risk of harm against its potential for benefit. 

Furthermore, the FDA has a powerful interest in ensuring that a drug is not only safe for each use 

for which a manufacturer markets it, but also effective. Marketing for a safe but ineffective usc 

can have detrimental health effects if it diverts patients from effective treatment. 14 

Moreover, a drug's safety for a second use is not established once a drug has been 

approved (and thus deemed safe and effective) for a first use. To the contrary, a drug that is safe 

for one use can be life threatening for another. For example, the drug bromocriptine is safe for 

use in treating certain diseases, such as Parkinson's disease, but has been linked to strokes when 

used to suppress lactation in postpartum women. See 59 Fed. Reg. 43347 (1994) (FDA notice of 

withdrawal of approval for usc to suppress lactation); FDA, http://www.accessdata.fda.gov/ 

drugsatfda_docs/label/2012/017962s065s068lbl.pdf, at 4, 11 (current product labeling, listing 

approved uses and warning against use by lactating women). 

Accordingly, it is not surprising that harms associated with taking marketed drugs for 

unapproved uses have been well-documented. For example, starting in the mid-1980s, doctors 

increasingly prescribed estrogen-progestin hormone replacement drugs to postmenopausal 

women as a preventative measure against a range of illnesses, including heart disease, breast 

cancer, and Alzheimer's disease-uses that were not FDA-approved. After tens of millions of 

prescriptions had been written, a large, U.S. government-funded randomized clinical trial found 

that such unapproved uses of the drugs significantly increased risks of coronary heart disease, 

stroke, pulmonary embolism, and invasive breast cancer, and that these risks exceeded the drugs' 

benefits when prescribed for several off-label uses. 15 

Unfortunately, this example is just one of many. 16 Risperdal, Xyrem, Avandia, Zofran, 

and Neurontin are other well-known examples of drugs that caused significant injury as a result 

14 See Friedman, 13 F. Supp. 2d at 56-57 (noting evidence that off-label use of calcium channel blockers deprived 

patients of more effective treatments). 15 Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. JAMA. 2002;288:366-368; 

Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in 

healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. 

.lAMA. 2002;288:321-333. 16 See also, e.g., Perry v. Novartis Pharm. Corp., 456 F. Supp. 2d 678 (E.D. Pa. 2006) (Elide! approved as safe and 

effective to treat dermatitis, but poses risk of causing cancer when used off-label in patients less than two years old); 

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of the manufacturers' off-label promotion and marketing. And the problem is not limited to 

drugs, as demonstrated by the hundreds of patients seriously injured by unapproved uses of 

Medtronic, Inc.'s Infuse medical device. 17 

Although prescribing drugs and devices for unapproved uses is common, scientific 

evidence supporting most such uses is lacking. For example, an observational study published in 

2008 examined the frequency with which drugs were prescribed for unapproved uses in the U.S. 

from January 2005 to June 2007. 18 The researchers found that, for the 25 drugs prescribed most 

frequently for unapproved uses that have inadequate evidence of effectiveness, 29 percent of the 

total prescriptions were for unapproved uses. Collectively, for these 25 drugs, scientific evidence 

was inadequate to support the effectiveness of the drugs for 82 percent of their off-label uses. 

A more recent observational study conducted in Canada likewise found that the vast 

majority of off-label uses-81 percent-lacked strong scientific evidence of effectiveness. 19 

Patients who received a prescription for an off-label usc lacking strong evidence of effectiveness 

were 54 percent more likely to experience an adverse drug reaction that resulted in stopping use 

of the drug than those who were prescribed a drug for an approved use. 

The increased risk of serious adverse events when drugs are prescribed for off-label uses, 

combined with the lack of strong evidence of benefit, demonstrates that a favorable risk-benefit 

relationship has not been established for most off-label uses of drugs and further supports strong 

restrictions against promotion of unapproved uses. 

In addition, allowing broad promotion of drugs for unapproved uses would deter clinical 

trials of unapproved uses. Manufacturers would not invest in expensive testing of new uses if 

they were free to market their products for those uses without evidence of benefit. As a result, 

physicians, patients, and the FDA would be deprived of important information about safety and 

effectiveness. 

Friedman, 13 F. Supp. 2d at 56-57 (noting off-label prescriptions ofanti-arrythrnic drugs encainide and flecainide to 

treat minor heart-rhythm disturbances in patients with recent heart attacks caused an estimated 3,000 to 10,000 

patient deaths per year); see generally Henry A. Waxman, A Hist01y of Adverse Drug Experiences: Congress Had 

Ample Evidence to Support Restrictions on the Promotion of Prescription Drugs, 58 Food & Drug L.J. 299, 301-{)6 

(2003) (detailing history of harms resulting from marketing of drugs for uses for which they had not been shown to 

be safe and effective). 17 See Patients who received Medtronic's Infuse product to get $8.45 million in settlements, StarTribune, Aug. 2, 

2016 ("Claims of injuries from such 'off-label' use have plagued Infuse almost from the time of its introduction into 

the market in 2002."); Medtronic Says Device for Spine Faces Probe; Wall St. J., Nov. 19. 2008 (describing 

Department of Justice probe into Medtronic's off-label promotion). 18 Walton SM, Schumock GT, Lee KV, ct al. Prioritizing future research on off-label prescribing: Results of a 

quantitative evaluation. Pharmacotherapy. 2008;28(12):1443-1452. 19 Eguale T, Buckcridge DL, Verma A, et al. Association of off-label drug use and adverse drug events in an adult 

population. JA.HA Intern Me d. 20 16; 176(! ):55-63. 

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MARKETING TECHNIQUES EXACERBATE THE RISKS 

In its January 2009 guidance for industry on good reprint practices20 and its more 

expansive February 2014 draft guidance on distributing scientific and medical publications on 

unapproved new uses,21 the FDA articulated "safe harbor" policies that permit pharmaceutical 

and medical device manufacturers to disseminate scientific and medical journal articles and other 

materials describing unapproved uses of approved or cleared medical products, provided certain 

conditions are met. These guidelines allow drug companies to engage in public discourse and 

scientific debate, while addressing (although not wholly solving) the most common problems 

resulting from unregulated marketing of drugs for unapproved uses. For example, the guidelines 

attempt to address the problem of incomplete, skewed, or biased data by stating that reprints 

should be accompanied by a disclosure that identifies any conflicts of interest and by limiting a 

manufacturer's distribution of publications funded by, written at the request of, or influenced by 

the manufacturer. They also include additional provisions designed to ensure that distributed 

information is scientifically sound, stating, for example, that reprints should address wellcontrolled studies and be published in a generally available, peer-reviewed journaL22 

Nonetheless, the FDA's policy of allowing distribution of peer-reviewed journal articles 

about unapproved uses allows companies to market drugs based on unreliable and in some cases 

deceptive evidence of safety and effectiveness. The FDA guidelines state that, if manufacturers 

distribute articles or other information as set forth in the guidance, the FDA does not intend to 

use such distribution as evidence of the manufacturer's "intent that the product be used for an 

unapproved new use" in violation of the FDCA. Yet the agency cannot overlook that the primary 

reason drug and device company representatives distribute scientific and medical information 

regarding unapproved uses undoubtedly is to promote those uses to physicians and other health 

care providers in the hope of increasing prescribing of the companies' products. Legalized offlabel marketing-even under the safe-harbor conditions specified in FDA guidance-threatens 

the U.S. regulatory process for ensuring that prescription drugs and medical devices are safe and 

effective for their intended uses. 

Peer-reviewed scientific and medical journals vary significantly in their credibility and 

rigor. But even among the most respected journals, the peer-review process suffers from 

shortcomings that can permit fraudulent or otherwise misleading articles to find their way into 

publication and then, via drug salespeople, into doctors' hands. Unlike the rigorous FDA review 

process for drugs and high-risk medical devices, the peer-review process for scientit1c and 

medical journals generally is not well equipped to uncover the wide range of problems that can 

undermine the integrity of clinical trial data, including outright fraud, flawed study design, 

2

° FDA. Good reprint practices for the distribution of medical journal articles and medical or scientific reference 

publications on unapproved new uses of approved drugs and approved or cleared medical devices: Guidance for 

industry. Jan 2009. Available at http://www.fda.gov/Regulatorylnformation/Guidances/ucml25126.htm. [Last 

accessed Mar. 9, 2017] 21 FDA. Revised draft guidance for industry: Distributing scientific and medical publications on unapproved new 

uses--recommended practices. Feb 2014. Available at http://www.fda.gov/downloads/drugs/guidancecompliance 

regulatoryinformation/guidances/ucm387652.pdf. [Last accessed Mar. 9, 2017] 

22 !d. 

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failure to adhere to protocol-specified procedures, poorly conducted statistical analyses, and 

incomplete reporting of key data. Conflicts of interest resulting from financial relationships 

between authors of peer-reviewed journal articles and manufacturers can increase the likelihood 

of such problems. And most busy physicians and other health care providers are even less 

equipped than journal peer reviewers to assess the validity and reliability of data presented in 

journal articles that are distributed by manufacturers. 

Underscoring the limitations of relying on peer-reviewed scientific and medical journals, 

the FDA recently explained: 

Although some of the assurances from independent review for a particular study can be 

obtained by review by non-governmental entities (such as peer review coordinated by a 

scientific or medical journal), the standards governing FDA review provide an assurance 

of data completeness, scientific rigor, and a thoroughness of evaluation that are not met 

by the more narrow examination of the peer review process, given the limited data 

typically available to and reviewed by peer reviewers, the more limited number of peer 

reviewers (and thus more limited areas of expertise), and the scope of a journal article.23 

Relying on articles published in peer-reviewed journals without digging deeper into the 

underlying data-as occurs when FDA scientists review new drug applications, medical device 

premarket approval applications, and some 51 O(k) device premarket clearance applications-can 

lead to the rapid adoption of ineffective or unsafe unapproved uses of drugs and medical devices 

and, thus, put patients in harm's way. 

Research Fraud and Misconduct - Research fraud and misconduct represent the most 

serious threat to the integrity of data presented in journal articles. The FDA itself has noted that 

fraud and misconduct have occurred in all phases of clinical research and have involved 

enrolling unqualified subjects, backdating information, fabricating data from tests that were not 

performed, failing to report adverse events, deviating from protocols, covering up mistakes, and 

submitting false data for publication.24 

Evidence suggests that the incidence of detected research fraud and misconduct, although 

very low, has increased significantly. For example, a 2012 study of the PubMed database found 

that the percentage of scientific articles retracted due to fraud had increased approximately 

tenfold since 1975.25 Fraud or suspected fraud were the most commonly identified reasons for 

retraction of an article, occurring in 43 percent of cases. The study authors noted that "the current 

number of articles retracted because of fraud represents an underestimation of the actual number 

of fraudulent articles in the literature." 

23 FDA Memorandum, supra note 13, at 9. 24 Hamre II MR. Raising suspicions with the Food and Drug Administration: Detecting misconduct. Sci Eng Ethics. 

20 I 0; 16(4):967-704. 25 Fang FC, Steen RG, Casadevall A. Misconduct accounts for the majority of retracted scientific publications. 

PA>1S. 2012;109(42):17028-17033. (Correction: PNAS. 2013;110(3): 1137.) 

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Biased Study Design- Equally insidious and far more widespread than outright research 

fraud are a wide range of practices that result in clinical trial bias. In a 20 I 5 editorial in the Mayo 

Clinic Proceedings, Prasad and Berger coined the term "hard-wire bias" to describe sources of 

potential bias originating in the initial design of randomized, double-blind clinical trials.26 They 

pointed out that hard-wire bias cannot be corrected by using statistical methods or reanalysis. 

Examples described by the authors include selection bias and unequal-comparison bias. 

Selection bias can occur when inclusion and exclusion criteria result in a very narrowly 

defined subject population, which prevents the generalizability of the results to a broader patient 

population, even though results of clinical trials routinely are used to justify use of a drug in a 

broader population.27 Unequal-comparison bias stems from designs that disadvantage one trial 

group relative to another, such as selecting an active comparator for the control group that is not 

consistent with standard-of-care treatment. 

Publication Bias Another well-documented problem that adversely affects the 

scientific and medical literature is publication bias-the tendency of investigators to submit, and 

the tendency of editors and reviewers to accept, manuscripts with positive research findings. A 

2009 systematic review by the Cochrane Library of studies assessing publication bias found that 

clinical trials with positive findings were nearly four times more likely to be published than trials 

with negative findings. 28 Furthermore, trials with positive findings tended to be published 

sooner-after four to five years-than those with negative findings, which were published after 

six to eight years. 

Publishing Datafi·om Phase 2 Clinical Trials Without Confirmatmy Data from Phase 3 

Trials - Under the FDA's existing guidance for industry on good reprint practices, 

pharmaceutical and medical device manufacturers may promote drugs and devices for 

unapproved uses by distributing reprints of medical journal articles that present results of phase 2 

clinical trials that tested medical products for such uses even if phase 3 trials related to those uses 

have not been conducted or completed. As the agency is well aware, however, results of phase 2 

clinical trials can provide misleading information about the safety and effectiveness of products. 

The FDA highlighted this point in its recent report describing 22 carefully documented 

case studies of drugs, vaccines, and medical devices for which promising phase 2 clinical trial 

results were not confirmed in phase 3 trials.29 The agency's analysis of these cases revealed that 

phase 3 results did not confirm effectiveness in 14 cases, did not confirm safety in one case, and 

failed to confirm both safety and effectiveness in seven cases. 30 Six cases involved prescription 

26 Prasad V, Berger V. Hard-wired bias: How even double-blind, randomized controlled trials can be skewed from 

the start. Mayo C!in Proc. 2015;90(9):1171-1175. 27 ld. 28 Hopewell S, Loudon K, Clarke MJ, ct al. Publication bias in clinical trials due to statistical significance or 

direction of trial results. Cochrane Database of Systematic Reviews. 2009, Issue I. Art. No.: MR000006. 

DOl: l 0.! 002/14651858.MR000006.pub3. 29 FDA. 22 Case Studies Where Phase 2 and Phase 3 Trials llad Divergent Results. Available at https://www.fda. 

gov/downloads/AboutFDA/ReportsManualsForms/Rcp011s/UCM535780.pdf. [Last accessed Feb. 27, 2017] at 2. 30 See id. 

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drugs that were already approved by the FDA for one use but undergoing clinical testing for 

another use. 31 The selected cases were "chosen from a large pool of similar examples."32 The 

FDA noted the following: 

These unexpected results [from phase 3 trials] could occur even when the phase 2 study 

was relatively large and even when the phase 2 trials assessed clinical outcomes. In two 

cases, the phase 3 studies showed that the experimental product increased the frequency 

of the problem it was intended to prevent.33 

The agency concluded the following: 

[T]he 22 cases explored in this paper demonstrate that phase 2 results can inaccurately 

predict safety and/or effectiveness for medical products in a wide range of diseases and 

patient populations. These cases also help illustrate the potential public health implications of undue reliance on phase 2 studies and the benefits of conducting Phase [3] 

studies. As a result of the Phase [3] studies discussed in this paper, patients outside of 

clinical trials were not subjected to drugs that would not benefit them or to the risk of 

unnecessary serious toxicities, and did not suffer unnecessary financial expenditures. 

Where effective alternative therapies existed, they were not diverted from proven 

treatments; where an implanted medical device was at issue, patients were spared 

unnecessary surgical procedures. 34 

The FDA's recent report thus demonstrates the risks of allowing promotion of uses 

before successful completion of phase 3 studies and subsequent review and approval by the 

FDA. Until that point, physicians and patients cannot be reasonably assured of the safety and 

effectiveness of the product. 

Selective Reporting in Educational Materials and Published Articles - Allowing 

distribution of peer-reviewed literature about unapproved uses also skews physicians' 

perceptions of the safety and effectiveness of those uses because, as has been well documented, 

manufacturers selectively report study findings that arc most favorable for their products. When 

selecting educational material to send to doctors or to present at seminars, manufacturers choose 

material that plays up positive results and omits information about side effects, adverse reactions, 

and warnings.35·

36 For exam~le, studies comparing information in documents submitted to the 

FDA for approval of a drug3 38 or high-risk medical device 39 with information reported in peer-

''See id. at 34. 12 /d. at2. 

3J !d. 34 !d. at 29-30 35 Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998), vacated on other grounds, 202 F.3d 

331 (D.C Cir. 2000). 36 Ford M. Another usc of OxyContin: The case for enhancing liability for off-label drug marketing. BU L Rev. 

2003 ;83 :429-464. 37 Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: 

Review of publication and presentation. PLoS Med. 2008;5(11): e217. DOI:IO.l371/journal.pmed.0050217. 

(Correction: !'LoS Med 6(l): cl0000!7. doi: !0.1371/journal.pmed.IOOOOI7) 

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reviewed medical journal articles have revealed frequent discrepancies in identified primary 

endpoints and primary study results. Likewise, another study found that drug companies 

selectively report the outcomes of clinical trials.40 Unsurprisingly, the studies drug companies 

choose not to publish overwhelmingly report negative or inconclusive results. 41 In 2004, for 

example, Merck withdrew Vioxx from the market after revelations emerged that the company 

had suppressed evidence that the drug caused an increased risk of heart attack and that the 

company had attempted to discredit or "neutralize" doctors who were critical of the drug. 42 

The FDA itself, in its 2010 Transparency Task Force report, noted, "Selective publication 

of clinical trials results has, in the past, created a misleading picture of the safety and efficacy of 

a product, with negative implications for the public health. This is particularly pronounced when 

the product is used off-label."43 

Ghostwriting- The problem of inherent bias in the reported studies is exacerbated when 

companies hire ghostwriters or recruit academics to pose as authors. 44 For example, Parke-Davis 

designed and commissioned research to promote its drug Neurontin and devised a "publication 

strategy" that included contracts with medical education companies to write articles on specified 

topics involving off-label use 45 

In sum, restrictions on marketing drugs and devices for unapproved uses are crucial 

because reliance on publication of a study is no substitute for the FDA's rigorous, independent 

evaluation of the evidence. '"FDA assigns review teams and primary reviewers who specialize in 

that scientific discipline to review that portion of the application and to generate a written 

evaluation. FDA then integrates the conclusions from these separate review activities to 

38 Turner EH, Knocpflmacher D, Shapley L. Publication bias in antipsychotic trials: An analysis of efficacy 

comparing the published literature to the US Food and Drug Administration database. PLoS Med. 2012;9(3): 

el00!189. DOl: 10.137l/journal.pmed.l001189. 39 Chang L, DhrUva SS, Chu J, et al. Selective reporting in trials of high risk cardiovascular devices: Cross sectional 

comparison between premarket approval summaries and published reports. BMJ. 2015 June 10;350:h2613. 40 Vedula SS, Bero L, Scherer RW, Dickcrsin K. Outcome Reporting in Industry-Sponsored Trials ofGabapentin for 

Off-Label Use. New EnglJ Med. 2009;361:1963-1971. 41 Turner EH, Matthews AM, Linardatos E, eta!. Selective Publication of Antidepressant Trials and Its Influence on 

Apparent Efficacy. New Eng/ J Med. 2008:358:252-260. 

"Walters C. Researchers Reveal Merck's Ghostwritten Vioxx Studies. Tria!. July 2008. 43 Food and Drug Administration Transparency Task Force. FDA Transparency Initiative: Draft Proposals for Public 

Comment Regarding Disclosure Policies of the U.S. Food and Drug Administration. May 20!0. Available at 

http://www. fda. gov/ downloads/ AboutFD A/Transparency/Pub! icDisc!osure/Giossaryof AcronymsandAbbreviations/ 

UCM2121IO.pdf. [Last accessed Nov. 6, 2016] 44 Ross J, Hill KP, Egilman DS, Krumholz HM. Guest Authorship and Ghostwriting in Publications Related to 

Rofecoxib. JAM4. 2008;180Q--18!2. 

'" See Landefeld S, Michael A, Steinman M. The Neurontin Legacy-Marketing through Misinformation and 

Manipulation. New Eng/ J ivied. 2009;360: 103-106 (Parke-Davis engaged in 'the systematic use of deception and 

misinformation to create a biased evidence base and manipulate physicians' beliefs and prescribing behaviors."). 

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determine the appropriate outcome for the application."46 The agency is correct that its "multidisciplinary scientific review cannot be replicated by individual health care providers."47 

As Avom and colleagues aptly explained in their 2015 New England Journal of Medicine 

article, "physicians and patients could not be expected to determine whether a given drug was 

safe and effective without having the benefit of the lengthy and complex evaluation process 

conducted by FDA scientists and its outside advisors, who assess reams of complex data on 

pharmacology and clinical trial results, not all of which are publicly available."48 Public Citizen 

believes that stronger restrictions would better protect patients and urges the agency to 

strengthen its efforts to block promotion of drugs and medical devices for unapproved uses. 

THE FIRST AMENDMENT 

As the FDA is well aware, the pharmaceutical and medical device industries invoke the 

First Amendment to support their push to engage in increased promotion for unapproved uses. In 

our view, the First Amendment provides strong support for the existing regulatory regime and 

restrictions. 

The pharmaceutical industry-most recently the drug company Amarin, supported by 

other members of the industry as amici curiae-has argued that federal laws and regulations 

providing that prescription drugs can be introduced in commerce only if intended for uses 

approved by the FDA are a form of content- and speaker-based regulation of speech. That 

proposition, if accepted, would grant a drug manufacturer the presumptive ability to promote and 

market a drug for any use once it has received FDA approval for a single use, with the burden on 

the FDA to prove that the manufacturer's marketing was deceptive or that the drug was unsafe 

for that use. But the implications do not stop there. Taken seriously, the proposition that 

introducing a substance into commerce for a particular purpose is speech fully protected by the 

First Amendment would imply that, unless it were otherwise unlawful to manufacture or sell a 

substance, a manufacturer could market that substance as a drug with no approval at all, and its 

conduct in so doing would receive First Amendment protection unless the government bore the 

burden of showing that prohibiting the marketing of the drug satisfied strict scrutiny. Such a 

result would overturn the carefully constructed, decades-old regulatory structure that governs 

pharmaceuticals, which is premised on the FDA's expertise in determining whether to permit 

marketing only of drugs that manufacturers have proven to be safe and effective for their 

intended use. 

The heart of the federal regulatory regime governing prescription drugs since the 1962 

amendments to the FDCA has been the requirement that manufacturers bear the burden of 

proving both the safety and effectiveness of their drugs to obtain FDA premarket approval to sell 

them: 

46 FDA. Memorandum, supra note 13, at 8-9. 47 Jd. 48 Avorn J, Sarpatwari A, Kesselheim AS. Forbidden and Permitted Statements about MedicationsLoosening the Rules. N Eng/J Med. 20 15;373( 1 0):967-973. 

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In 1962, Congress amended the FDCA and shifted the burden of proof from the 

FDA to the manufacturer. Before 1962, the agency had to prove harm to keep a 

drug out of the market, but the amendments required the manufacturer to 

demonstrate that its drug was "safe for use under the conditions prescribed, 

recommended, or suggested in the proposed labeling" before it could distribute 

the drug .... In addition, the amendments required the manufacturer to prove the 

drug's effectiveness by introducing "substantial evidence that the drug will have 

the effect it purports or is represented to have under the conditions of use 

prescribed, recommended, or suggested in the proposed labcling."49 

The interlocking provisions of the FDCA and its implementing regulations establish that if a 

manufacturer places a drug into commerce with the intent that it be sold for an unapproved use, 

the manufacturer violates the FDCA's prohibition on introduction of an unapproved new drug. 5° 

Marketing a drug with such intent also violates the prohibition on misbranding a drug, because 

the drug's approved labeling will lack adequate directions for the unapproved use. 51 

As is generally true of a person's or company's intent, the intent with which a drug 

manufacturer introduces its products into commerce must be inferred, and a pharmaceutical 

company's statements in promoting its drugs are a primary source of evidence about its intent. 52 

The industry contends, however, that because it will manifest that intent through commercial 

speech aimed at encouraging doctors to prescribe products for an unapproved use, its marketing 

is entitled to First Amendment protection. On this point, the industry often invokes the Second 

Circuit's decision in United States v. Caronia, 53 but the holding of Caronia was only that the 

FDCA does not outlaw promotional speech in and of itself. If it did, the court held, its 

application to the facts of that case would not have comported with the First Amendment. 54 The 

court took care not to hold that using speech to establish a pharmaceutical company's intent to 

introduce a drug into commerce for an unapproved use would violate the First Amendmentindeed, it explicitly stated its assumption that "such use of evidence of speech is permissible." 55 

Caronia's assumption was firmly grounded in the Supreme Court's holding in Wisconsin v. 

Mitchell that "[t]he First Amendment ... does not prohibit the evidentiary use of speech to 

establish the elements of a crime or to prove motive or intent."56 

49 Wyeth v. Levine, 555 U.S. 555, 567 (2009) (quoting provisions now codified at 21 U.S.C. § 355(d)). 50 21 U.S.C. §§ 33l(d), 355(a). 

51 See id §§ 33l(a) & (b), 352(1)(1). 52 See United States v. An Article Consisting of 216 Cartoned Bottles, More or Less, 409 F.2d 734, 739 (2d Cir. 

1969) ("It is well settled that the intended use of a product may be determined from its label, accompanying 

labeling, promotional material, advertising and any other relevant source."), 53 703 F.3d 149 (2d Cir. 2012). 54 See id. at 161-62. 55 /d. at 162 n.9. The court further stated that it would be "unclear" whether a manufacturer's mere knowledge that a 

doctor intended to put a drug to an unapproved usc would establish an illicit intent by the manufacturer in 

distributing the drug. 703 F.3d at 162 n.9. 56 508 U.S, 476, 489 (1993); see also United States v. Pierce, 785 F.3d 832, 841 (2d Cir. 2015); United States v. 

Sa/ameh, 152 F.3d 88, 112 (2d Cir. 1998); United States v. Kaziu, 559 F. App'x. 32, 35 (2d Cir. 2014). 

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Even if restrictions on manufacturers' marketing of their products for unapproved uses 

were properly viewed as speech restrictions, the restrictions would pass muster as reasonable 

steps to advance the government's substantial interest in protecting and advancing public health 

by ensuring the safety and effectiveness of drugs and medical devices for each intended use. 5

7 

This conclusion is bolstered significantly by the fact, discussed above, that so much of 

manufacturers' promotion for unapproved uses is misleading. 

Some manufacturers have argued that the Supreme Court's decisions in IMS v. Sorrell 

and Reed v. Town of Gilbert suggest that restrictions on their commercial speech concerning 

drugs are subject to strict scrutiny under the First Amendment. Those cases, however, are 

inapposite. First, unlike the FDCA, the state law at issue in Sorrell, did not restrict the marketing 

of a product based on the marketer's intent; it directly restrained speech-the dissemination of 

inforn1ation. 58 And Reed did not involve commercial speech but a local ordinance that allowed 

the posting of some temporary signs and barred others based on the content of the signs. 59 

Moreover, even if marketing a drug with the intent that it be put to an unapproved use 

were subject to First Amendment protection, it would not follow that Sorrell or Reed would 

command the application of strict scrutiny. Sorrell held that a law that placed content- and 

speaker-based burdens on pharmaceutical manufacturers' commercial speech was subject to 

what it called "heightened scrutiny," but the Supreme Court used that term to differentiate the 

scrutiny applicable in general to "expression protected by the Free Speech Clause of the First 

Amendment" from the rational-basis scrutiny applicable to non-speech economic regulation, 

which the state in Sorrell advocated.60 The Court did not use the term "heightened scrutiny" to 

specify a par1icular level of First Amendment scrutiny. To the contrary, the Court declined to 

determine whether strict scrutiny or the intermediate scrutiny applicable to commercial speech 

applied to the law at issue because it held that the law could not be upheld under either 

standard.61 Reed, for its part, said nothing about standards applicable to commercial speech. 

Subsequently, numerous courts have rejected the argument that Sorrell or Reed overturned 

established law that regulations of commercial speech are subject to a lesser standard of 

justification under the First Amendment than restrictions of non-commercial speech.62 

The notion that the use of speech as evidence of someone's intent in distributing a 

product is not only subject to First Amendment scrutiny, but to strict scrutiny at that, would have 

broad consequences. Speech is used to discern intent, without First Amendment scrutiny, in a 

broad range of cases, including, among others, criminal conspiracy, antitrust, and employment 

57 See Central Hudson, 447 U.S. 557 (1980) (setting for standard for restrictions on commercial speech). 58 131 S. Ct. 2653,2667 (2011). 59 135 S. Ct. 2218 (2015). 60 131 S. Ct. at 2659. 61 See id. at 2667; see also Caronia, 703 F.3d at 164 (stating that Sorrell "did not decide the level of heightened 

scrutiny to be applied, that is, strict, intermediate, or some other form of heightened scrutiny"). 60 See, e.g, Chiropractors United for Research & Educ., LLC v. Comvay, 2015 WL 5822721, at *5 (W.D. Ky. Oct. 

1, 2015); Contest Promotions, LLC v. Cit)' and Cty. qf SF., 2015 WL 4571564, at *4 (N.D. Cal. July 28, 2015); 

California Outdoor Equity Partners v. City of Corona, 2015 WL 4163346, at *10 (C.D. Cal. July 9, 2015); King v. 

Gen. Info. Servs., 903 F. Supp. 2d 303,307-09 (E.D. Pa. 2012). 

13 
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Public Citizen April 19,2017 

Comments on FDA Draft Guidance 

Docket No. FDA-2016-D-1149 

discrimination cases. In particular, it is not unusual for a person's intent concerning the 

commercial use of an item to have consequences with respect to whether his conduct is lawful or 

unlawful. The Supreme Court, for example, recently considered the federal Controlled Substance 

Analogue Enforcement Act, which makes unlawful the knowing manufacture or distribution (or 

possession with intent to distribute) of a substance that is similar in chemical structure and 

physiological effect to a federally listed controlled substance if the substance is "intended for 

human consumption."63 The Court held that a conviction under the Act requires that the jury find 

the defendant possessed knowledge that the substance was an analogue of a controlled substance 

as well as intent that it be used for human consumption 64 Unsurprisingly, the Court's opinion 

suggests no discomfort with the First Amendment implications of making the defendant's guilt 

depend on his or her intent with respect to the purchaser's use of the substance. 

Under the view of the First Amendment espoused by industry, however, the law would 

require First Amendment scrutiny if the government sought to prove a defendant's intent based 

on his or her statements that a buyer could get high if he or she used the analogue. Imposing 

liability where the defendant had promoted an analogue for such usc but not where he or she had 

sold the substance for use as, say, an engine lubricant would be a "content-based" restriction on 

speech. And punishing a manufacturer or distributor who had advocated human consumption of 

a controlled substance analogue, but not a bloggcr who supported the use of the substance by 

humans, would, in industry's view, be a "speaker-based" speech regulation. A theory under 

which the use of speech to prove intent concerning the distribution of controlled substances 

would be subject to First Amendment scrutiny, let alone strict scrutiny, is dubious, to say the 

least. 

As the FDA has recognized, the industry view of the First Amendment's scope would 

have extremely broad implications for drug and device regulation because it would call into 

question the foundation of the regulatory regime.65 The regulatory regime is, at its most basic 

level, triggered by the introduction of a substance into commerce with the intent that it be used to 

diagnose, cure, mitigate, treat, or prevent disease or to affect the structure or function of the 

body66 It would, for example, be perfectly legal from the standpoint of the FDCA to introduce a 

new drug into commerce as an indoor plant food, without FDA review and approval: The FDCA 

would not classify the substance as a drug if sold with the intent that it be used in that manner, 

and, hence, it would not require FDA approval. The industry's First Amendment theory, 

however, suggests that if a manufacturer could lawfully market the substance for that non-drug 

use but could not, without approval, lawfully market it for use to prevent disease, the imposition 

of criminal or civil liability on the manufacturer for selling the product as a drug without 

63 McFadden v. United States. U.S._, 2015 WL 2473377, at *4 (2015) (discussing 21 U.S.C. § 813). 64 See id. at *5. 65 Amarin Pharma fnc. v United States Food & Drug Administration, 119 F. Supp. 3d 196, 226 (S.D.N.Y. 2015) 

(quoting FDA brief and FDA statement at oral argument). 66 See 2!6 Cartoned Bottles, 409 F.2d at 739 ("Regardless of the actual physical effect of a product, it will be 

deemed a drug for purposes of the Act where the labeling and promotional claims show intended uses that bring it 

within the drug definition."); see also, e.g., Whitaker v. Thompson, 353 F.3d 947, 949-52 (D.C. Cir. 2004); United 

States v. Cole,_ F.3d _, 2015 WL 471594, at *3 (D. Or. Feb. 5, 2015); United States v. Livdahl, 459 F. Supp. 2d 

1255, 1259-<iO (S.D. Fla. 2005). 

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Public Citizen April I 9, 2017 

Comments on FDA Draft Guidance 

Docket No. FDA-2016-D-1149 

approval would require First Amendment scrutiny because liability would be based on the 

manufacturer's speech in promoting the product as a drug. 67 Moreover, according to some 

industry arguments, the prohibition on selling an unapproved drug as a drug rather than as 

fertilizer would be subject to strict scrutiny, under which, they argue, the burden would be on the 

FDA to prove that the unapproved substance posed dangers that were sufficient to create a 

compelling interest in stopping the manufacturer from marketing it as a drug. 

Assertions that the FDCA's fundamental requirement of premarkct approval violates the 

First Amendment because it is based on an inference of intent from the manner in which a 

manufacturer markets a product have, when made directly, been rejected by the courts.68 The 

FDA should not allow expanded promotion for unapproved uses based on that argument Such 

expansion is not constitutionally required and would be detrimental to important protections for 

public health and safety. The FDCA's requirement that manufacturers bear the burden of proving 

both the safety and effectiveness of new drugs for their intended uses is critical to achieving 

Congress's objectives of protecting the public against unsafe or worthless pharmaceutical 

products. 

Last year, the judge presiding over the Amarin Pharma litigation suggested that the 

current drug-approval framework may be inconsistent with "modern First Amendment law."69 

That judge's worrisome suggestion is not correct. The First Amendment provides no protection 

to commercial speech-speech that proposes a commercial transaction-if that speech is false or 

misleading. And messages promoting unapproved uses are necessarily misleading when they 

suggest a health benefit that has not been established. Even beyond the misleading nature of 

much off-label promotion, the First Amendment is no bar to commercial speech restrictions that 

advance substantial government interests. The FDCA regulatory scheme, and in particular the 

drug-approval process, was developed over the 20th Century to protect a very substantial 

government interest: protecting public health. The First Amendment view set forth in the A marin 

decision fails to understand the balancing that is at the very heart of First Amendment cases and 

the invaluable role of the regulatory scheme in protecting patients from unsafe or ineffective 

drugs. 

CONCLUSION 

History shows that after-the-fact enforcement is inadequate to protect patient safety. 

Rather, when an unproven assertion of safety and effectiveness is relied on, the resulting harm 

may be severe--even, as was the case with Elixir Sulfanilamide, irreparable. In the strongest 

67 Cf Caronia, 703 F .3d at 180 (Livingston, J ., dissenting). 68 See Whitaker, 353 F.3d at 953; United States v. Cole, 2015 WL 471594, at *4-5; see also Holistic Candlers & 

Consumer Ass'n v. FDA, 770 F. Supp. 2d 156, 164 & n.l5 (D.D.C. 2011) (characterizing First Amendment 

challenge to requirement of pre market approval for medical device as "foreclosed by settled law holding that use of 

speech to establish an element of a violation does not violate the First Amendment"), aff'd on other grounds, 664 

F.3d 940 (D.C. Cir. 2012). 69 Amarin Pharma Inc. v United States Food & Drug Administration, 119 F. Supp. 3d at 226. 

15 
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Public Citizen Aprill9, 2017 

Comments on FDA Draft Guidance 

Docket No. FDA-2016-D-1149 

terms, we urge the FDA to strengthen, not loosen, its restrictions on promotion of drugs and 

medical devices for unapproved uses. 

Michael A. Carome, M.D. 

Director 

Public Citizen Health Research Group 

16 

Allison M. Zieve 

Director 

Public Citizen Litigation Group 
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lS]n 

SUSTAINABlE Rx PRICING 

Value. 

Testimony Submitted for the Record 

U.S. House Energy and Commerce Committee 

Subcommittee on Health 

Hearing on "Examining Medical Product Manufacturer Communications" 

John Rother 

Executive Director 

The Campaign for Sustainable Rx Pricing (CSRxP) 

July 12, 2017 

Chairman Burgess, Ranking Member Green, and members of the House Energy and Commerce 

Subcommittee on Health, the Campaign for Sustainable Rx Pricing (CSRxP) thanks you for the 

opportunity to submit testimony for the record on medical product manufacturer 

communications. 

CSRxP is a project of the National Coalition on Health Care Action Fund. We are a broad-based 

coalition of leaders- physicians, nurses, hospitals, consumers, health plans, PBMs, pharmacists, 

and businesses- promoting bipartisan, market-based solutions to lower drug prices in America. 

It is a fact: prescription drug prices are out of control. The consequences of this crisis hurt 

everyone, from patients and consumers to doctors, hospitals, and hardworking taxpayers. 

That's why it is critical to solve this crisis now with smart, effective solutions that work. 

CSRxP believes that permitting more open medical product manufacturer communications will 

provide increased certainty and clarity to payers as they predict and prepare for future 

spending on emerging therapies, thus allowing them to set more stable premium and out-ofpocking spending levels for consumers over time. Such communications should have 

appropriate parameters, however, so that manufacturers maintain incentives to undergo the 

FDA approval process, thereby giving U.S. patients, their families, and their healthcare 

providers peace of mind that the products they use are safe and effective. 

H.R. 2026, the Pharmaceutical Information Exchange Act would facilitate more open, predecisional communication- communication about an emerging therapy prior to FDA approval 

or clearance- between manufacturers and payers while at the same time preserving 

appropriate incentives for manufacturers to seek FDA approval for their products. With respect 

to H.R. 1703, the Medical Product Communications Act of 2017, CSRxP believes Congressional 

action may be premature and warrant further consideration of the issues as presented in the 

legislation. 
144 


I. Pre-decisional manufacturer communications can help payers establish more predictable 

rates for patients and consumers over time, as well as enable more use of value-based 

payment arrangements. 

Healthcare stakeholders try to forecast costs of healthcare spending several years into the 

future to keep rates and premiums as predictable as possible for patients and their families. 

Predictability results in more stable rates and fewer unexpected spikes in year-over-year out-ofpocket costs and premiums- a particularly meaningful benefit to U.S. consumers as they 

consider their healthcare needs. 

Accurate rate development relies on detailed assumptions about the anticipated utilization of 

health care services, including prescription drugs and medical devices. Without accurate, 

reliable, and more transparent clinical and pharmacoeconomic information about new products 

or expanded indications of existing products, payers cannot appropriately account for emerging 

therapies when budgeting for the future- whether it be for a hospital system or for a health 

plan setting premiums. The concern is becoming more acute as medical products are moving 

more quickly and efficiently through the FDA approval process. 

Moreover, more open and transparent pre-decisional communications may better position 

payers to conduct their own population-based value assessments of therapies and related 

benefit designs to broaden use of value-based healthcare payment strategies. For example, 

such information could support development of outcome-based contracts and indicationsbased pricing arrangements. 

II. Drug makers should be able to engage in more transparent pre-decisional communications 

about their products only if they also are required to be more transparent in their drug 

pricing strategies prior to FDA approval. 

More open communications should be considered just the first step in the broader goal of 

creating more transparency into how pharmaceutical companies determine how they are going 

to price their products. Without requiring the pharmaceutical industry to be more transparent 

on drug pricing and price growth, American patients and their families will continue to face 

unsustainable and needless increases in prescription drug costs. 

Consequently, CSRxP strongly urges that any legislation which permits drug makers to conduct 

more open and transparent pre-decisional communications about their products also must 

require them to be more transparent about product pricing prior to FDA approval. Such 

information should include the maximum unit price the drug maker intends to charge for the 

product; the cost of a course of treatment; the label under discussion with the FDA that 

indicates the target population with other important clinical details; and a projection of federal 

spending on the product. 

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More transparent pre-decisional drug pricing also could help payers expand use of value-based 

health care payment strategies, which potentially can lower costs, increase access and improve 

health outcomes for patients taking these medications. In other words, pre-approval drug 

pricing transparency is a critical strategy in making prescription drugs more affordable for all 

Americans, while at the same time, maintaining and potentially expanding access to treatments 

that can improve patient health and quality of life. 

Ill. Communications should follow a regulatory framework that enables manufacturers to 

convey pre-decisional information about their products while at the same time ensuring that 

incentives remain to have the products go through the FDA approval process. 

Knowing that medical products are safe and effective for use is critical for both patients and the 

prescribing physicians. Hence, any pre-decisional manufacturer communications should 

maintain appropriate safeguards to incentivize manufacturers to go through the FDA approval 

process, which deems their products safe and effective for patient use. Such safeguards should 

include the following: 

• Pre-decisional communications only should reflect scientifically-sound, competent and 

reliable evidence that is truthful, non-misleading, and unbiased. The communications 

should include information such as risk/benefit and quality data, as well as appropriate 

disclaimers on the limitations of the data presented. 

• Existing FDA policies should not be modified in any way that would extend increased 

flexibility to manufacturers to promote off-label uses of their products directly to 

consumers. Rather, pre-decisional communications only should occur between entities 

with both financial and clinical interests in avoiding the unintended consequence of 

affecting prescribing practices by physicians directly treating patients. For example, any 

communications between manufacturers and medical service providers should adhere 

to specific criteria to ensure the information is relevant, scientifically sound and 

responsibly presented. They should be limited to appropriate proactive requests to 

manufacturers or to certain venues that meet widely accepted and recognized 

standards for communications about scientific and clinical data such as scientific 

journals, clinical practice guidelines, and compendia, but not to lay media, letters to the 

editor, or proactive and reactive communications. 

• Manufacturers only should discuss information related to medical product indications 

undergoing FDA review. 

• The pre-decisional communications only should occur within a certain timeframe of the 

expected FDA approval date. 

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146 


• Given the many emerging technologies and evolving organizations and relationships into 

which manufacturers enter, the FDA should have latitude to periodically revisit and 

reassess the definitions of entities covered by the pre-decisional communications 

safeguards. 

The FDA currently is reviewing the extent to which appropriate safeguards, such as those 

outlined above, may allow for additional communications from manufacturers about their 

products. As noted above, with respect to H.R. 1703, CSRxP believes the FDA should complete 

its review prior to any Congressional action to expand the definition of scientific exchange 

between manufacturers and health care professionals so that any expanded communications 

strictly include information that is truthful, non-misleading, unbiased, supported by competent 

and reliable evidence, relevant, and responsibly presented. 

IV. Conclusion 

CSRxP appreciates the Subcommittee's leadership and, again, thanks the Subcommittee for the 

opportunity to submit testimony for the record on medical product manufacturer 

communications. We look forward to collaboration in the future on developing market-based 

policies that promote competition, transparency, and value to make prescription drugs more 

affordable for all American patients and their families while at the same time maintaining 

access to the treatments that can improve health outcomes and save lives. 

4 
147 


_A, 

AH/P 

STATEMENT FOR THE RECORD 

Submitted to the 

House Energy and Commerce Committee 

Subcommittee on Health 

Examining Medical Product Manufacturer Communications 

July 12, 2017 

America's Health Insurance Plans 

601 Pennsylvania Avenue, NW 

Suite 500, South Building 

Washington, D.C. 20004 

1 
148 


America's Health Insurance Plans (AHIP) is the national association whose members provide 

coverage for health care and related services to millions of Americans every day. Through these 

offerings, we improve and protect the health and financial security of consumers, families, 

businesses, communities and the nation. We are committed to market-based solutions and 

public-private partnerships that improve affordability, value, access and well-being for 

consumers. 

We appreciate this opportunity to offer our comments on two draft bills addressing 

pharmaceutical manufacturer communications on medical products: the "Medical Product 

Communications Act" and the "Pharmaceutical Information Exchange Act." Proposed changes 

to the rules surrounding these communications could have far-reaching implications for the 

decisions made by health care providers, in consultation with their patients, about which 

medications and other medical products are safe, effective, and appropriate for treating their 

patients. We believe it is critically important for Congress to fully consider the potential impact 

of these proposed changes on patient safety, health outcomes, and our shared goal of promoting 

high quality, affordable health care for all Americans. 

"Medical Product Communications Act" (H.R. 1703) 

Patients deserve to have more information about their medical care from the cost of their care, 

to the quality of their providers, to the efficacy of their treatments. With more information, more 

consumers can make better-informed decisions. However, it is critical to understand that better 

decisions are based on accurate, evidence-based information- not just more information. 

Information that is inaccurate, incomplete, or inconclusive helps no one. 

Health insurance providers are committed to helping every patient access high-quality care that 

gets them well when they're sick and keeps them well when they're healthy. That means finding 

the safest, most effective treatments that best meet the individual needs of individual patients. 

That may include the innovative usc of prescription drugs for conditions that are not specifically 

approved by the Food and Drug Administration (FDA) and not included or indicated on the 

product label. This "off-label" use has helped many patients get well and stay healthy. When 

there is strong evidence to support off-label usc of prescriptions drugs, health plans often provide 

coverage for such usage. For example, in the Medicare prescription drug program, Part D plans 

2 
149 


cover drugs prescribed for off-label usc if the drugs are identified as safe and effective for that 

use in certain officially recognized drug compendia. 1 

The "Medical Product Communications Act" would not provide or ensure that patients and care 

providers have access to better research and evidence. Rather, it would allow drug 

manufacturers to communicate information about prescription drugs that has not been approved 

by the FDA. The lack of approval may be due to contradictory evidence- or the lack of any 

evidence at all or the need for additional research. 

The FDA's current requirements for meeting high standards of evidence for safety and efficacy 

help ensure that robust evidence exists to support approval of drugs, biologics, and devices for 

specific uses and indications. To truly help patients get the most effective treatments, it is 

essential to maintain the highest standards of safety, research and evidence. These rules- and 

the incentives for manufacturers to comply with proper FDA processes- should be preserved. 

Because we want to ensure that patients and care providers have access to accurate information 

based on the best possible research and the strongest possible evidence, AHIP does not support 

this legislation. We have serious concerns that it could undermine the FDA's efforts to ensure 

that providers and patients receive information that is truthful, is supported by rigorous scientific 

evidence, and is not misleading or biased. Specifically, we are concerned that allowing drug 

manufacturers to communicate about unapproved uses of their products reduces the incentive for 

them to go through the FDA's supplemental application approval process. The draft legislation 

proposes removing the scientific exchange of off-label uses from the definition of "intended use" 

of the drug or device, preventing the FDA from any oversight of the scientific exchange of 

information about off-label uses of drugs and devices. This, in turn, reduces the incentive for 

manufacturers to conduct large, well-controlled, randomized clinical trials that would prove a 

product is both safe and effective for a particular indicated use. 

Ultimately, this result would weaken the FDA's role to ensure patient safety and public health, 

introducing far more safety risks into the health care system than potential rewards. 

Additionally, at a time when policymakers are working on ways to increase value and decrease 

1 Social Security Act§ 1860D-2(e)(4)(A). Also of note, drugs indicated to treat sexual or erectile dysfunction are not 

covered in Medicare Part D, and coverage of any off-label uses of such indicated drugs are also prohibited under 

Social Security Act §1860D-2(c)(2)(A). 

3 
150 


costs across the health care system, we must consider that this has the potential to dramatically 

increase costs by utilizing potentially expensive therapies, without substantial evidence of better 

care, better quality, or better outcomes. 

We also want to emphasize that- even without the proposed legislation- health care service 

providers already have access to scientific information about unapproved uses of medical 

products, and physicians currently are free to use drugs for "off-label" indications. This 

information is widely available through public sources such as scientific journals, clinical 

practice guidelines, and compendia. 

While these existing sources of information provide evidence-based information with respect to 

the safety and efficacy of medical products, a recent Journal of the American Medical 

Association (JAMA) study tracking off-label use in 45,000 adults through electronic health 

records (EHRs) over 2005-2009 found that, of the off-label prescriptions studied, 80 percent 

lacked scientific evidence and had a higher occurrence of adverse drug events (ADEs). The 

study concluded that off-label use is associated with a higher occurrence of A DEs, and 

recommended that EHRs "be designed to enable postmarketing surveillance of treatment 

indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs."2 

We appreciate that the parameters around the scientific exchange of off-label uses have been 

strengthened in the draft legislation, preventing the communications from promotional use and 

requiring competent and reliable scientific evidence and appropriate contextual information 

regarding any limitations of evidence. However, we believe these communications would be 

inherently promotional and less likely to reflect the rigorous scientific analysis that providers 

need to serve the best interests of their patients while preventing adverse events. 

The FDA currently is reviewing its policies to determine the extent to which additional 

communications from manufacturers can provide access to information on off-label uses that is 

relevant, scientifically sound, and responsibly presented. We believe this process offers promise 

for developing a common sense policy. AHIP has submitted comments to the FDA, urging the 

agency to consider defining allowable parameters for these communications, such as limiting 

2 Tewodros Equale, et al., "Association of Off-label Drug Use and Adverse Drug Events in an Adult Population," 

Journal of the American Medical Association Internal Medicine 176, no. I (2016): 55-63, 

doi: 10.1 00lljamaintcrnmed.20 15.6058. 

4 
151 


them to indications undergoing FDA review and occurring within a certain timeframe of the 

expected FDA approval date. We also recommend that the communications include risk-benefit 

and quality data, appropriate disclaimers (including the limitations of such evidence), and other 

relevant information.3 

We appreciate the committee's interest in examining the rules that apply to manufacturer 

communications on "off-label" uses, as many of these issues have been the subject of legal 

disputes. However, we urge you to proceed cautiously when considering the pending draft 

legislation and take into consideration the long-term patient safety implications, the potential 

increase in health care costs associated with investigational drug use, and the FDA's 

deliberations on this issue. 

"Pharmaceutical Information Exchange Act" (H.R. 2026) 

The "Pharmaceutical Information Exchange Act" would expand the ability of drug and device 

manufacturers to share health care economic information (HCEI) and scientific information with 

payors, formulary and technology review committees, and similar entities for investigational use 

drugs and devices before they are approved by the FDA. 

We addressed these issues in a comment letter we recently submitted to the FDA. 4 Our letter 

highlighted our members' priorities in three areas: 

• The importance of holding communications between manufacturers and payers, formulary 

committees, and similar entities to strong evidentiary standards; 

• The value of a regulatory framework that enables manufacturers to communicate HCEI or 

real world evidence (RWE) related to an FDA-approved indication to payers, formulary 

committees, and similar entities; and, 

3 AillP letter to Food and Drug Administration, responding to request for comments on "Manufacturer 

Communications Regarding Unapproved Uses of Approved or Cleared Medical Products." April 18, 2017. 

' AHIP letter to Food and Drug Administration, providing comments on draft guidance on "Drug and Device 

Manufacturer Communications with Payors, Formulary Committees, and Similar Entities --Questions and 

Answers." April 18, 2017. 

5 
152 


• The need for timely and appropriate communications based on strong evidentiary standards 

between manufacturers and payers, formulary committees, and similar entities about products 

that are investigational or under review by the FDA. 

AHIP supports the goals of this draft legislation. The current uncertainty over what 

communications are permitted often makes it difficult for health plans to obtain reliable HCEI 

related to an FDA-approved indication and therefore complicates their efforts to make accurate 

assessments regarding value, pricing, and utilization. Health plans need sound information based 

on strong evidentiary standards to inform estimates of anticipated costs for up to several years 

into the future when making business decisions involving pricing and contracts. 

In addition, because this information is not permitted for products that are labeled investigational 

or under FDA review, it is currently difficult for plans to obtain information about manufacturer 

pipelines (including both new products and additional indications for existing FDA-approved 

products), which is also essential to their ability to make accurate assessments about value, 

pricing, and utilization in the longer term. A regulatory framework that enables manufacturers to 

communicate with payers regarding products that are investigational and under review by the 

FDA will allow payers to take that information into consideration as they plan for and make 

coverage and reimbursement policies far in advance of the effective date of the decisions. 

Additionally, early and appropriate communication ofthis type of information can enable 

manufacturers and payers to develop alternative, value-based payment arrangements, such as 

outcome-based contracts and indication-specific pricing. 

While we support the goals of this draft legislation, we would like to reemphasize the importance 

of ensuring these communications promote patient safety and public health. Safeguards must be 

in place so that information communicated regarding HCEI for products that are investigational 

or under review be held to strong evidentiary standards. We appreciate that the draft legislation 

requires these communications to be based on "competent and reliable scientific evidence" 

(CARSE), and support the FDA's intent to consider HCEI to be based on CARSE if"the HCEI 

has been developed using generally-accepted scientific standards, appropriate for the information 

being conveyed, that yield accurate and reliable results." 

Additionally, we believe the FDA should periodically revisit and reassess the definitions and 

entities covered. Over time, emerging technology, evolving organizations and relationships, 

6 
153 


along with other changes in health care may create some ambiguity in the intended audience for 

these communications. It will be important to ensure that the information sharing occurs 

between sophisticated entities with both a financial and clinical interest to avoid the unintended 

consequence of affecting prescribing practices by physicians who are directly treating patients. 

Thank you for considering our views on these draft bills. We stand ready to work with you on 

medical product manufacturer communications. We also look forward to working with you on 

broader issues surrounding the high cost of prescription drugs and the need for market-based 

solutions to ensure that consumers have access to affordable medications. 

7 
154 


GREG WALDEN, OREGON 

CHAIRMAN 

ONE HUNDRED FIFTEENTH CONGRESS 

FRANK PALLONE. JR .. NEW .JERSEY 

RANKING MEMBER 

C!ongre~~ of tbe 'mlniteb $tate~ 

1t,)oul'ie of l\cprcl'ientatil.lel'i 

COMMITTEE ON ENERGY AND COMMERCE 

2125 RAvsuRN HousE OFFICE BuiLDING 

WASHINGTON, DC 20515-6115 Ma!1.mty 

Mm<mty 

August 17, 2017 

Ms. Coleen Klasmeier 

Partner 

Sidley Austin LLP 

I SOl K Street, N.W. 

#600 

Washington, DC 20005 

Dear Ms. Kiasmeier: 

Thank you for appearing before the Committee on Energy and Commerce on July 12, 20 17, to 

testify at the hearing entitled "Examining Bipartisan Legislation to Improve the Medicare Program." 

Pursuant to the Rules of the Committee on Energy and Commerce) the hearing record remains 

open for ten business days to permit Members to submit additional questions for the record, 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 ptinting of the hearing record, please respond to these questions with a 

transmittal letter by the close of business on August 31,2017. Your responses should be mailed to Zack 

Dareshori, Legislative Clerk, Conunittee on Energy and Commerce, 2125 Rayburn House Office 

Building, Washington, DC 20515 and e-mailed in Word format to zack.dareshori@mail.house.gov. 

Thank you again for your time and effort preparing and delivering testimony before the 

Committee. 

cc: The Honorable Gene Green, Ranking Member, Subcommittee on Health 

Attachment 
155 


Responses to Additional Questions for the Record 

The Honorable Michael C. Burgess 

1. We heard testimony as to the need for FDA to act as a "learned intermediary" between 

manufacturers and prescribers with respect to scientific information disseminated under the 

proposed legislation. Would it represent a significant shift in federal medical product 

regulation if the law were to require all manufacturer communications to be reviewed by FDA 

in advance? What is the scope of FDA's authority under current law to substitute its judgment 

for that of a prescriber when it comes to drug and medical device use? 

Requiring prior FDA review of all manufacturer communications would represent a significant shift in 

federal medical product regulation, because Congress has expressly limited FDA's authority to require 

prior agency review of manufacturer communications. Under Section 502(n) and (r) of the Federal 

Food, Drug, and Cosmetic Act (FDCA), "except in extraordinary circumstances, no regulation issued 

under this paragraph shall require prior approval by the Secretary of the content of any [prescription 

drug or restricted device] advertisement[.]"' If the law were changed to require prior FDA review of all 

manufacturer communications, then FDA would be unable to maintain its well-established policy of 

permitting manufacturers to engage in certain communications with respect to new uses of lawfully 

marketed medical products. A new requirement of prior FDA approval would also raise constitutional 

issues. 

Congress did not give FDA the power to regulate all manufacturer speech. The FDCA authorizes FDA to 

regulate the content of prescription drug and restricted device "labeling" and "advertising."' 

Manufacturer communications outside the scope of the relevant statutory provisions are not subject to 

regulation by FDA. In addition, although FDA requires manufacturers to substantiate efficacy claims 

prior to marketing through the new drug and device clearance and approval processes, FDA rules have 

long permitted manufacturers to promote their products using accurate, substantiated claims about 

clinical benefits, price, and other product attributes, all without prior authorization and without 

requiring that the claims be derived from approved labeling.3 

Nor does FDA regulate "scientific information" about drugs and medical devices, except to the extent 

such information qualifies as "labeling" or "advertising" as discussed above. FDA has determined, as a 

matter of policy, that manufacturers should have the ability to provide scientific information to 

practitioners, payers, and patients about drugs and medical devices, including investigational products 

1 21 U.S.C. § 352(n), (r). See also 21 C.F.R. §§ 202.1(j)(1)-(3), 314.550. In rare instances, FDA prior approval of 

promotional materials has been a component of a negotiated resolution of an enforcement action or investigation. 

2 21 U.S.C. §§ 321(n), 352(a), (f)(l), (n), and (r). FDA is also authorized to regulate oral statements by sales 

representatives indirectly, on the ground that such statements create new "intended uses" for lawfully marketed 

products. See 21 C.F.R. §§ 201.128, 801.4. 

3 E.g., 21 C.F.R. §§ 200.200, 202.1(e)(2)(i) & (6)(i). 
156 


and new uses of lawfully marketed products, without those communications triggering FDA regulation. 

FDA's policy is reflected in numerous agency statements, including regulations and guidance documents, 

facilitating manufacturer "scientific exchange," manufacturer dissemination of journal article reprints 

and other publications that include information regarding new uses of medical products, manufacturer 

responses to unsolicited requests, and manufacturer support for continuing education and similar 

events at which new uses will be discussed. FDA's policy is one of "delicate balance" between 

enforcement of the FDCA and support for patient care through manufacturer communication of useful 

information to facilitate health care practitioner decisions with respect to the uses of drugs and medical 

devices.4 

Once FDA has authorized marketing, the agency generally lacks the authority "to substitute its judgment 

for that of a prescriber" with respect to the use of that product. The FDCA is not a broad grant of power 

with respect to health care delivery or medical or surgical practice. Congress intended for FDA to 

influence medical practice only indirectly, by applying the statutory provisions governing the market 

introduction of new drugs and medical devices and the related provisions governing the content of 

labeling.5 As FDA explained more than four decades ago: 

[A]Ithough it is clear that Congress did not intend the Food and Drug Administration to 

regulate or interfere with the practice of medicine, it is equally clear that it did intend 

that the Food and Drug Administration determine those drugs for which there exists 

substantial evidence of safety and effectiveness and thus will be available for 

prescribing by the medical profession, and additionally, what information about the 

drugs constitutes truthful, accurate, and full disclosure to permit safe and effective 

prescription by the physician. As the law now stands, therefore, the Food and Drug 

Administration is charged with the responsibility for judging the safety and effectiveness 

of drugs and the truthfulness of their labeling. The physician is then responsible for 

making the final judgment as to which, if, any, of the available drugs his patient will 

receive in the light of the information contained in their labeling and other adequate 

scientific data available to him.6 

4 59 Fed. Reg. 59,820, 59,825 (Nov. 18, 1994). See also 61 Fed. Reg. 52,800, 52,800 (Oct. 8, 1996); 57 Fed. Reg. 

56,412, 56,412 (1992). 

5 In addition to reviewing and approving the official product labeling for a drug or medical device, FDA has the 

opportunity to review and provide comments on promotional labeling and advertising for prescription drugs when 

those materials are submitted to the Office of Prescription Drug Promotion (OPDP) within the Center for Drug 

Evaluation and Research (CDER) in accordance with 21 C.F.R. § 314.81(b)(3)(i). Manufacturers also commonly 

submit proposed promotional materials to OPDP for prior review incident to launch, and consumer-directed 

television advertisements are routinely submitted for prior review by OPDP in accordance with industry guidelines. 

6 37 Fed. Reg. 16,503, 16,504 (Aug. 15, 1972). See also 21 U.S.C. § 396 ("Nothing in this chapter shall be construed 

to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed 

device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship. 

This section shall not limit any existing authority of the Secretary to establish and enforce restrictions on the sale 
157 


In certain cases, FDA may impose specific restrictions on the use of a product in order to mitigate 

serious risks, such as requirements that prescribers of a drug have particular training, experience, or 

certification. Congress has authorized FDA to restrict the uses of a medical product by prohibiting the 

use of human growth hormone for uses not approved by the Agency.' In all other cases, prescribers 

employ their own medical judgment in determining the appropriate uses of medical products. 

A change in federal law to require prior FDA approval of all manufacturer communications would raise 

significant constitutional concerns. As the Supreme Court has recognized, the First Amendment protects 

truthful and non-misleading speech by medical product manufacturers, including commercial speech 

comprising "labeling" and "advertising." Moreover, the government may not restrict accurate speech 

about lawful activity (including off-label use) in order to prevent "bad decisions" or to influence health 

care practitioners or patients to make choices the government prefers. 

or distribution, or in the labeling, of a device that are part of a determination of substantial equivalence, 

established as a condition of approval, or promulgated through regulations. Further, this section shall not change 

any existing prohibition on the promotion of unapproved uses of legally marketed devices."). 

7 21 U.S.C. § 353{e). Product use is also limited by prescription-only designation (including restricted designation 

for medical devices). 
158 


2. We heard testimony regarding the inability of any manufacturer to provide complete 

information about a new use. It was also suggested that FDA is the only source of complete 

information about the full range of medical product uses. What information does FDA receive 

from manufacturers, adverse event reporting, and other sources, and how does that 

information compare to the data and analysis to which the manufacturer has access? 

In general, FDA will not have "complete" information about all uses of a medical product. 

Manufacturers often have unique access to information about their products, including new uses.• FDA 

has acknowledged for many years, and recently reaffirmed, that "[s]cientific departments within 

regulated companies generally maintain a large body of information on their products."9 FDA generally 

relies on manufacturers to provide the agency with information about their products, such as adverse 

events and other product information subject to reporting by manufacturers under the FDCA. This 

includes information about off-label uses. For example, FDA requires manufacturers to review and 

analyze information about adverse events associated with their products, including events that involve 

an off-label use. 10 

In recent years, FDA has sought to supplement the current regulatory scheme driven by manufacturer 

reporting with national systems for active identification of new risks associated with approved products, 

including Sentinel and the National Evaluation System for Health Technology (NEST). The regulatory 

scheme is nonetheless largely designed to require the manufacturer to collect and analyze information 

in the first instance, thereby enabling FDA to allocate finite resources effectively by focusing on issues 

and categories of information that are most likely to have public health impact. For example, FDA does 

not require manufacturers to inform the agency of every published study about a product. Rather, the 

manufacturer is required to notify FDA on an expedited basis if such a study describes a serious adverse 

event." 

8 Wyeth v. Levine, 555 U.S. 555, 578-79 (2009) ("manufacturers have superior access to information about 

their drugs"). 

9 59 Fed. Reg. 59,820, 59,823 (1994); FDA, Guidance for Industry: Responding to Unsolicited Requests for Off-Label 

Information About Prescription Drugs and Medical Devices 2 (Dec. 2011). 

10 21 C.F.R. § 314.80(b)-(c). 

11 E.g., 21 C.f.R. § 314.80(d). 
159 


3. It has been suggested that off-label information might be more useful in some areas of 

practice than in others. How _should the subcommittee evaluate that issue, and is there a 

principled basis in the law for making a distinction in the regulation of information 

dissemination according to the nature ofthe disease area (e.g., rare diseases, oncology) or 

patient population (e.g., pediatrics)? 

Off-label use is particularly prevalent in certain patient populations and disease areas. These include: 

Pediatrics, where most drugs simply have no information in approved labeling addressing use in 

children. This is a particular issue for preterm infants, newborns, young children, and children 

with chronic or rare diseases. 

Oncology. where off-label use is a mainstay and satisfies critical, unmet patient needs. Because 

of the high morbidity and mortality observed in many cancer patients, oncologists quickly 

incorporate into clinical practice emerging data regarding potentially effective new uses. 

Psychiatry, where multiple treatment attempts and methods may be necessary before a 

successful therapy can be found for a patient, and a drug that is approved to treat one condition 

may also treat a related, but unlabeled, one. Psychiatric patients are treated based on 

symptoms rather than on specific diagnoses, and there are even psychiatric disorders for which 

no approved drug has an indication, such that off-label use is the only option for drug therapy. 

Even if FDA has approved a drug for a particular condition, the patient may fall outside the 

labeled patient population, or might need a higher or lower dosage. 

Rare diseases, where many patients are prescribed at least one drug for an off-label use." 

Legally, however, there is no basis on which to regulate all information dissemination according to 

disease area or patient population. The FDCA simply does not authorize FDA to regulate speech on that 

basis. And, although the case law is extensive and complex, a basic First Amendment principle prohibits 

a government agency from forbidding truthful, non-misleading speech about lawful activity, and offlabel use remains lawful and appropriate (and indeed may constitute the standard of care) across many 

therapeutic scenarios. As a result, FDA would encounter significant constitutional obstacles if it were to 

adopt categorical rules prohibiting truthful, non-misleading speech about medical product uses in some 

therapeutic areas but not others. 

12 James O'Reilly & Amy Dalal, Off-Label or Out of Bounds? Prescriber and Marketer Liability for Unapproved 

Uses of FDA Approved Drugs, 12 Ann. Health Law 295 (2003). 
160 


4. We heard testimony regarding the need for FDA to adjudicate "claims" and "promotion" in 

view of prior public health tragedies such as thalidomide and elixir sulfanilamide. What 

lessons should we take from those prior episodes, and how do they relate to the legislation 

under consideration and to the off-label communications issue more broadly? 

The elixir sulfanilamide and thalidomide episodes are part of the canonical history of FDA regulation and 

are widely understood to have prompted Congress to enact the laws that form the basis of 

contemporary standards for the marketing of therapeutic products. But neither one is instructive with 

regard to the specific policy questions addressed in the hearing, which relate to off-label uses of 

approved products, rather than uses of products not approved for any purpose. 

Elixir sulfanilamide was an antibiotic product introduced in the mid-1930s, before the law required any 

approval or proof of safety before marketing. It was formulated with diethylene glycol, which was 

intended to make sulfanilamide (the active ingredient) soluble and stable in a liquid form. Diethylene 

glycol is highly toxic, and more than 100 people died after consuming the product. 

Thalidomide was introduced as a sleeping pill in Europe in the 1950s, and was used to treat morning 

sickness in pregnant women. It was never approved for marketing in the United States, but was 

distributed to U.S. doctors for investigational use before the law required FDA oversight of such use. 

The drug caused significant deformities in thousands of children, including 17 in the U.S. 

These tragedies dramatized the need for regulatory oversight of investigational drugs, robust premarket 

review, and mandatory reporting of adverse events-key features of the current regulatory regime for 

drugs and medical devices. But neither episode involved a product that had been reviewed and 

approved by FDA according to the standards that exist in the law today. Moreover, these products were 

dangerous because of their inherent properties, and because they were made available to patients with 

grossly inadequate accompanying labeling and other information. As a result, they are not instructive 

with regard to the specific policy questions presented by the hearing, which relate to the dissemination 

of truthful and non-misleading information about off-label uses of lawfully marketed products. 
161 


5. We heard testimony regarding the risk of clinical decisions as a result of scientific information 

provided directly to prescribers without FDA intermediation. What is the proper role of FDA 

in regulating information as a means of encouraging prescribers to make therapy selection 

decisions that accord with the agency's view of patient care? 

FDA determines whether medical products satisfy applicable premarket review standards under the 

FDCA. A constituent part of that system is the review of the labeling that accompanies a product and 

reflects FDA's authoritative conclusions as to the circumstances in which the risk-benefit ratio of the 

product can be optimized. Prescribers also obtain scientific information from scientific meetings, 

continuing education, medical journal articles, and other sources. 

A health care practitioner may make an informed decision that a use not approved by FDA is 

nevertheless clinically appropriate, based on the prescriber's knowledge of the mechanism of disease, 

the technological principles oft he product, the individual patient's medical history, and other relevant 

considerations. 

To the extent FDA has its own views as to the proper role of an approved product in patient care, it can 

and does share those views with prescribers by requesting that manufacturers include clinically relevant 

information in product labeling and by engaging in its own communications directed to health care 

professionals, such as product safety alerts. But in the current statutory scheme, the agency is generally 

not permitted to impose its own views on prescribers, patients, payors, and other audiences as to the 

appropriate use of medical products. 

As FDA has explained, the agency is responsible for evaluating the safety and effectiveness of drugs and 

medical devices and the truthfulness of their labeling. The health care practitioner "is then responsible 

for making the final judgment as to which, if, any, of the available" products the patient "will receive in 

the light of the information contained in their labeling and other adequate scientific data available to" 

the practitioner13 

13 37 Fed. Reg. 16,503, 16,504 (Aug. 15, 1972). See also 21 U.S.C. § 396 ("Nothing in this chapter shall be construed 

to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed 

device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship."). 
162 


6. Assuming there is agreement regarding the utility of independent FDA review of manufacturer 

information before it is shared with prescribers, what are the costs associated with the delay 

that would accompany FDA's review? 

Under existing law, if a manufacturer wishes to promote a lawfully marketed product for a new use, the 

manufacturer is required to make a new submission to FDA and await agency authorization to market 

the product using the desired claim. The requirement of an additional submission to FDA is triggered 

only when the prospective claim promotes a "new use" -defined in the law as a new disease state or 

health condition. As a result, a wide variety of claims can lawfully be made by a manufacturer for an 

already-marketed product without any prior FDA review as long as the claims satisfy applicable statutory 

requirements. The claims must be truthful, non-misleading, supported by adequate data, and presented 

with sufficient contextual information, including information about product risks." Additionally, FDA 

has adopted several safe harbors and policies that allow manufacturers to communicate certain "offlabel" information as part of scientific exchange, in response to unsolicited requests, in continuing 

education and analogous events, and through reprints and similar materials. 

Requiring prior review would significantly restrict and delay the ability of manufacturers to 

communicate up-to-date information about their medical products to inform treatment decisions. As a 

result, the public health would be negatively affected by any across-the-board requirement of prior FDA 

review of manufacturer communications. For example, FDA review of supplemental applications for 

new indications for oncology products can take many months, and in the past such review has 

sometimes required years. 15 In this therapeutic area, drugs are often approved based on a survival 

benefit of shorter duration. The human cost of the aggregated delay across all product categories is 

impossible to quantify. 

14 See generally 21 U.S.C. §§ 321(n), 352(a), {n) & (r); 21 c.F.R. §§ 201.100(d), 202.1(e)(4) & {S)(ii). 

15 FDA is subject to a performance goal of reviewing and acting on 90 percent of efficacy supplements within 6-10 

months. In addition, regional variations in treatment reflect differences in physicians' access to the most up-todate information about clinical options, and correspond to differences in outcomes based on geography. See, e.g., 

l. Pilote, M.D., M.P.H., eta!., Regional Variation Across The United States In the Management of Acute Myocardial 

Infarction, 333 NEJM 565 (1995) (describing results of study demonstrating "marked regional variation in the 

management of acute myocardial infarction in the United States," including both use of medications and 

performance of procedures). Community-based physicians need complete and up-to-date information about 

treatment options and often manufacturers are the only or the best source of such information. Under the current 

federal regulatory system, manufacturers have some ability to provide information about emerging efficacy 

information across the full range of uses of medical products, and about investigational products that might be 

made available to patients, including through expanded access mechanisms. 
163 


The Honorable Richard Hudson 

North Carolina is home to some of the finest medical research institutions in the world, with notable 

institutions like the University of North Carolina at Chapel Hill, Duke University, North Carolina State 

University and Wake Forest University, where cutting edge medical research is carried out every day. 

North Carolina is also home to a burgeoning life sciences industry, with over 100 small, medium, and 

large device and pharmaceutical manufacturers. Together, this ecosystem of innovation fosters and 

creates cutting edge treatments for diseases and illnesses. 

Oftentimes, these innovative drugs and devices are able to be used for diseases the original FDA 

application did not envision. As our healthcare system moves into a value based model of patient 

care, where collaboration between providers and payers helps manage care to provide better long 

term outcomes, it is important to encourage communication about new uses for these drugs and 

devices to disseminate better modalities of care across our healthcare system. 

1. Would you agree that it is in the public's best interest to allow the companies who produce 

these drugs and devices the ability, in a tailored way, to communicate with providers and 

payers about off-label uses? And can you elaborate on ways these companies can be helpful 

to both the providers and payers, whether that's through data analytics, clinical expertise, or 

ways to reduce costs? 

Yes. The public interest is best served when decisions regarding uses of medical products are informed 

by truthful, accurate, and non-misleading information. Manufacturers are well-positioned provide a 

variety of analyses that may be helpful to providers and payers. These include, among others: 

Up-to-date case series or retrospective subgroup analysis, which may be particularly helpful in 

ultra-rare conditions, oncology, and similar fields where clinical practices are rapidly evolving 

and adequate and well-controlled data are not available. 

Healthcare economic analysis, which is particularly important given the increasing influence of 

value-oriented considerations on health care delivery. 

• Analysis of data obtained in the real world, including data from electronic health records, claims 

and billing activities, product and disease registries, and mobile devices, which offers the 

potential for information that can be based on larger sample sizes with a broader range of 

patients, and can be more up-to-date, than data from randomized controlled clinical trials. 
164 


GREG WALDEN, OREGON 

CHAIRMAN 

Ms. R. Alta Charo 

ONE HUNDRED FIFTEENTH CONGRESS 

FRANK PALLONE. JR., NEW JERSEY 

RANKING MEMBER 

lttongrcss of tbc 1lnitcb ~Mates 

~>ousc of l\cprtsentatillcs 

COMMITTEE ON ENERGY AND COMMERCE 

2125 RAYBURN HousE OmcE BuiLDING 

WASHINGTON, DC 20515-6115 

MvJOntv 11021 ns-29:77 

Mmomy (:<'01)2?5-3641 

August 17,2017 

Wan·en P. Knowles Professor of Law 

975 Bascom Mall 

University of Wisconsin 

Madison, Wl53706 

Dear Ms. Charo: 

Thank you for appearing before the Conunittee on Energy and Commerce on July 12, 2017, to 

testify at the hearing entitled "Examining Bipa1iisan Legislation to Improve the Medicare Program." 

Pursuant to the Rules of the Committee on Energy and Commerce, the hearing record remains 

open for ten business days to pennit Members to submit additional questions for the record, which are 

attached. The fonnat of your responses to these questions should be as follows:(!) 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 respond to these questions with a 

transmittal letter by the close of business on August 31,2017. Your responses should be mailed to Zack 

Darcshori, Legislative Clerk, Conunittee on Energy and Commerce, 2125 Rayburn House Office 

Building, Washington, DC 20515 and e-mailed in Word fom1at to zack.dareshori@mail.house.gov. 

Thank you again for your time and eff011 preparing and delivering testimony before the 

Committee, 

cc: The Honorable Gene Green, Ranking Member, Subcommittee on Health 

Attachment 
165 


Attachment- Additional Questions for the Record 

The Honorable Michael C. Burgess 

1. We heard testimony as to the need for FDA to act as a "learned intermediary" 

between manufacturers and prescribers with respect to scientific information 

disseminated under the proposed legislation. Would it represent a significant shift 

in federal medical product regulation if the law were to require all manufacturer 

communications to be reviewed by FDA in advance? What is the scope of FDA's 

authority under current law to substitute its judgment for that of a prescriber when 

it comes to drug and medical device use? 

RESPONSE: It would be unusual for the government to take on the task of 

reviewing all communications in advance, as this would certainly face powerfitl 

challenges under the First Amendment. Prior restraint of speech is given much 

stricter scrutiny than post-speech review and request for correction of false or 

misleading statements. As to substituting the judgement of a prescriber, FDA has 

fairly limited authority. Providers are free to prescribe offlabel, based on their 

own judgement, and subject to quality controls in the form of state licensing and 

disciplinary boards, or medical malpractice suits, if their judgement proves to be 

at odds with the standard of care. 

2. W c heard testimony regarding the inability of any manufacturer to provide 

complete information about a new use. It was also suggested that FDA is the 

only source of complete information about the full range of medical product 

uses. What information does FDA receive from manufacturers, adverse event 

reporting, and other sources, and how does that information compare to the data 

and analysis to which the manufacturer has access? 

RESPONSE: Because submissions to FDA are confidential, it is possible at 

times that FDA will be aware of multiple sponsors testing similar formulations 

in various pre-clinical and clinical trials. As a result, FDA may know from 

Sponsor X that a particular side effect is possible, or that a particular 

interaction with another drug is problematic, but Sponsor Y- who is testing a 

similar drug will not have this informarion. 

3. It has been suggested that off-label information might be more useful in some 

areas of practice than in others. How should the subcommittee evaluate that issue, 

and is there a principled basis in the law for making a distinction in the regulation 

of information dissemination according to the nature of the disease area (e.g., rare 

diseases, oncology) or patient population (e.g., pediatrics)? 

RESPONSE: In an ideal world this might be possible, but in reality it would not 

be easy to make clean categories that separate the tightly regulated from the 

loosely regulated That said, one might take advantage of some existing 

distinctions, e.g. for those products that are being reviewed as 'orphan drugs' due 

to the rarity of the condition. 

4. We heard testimony regarding the need for FDA to adjudicate "claims" and 

"promotion" in view of prior public health tragedies such as thalidomide and elixir 

sulfanilamide. What lessons should we take from those prior episodes, and how 

do they relate to the legislation under consideration and to the off-label 

communications issue more broadly? 
166 


RESPONSE: The risk with off-label promotion is that a drug tested for one 

purpose/dose/population will now be disseminated quickly for a new 

use/dosage/target population. Expanding the range of uses and users is a way to 

increase profits during the crucial post-approval years when there is some 

market exclusivity (i.e. before generics drive prices and profits down.) But the 

absence of a round of trials specific to these new uses/doses/target populations 

means that any indication of a problem, whether toxicity or lack of effectiveness, 

will likely not be visible to providers or even to the sponsor-company itself The 

business model drives toward rapid expansion of sales at the very same time that 

the lack of trials for a supplemental labeling will hinder the ability to confirm the 

safety and efficacy of the expanded applications. 

5. We heard testimony regarding the risk of clinical decisions as a result of 

scientific information provided directly to prescribers without FDA 

intermediation. What is the proper role of FDA in regulating information as a 

means of encouraging prescribers to make therapy selection decisions that 

accord with the agency's view of patient care? 

RESPONSE: FDA regulates the quality of the products and the information on 

the labels. It does not regulate the practice of medicine. The FDA has a 

proper role as a unbiased source of information about what is known about the 

risks and benefits of the product for various diseases and populations. This 

should inform provider judgement but it does not control it. 

6. Assuming there is agreement regarding the utility of independent FDA 

review of manufacturer information before it is shared with prescribers, 

what are the costs associated with the delay that would accompany FDA's 

review? 

RESPONSE: It is hard to answer this without specifics -length of delay, 

urgency of patient needs, number of patients, and degree of sub-optimal 

prescribing in the absence of a neutral eye confirming that the 

information given to providers is complete and neither false nor 

misleading. 
167 


The Honorable Frank Pallone .. Jr. 

Pre-Approval Communication and Intent to File 

As you know, the discussion draft released Representative Guthrie would allow 

drug and device manufacturers to communicate certain information to payors and other 

entities about an unapproved use of a drug or device, so long as the manufacturer 

"intends" to submit a supplemental application to FDA in the future with evidence that the 

use of the product is safe and effective. However, unfortunately, what constitutes intent is 

left undefined in this draft. I have concerns that this preapproval communication may 

expand unproven uses and may create a pathway for manufacturers to increase access to 

therapies that may not be effective. 

QI: What is your view of this language? Do you understand how this 

provision could be implemented? Is the language sufficient to 

bind a drug or device manufacturer to actually go through the 

application process? 

Q2: You noted in your testimony that this provision could result 

in increased patient use of unproven or unsafe therapies. 

Can you explain how? 

Q3: Without clearly defining what constitutes intent, could this 

create a loophole for manufacturers? 

Q4: Is there an enforcement mechanism available to FDA either 

from the discussion draft, or through current law, in the case 

where a manufacturer ultimately decides not to seek 

approval for this indication after it has shared information 

with the payer? 

RESPONSE: Please allow me to respond to all four questions in an 

integratedfashion. I share the concern about a provision that 

hinges on the 'intent' of the sponsor. Certainly a sponsor might 

have a genuine intent to come at a later date to the FDA but 

nonetheless find that circumstances have changed and that the 

planned action is no longer in the sponsor's interest. Indeed, 

the experience of patients who are the subjects of the nowpromoted off label use may demonstrate the risks or lack of 

benefits that would lead the sponsor to change its plans. In a 

sense, this is aform of unregulated, uncontrolled research with 

the patients who are the subject of the o.fJ-label use, and without 

any of the usual protections. The patients would not realize 

they were experimental subjects, would ojien be paying for the 

product (whereas in a clinical trial they might well get it free), 

and would not be assured that there is an oversight body 

monitoring the patient experiences in a rigorous way with a 

capacity to cease use of the product if there are indications its 

risks exceed its benefits. 
168 


Promotional Speech 

During the hearing there was considerable discussion over the 

distinctions between promotional and non-promotional communication, and 

whether or not the proposed discussion draft offered by Representative 

Griffith would protect against promotional communication by a 

manufacturer of scientific information. 

QI: Will you discuss further the distinctions between nonpromotional and promotional communication by a medical 

product manufacturer, and how those two have been 

defined in case law? 

Q2: What is your view ofthe discussion draft released by Rep. 

Griffith? Does this draft adequately protect against 

promotional communication by a manufacturer? If so, what 

enforcement tools would be available to FDA to ensure that 

manufacturer communications are truthful, non-misleading, 

and non-biased, and limited to the sharing of appropriate 

non-promotional scientific information? 

RESPONSE: The distinction between promotional and nonpromotional speech can at times be subtle, and often relies 

upon context. For example, distributing a peer-reviewed 

article ji-om a respected scientific journal about possible off 

label uses would not in itself be promotional, but it would be 

promotional if it were accompanied by clearly promotional 

literature aimed at encouraging purchase of the product in 

order to prescribe it for the off-label use, or if the article is 

presented as if it were definitive when in fact there are many 

other articles from equally respectable sources that come to 

contrary conclusions. This is why FDA has published 

guidances that lay out best practices which, if followed, act as 

a 'safe harbor'for sponsors who distribute such information 
169 


WALDEN, OREGON 

CHAIRMAN 

Dr. George Van Hare 

ONE HUNDRED FIFTEENTH CONGRESS 

FRANK PALLONE, JR., NEW JEilSEY 

RANKING MEMBER 

<!t:ongnss of tbe m:ntteb $tates 

j!)omie of lteprcsentatibcss 

COMMITIEE ON ENERGY AND COMMERCE 

2125 RAYBURN HousE OFFICE BuiLDING 

WASHINGTON, DC 20515-6115 Mi:I]Otityj;!07)22{)"7927 

M•rlCnty 1202)225-.1641 

August 17,2017 

Division Chief- Pediatric Cardiology 

Washington University School of Medicine 

One Children's Place 

Campus Box 8116 - NWT 

St. Louis, MO 63110 

Dear Dr. Van Hare: 

Thank you for appearing before the Conm1ittee on Energy and Conm1erce on July 12, 2017, to 

testify at the hearing entitled "Examining Bipartisan Legislation to Improve the Medicare Program." 

Pursuanl to the Rules ofthe Committee on Energy and Commerce, the hearing record remains 

open for ten business days to pem1it Members to submit additional questions for the record, which are 

attached. The format of your responses to these questions should be as follows: (1) 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 respond to these questions with a 

transmittal letter by the close of business on August 31, 2017. Your responses should be mailed to Zack 

Darcshori, Legislative Clerk, Committee on Energy and Commerce, 2125 Rayburn House Office 

Building, Washington, DC 20515 and e-mailed in Word format to zack.dareshori@mail.house.gov. 

Thank you again for your time and eftbrt preparing and delivering testimony before the 

Committee. 

. 11') 

(,),Urflla!l ·.·';,,~ u·H·'-'· Subcommittc~· t'n I kalth 

cc: The Honorable Gene Green, Ranking Member, Subcommittee on Health 

Attachment 
170 


ANSWERS BY DR. VAN HARE, HEART RHYTHM SOCIETY, TO QUESTIONS FOR THE RECORD 

RELATED TO: 

"EXAMINING BIPARTISAN LEGISLATION TO IMPROVE THE MEDICARE PROGRAM" 

ENERGY & COMMERCE COMMITTEE, JULY 12, 2017 

The Honorable Michael C. Burgess 

1. We heard testimony as to the need for FDA to act as a "learned intermediary" between 

manufacturers and prescribers with respect to scientific information disseminated under 

the proposed legislation. Would it represent a significant shift in federal medical product 

regulation if the law were to require all manufacturer communications to be reviewed by 

FDA in advance? What is the scope of FDA's authority under current law to substitute its 

judgment for that of a prescriber when it comes to drug and medical device use? 

FDA already reviews pharmaceutical advertisements in advance, in part due to the fact that 

these are disseminated to the public at large. The risk for misinterpretation is greater in the 

case of information disseminated directly to the public than in the case of information 

disseminated to healthcare professionals, who are trained to analyze clinical and scientific 

information. By law, communications with healthcare professionals must be truthful and 

non-misleading, but they receive no pre-distribution review from the agency. Rather, the 

prescriber is the "learned intermediary" between the manufacturer and the patient. It is 

unlikely that adding FDA review as an additional step will accomplish much other than 

slowing down the distribution of clinical data and diverting precious agency resources from 

its main mission with regard to pharmaceuticals and devices, which is to ensure the safety 

and efficacy of these products. 

2. We heard testimony regarding the inability of any manufacturer to provide complete 

information about a new use. It was also suggested that FDA is the only source of 

complete information about the full range of medical product uses. What information 

does FDA receive from manufacturers, adverse event reporting, and other sources, and 

how does that information compare to the data and analysis to which the manufacturer 

has access? 

FDA may receive a broader range of information than the manufacturer can provide, as 

most of the manufacturer's data will be related only to its specific product. For example, 

FDA may sooner flag a safety issue with a class of drugs, given that the agency would 

receive adverse event reports related to the entire class, rather than just a single member 

of the class. Conversely, FDA would not be in receipt of "real-world" evidence, such as 

observational studies, pharmacoeconomic studies, or information on subpopulations that is 

gathered by the manufacturer in post-market settings. Both kinds of data are useful to 

clinicians and we are eager to receive them, as long as the data are truthful, presented in 

context, and scientifically valid. 

E&C 2017-07-12 QFR Responses VanHare 1 
171 


3. It has been suggested that off-label information might be more useful in some areas of 

practice than in others. How should the subcommittee evaluate that issue, and is there a 

principled basis in the law for making a distinction in the regulation of information 

dissemination according to the nature of the disease area (e.g., rare diseases, oncology) or 

patient population (e.g., pediatrics)? 

As someone who specializes in pediatric cardiology, I am particularly appreciative of this 

question as it is an indisputable fact that off-label information is critical for certain 

populations and diseases. Especially with regard to these populations, it is important to 

note that off-label uses are often not experimental uses. In fact, some are so common they 

have become the standard of care. Many off-label uses are well-documented in the peerreviewed literature, are discussed widely among physicians, and are cited as standard uses 

in medical textbooks. For me and other pediatric subspecialists- as well as clinicians who 

treat rare diseases- off-label use of drugs or devices is not a choice. It is a necessity. For 

example, very few of the currently marketed medications for arrhythmias are formally 

approved for use in children. Thus, using treatments off-label is often our main method of 

treatment. 

Under the current regulatory paradigm, we do not get the benefit from any data that is not 

derived from a randomized, controlled clinical trial. Unfortunately, that means we do not 

receive any data related to pediatric populations, as these are still not well-represented in 

clinical trials, despite regulatory incentives for manufacturers to include them. While there 

are an additional six months of exclusivity granted to manufacturers who generate data 

related to pediatric populations under the Pediatric Research Equity Act (PREA), this has not 

been sufficient to produce the amount of shareable data we might like, particularly for 

older drugs. As such, our clinical decisions often rest on anecdotal evidence and informal 

information-sharing among physicians. This is not an ideal environment in which to make 

treatment decisions, and it does not inspire confidence in the parents ofthese children with 

regard to the available drugs and devices. 

It is difficult to articulate a principled basis in law by which to make a distinction in the 

information that may be disseminated. A better approach would be to let manufacturers 

share with clinicians data that is truthful, presented in context, and scientifically valid. 

Barring that, at a minimum, clinicians treating rare diseases or diseases in pediatric 

populations should have access to all data within those parameters. 

4. We heard testimony regarding the need for FDA to adjudicate "claims" and "promotion" 

in view of prior public health tragedies such as thalidomide and elixir sulfanilamide. What 

lessons should we take from those prior episodes, and how do they relate to the 

legislation under consideration and to the off-label communications issue more broadly? 

In the late 1930s, the fatalities caused by "Elixir Sulfanilamide" resulted in creation of the 

Food, Drug, and Cosmetic Act. Similarly, the serious consequences arising from use of 

thalidomide during pregnancy was the result of marketing in the 1950s and 1960s -long 

E&C 2017-07-12 QFR Responses Van Hare 2 
172 


before the FDA's current, rigorous safety standards around clinical trials and off-label 

promotion were in place. Indeed, the thalidomide tragedy was a catalyst for the creation of 

many of these standards. These examples illustrate the dangers of allowing promotional 

claims to the public that are not scientifically sound and not truthful. 

However, there is a difference between advertising an unapproved use to the public and 

sharing scientifically valid data with clinicians, and this difference can be reflected in the 

regulatory approach to each type of activity. There is a vast space between our current 

regulatory approach and the "Wild West" environment that allowed any sales (let alone 

promotion) of a poisonous product like "Elixir Sulfanilamide" and unfettered promotion of a 

product harmful to fetal development like thalidomide. 

Considering our current standards related to clinical trial and drug approval, the key 

question in the context of off-label information is: what is promotion? The answer to that 

may differ based on the audience. Physicians are trained to analyze data; we know how to 

evaluate the validity of studies. If regulatory restrictions ensure that the data is truthful and 

presented in context, physicians can analyze such data effectively. Unfortunately, the 

current regulatory approach limits the ability of a manufacturer to share any data that is not 

referenced in the package insert. That means a lot of valuable information may never be 

conveyed to clinicians and other medical decision-makers. 

5. We heard testimony regarding the risk of clinical decisions as a result of scientific 

information provided directly to prescribers without FDA intermediation. What is the 

proper role of FDA in regulating information as a means of encouraging prescribers to 

make therapy selection decisions that accord with the agency's view of patient care? 

As noted above, FDA's role should be to ensure that any data shared with clinicians is 

truthful, presented in context, and scientifically valid. For the reasons noted above, a predissemination review of information intended for physicians would not be helpful and 

would slow down the distribution of information. A better approach would be for FDA to 

define, via notice-and-comment rulemaking which would allow for input from stakeholders, 

what constitutes truthful, presented in context, and scientifically valid, and then utilize its 

various enforcement tools for manufacturers who distribute information that fails to meet 

those standards. 

6. Assuming there is agreement regarding the utility of independent FDA review of 

manufacturer information before it is shared with prescribers, what are the costs 

associated with the delay that would accompany FDA's review? 

While I cannot make specific budgetary predictions from the agency's perspective, as noted 

above, I would be concerned that a new, independent review function would divert 

resources from the agency's main functions. From the provider perspective, this would slow 

down the dissemination of clinical data- even the data we can readily receive under 

E&C 2017-07-12 QFR Responses VanHare 3 
173 


current law. Outdated clinical information is not helpful for prescribers and, in turn, comes 

with a cost to patients. 

The Honorable Richard Hudson 

Would you agree that it is in the public's best interest to allow the companies who produce 

these drugs and devices the ability, in a tailored way, to communicate with providers and 

payers about off-label uses? And can you elaborate on ways these companies can be helpful 

to both the providers and payers, whether that's through data analytics, clinical expertise, or 

ways to reduce costs? 

I agree that manufacturers sharing data with clinicians, particularly those treating patients with 

rare diseases and children, is in the public's best interest, provided that the data is truthful, 

presented in context, and scientifically valid. For example, manufacturers may have real-world, 

post-market evidence indicating that their product is not as effective in a particular 

subpopulation. That would be valuable for clinicians to know, as it would prevent us from using 

the product in a population that may not benefit from it sufficiently to offset any safety risks. 

While any physician is nervous about providing more information to payers in a quest to reduce 

costs, a payer may wish to have such information as well, given that it could prevent spending 

resources on a product that will ultimately not help the patient. 

E&C 2017-07-12 QFR Responses Van Hare 4 
174 

[Mr. Kesselheim did not answer submitted questions for the 

record by the time of printing.] 


GREG WALDEN, OREGON 

CHAIRMAN 

ONE HUNDRED FIFTEENTH CONGRESS 

FRANK PALLONE, JR., NEW JERSEY 

RANKING MEMBER 

QJ:ongress of tbc ilnitcb ~tatcs 

~ouse of !~epn!lentatll.tc!i 

COMMITTEE ON ENERGY AND COMMERCE 

2125 RAYBURN HousE OFFICE Buu.OING 

WASHINGTON, DC 20515--6115 

August 17, 2017 

Dr. Aaron S. Kesselheim 

Associate Professor of Medicine 

Harvard Medical School 

1620 Tremont Street 

Suite 3030 

Boston MA 02120 

Dear Dr. Kesselheim: 

Thank you for appearing before the Committee on Energy and Commerce on July 12, 2017, to 

testify at the hearil)g entitled "Examining Bipartisan Legislation to Improve the Medicare Program.~· 

Pursuant to the Rules of the Committee on Energy and Commerce, the hearing record remains 

open fm ten business days to permit Members to submit additional questions for the record, wl1ich are 

attached. The fom1at of your responses to these questions should be as follows: (1) 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 respond to these questions with a 

transmittal letter by the close of business on August 31, 2017. Your responses should be mailed to Zack 

Dareshori, Legislative Clerk, Committee on Ener;.'Y and Commerce, 2125 Raybum House Office 

Building, Washington, DC 20515 and e-mailed in Word format to zack.dareshori@mail.house.gov. 

Thank you again for your time and effort preparing and delivering testimony before the 

Committee. 

cc: The Honorable Gene Green, Ranking Member, Subcommittee on Health 

Attaclunent 
175 


Attachment- Additional Questions for the Record 

The Honorable Michael C. Burgess 

1. We heard testimony as to the need for FDA to act as a "learned intermediary" between 

manufacturers and prescribers with respect to scientific information disseminated under 

the proposed legislation. Would it represent a significant shift in federal medical product 

regulation if the law were to require all manufacturer communications to be reviewed by 

FDA in advance? What is the scope of FDA's authority under current law to substitute 

its judgment for that of a prescriber when it comes to drug and medical device use? 

2. We heard testimony regarding the inability of any manufacturer to provide complete 

information about a new use. It was also suggested that FDA is the only source of 

complete information about the full range of medical product uses. What information 

does FDA receive from manufacturers, adverse event reporting, and other sources, &'ld 

how does that information compare to the data and analysis to which the manufacturer 

has access? 

3. It has been suggested that off-label information might be more useful in some areas of 

practice than in others. How should the subcommittee evaluate that issue, and is there a 

principled basis in the Jaw for making a distinction in the regulation of information 

dissemination according to the nature of the disease area (e.g., rare diseases, oncology) or 

patient population (e.g., pediatrics)? 

4. We heard testimony regarding the need for FDA to adjudicate ''claims" and "promotion" 

in view of prior public health tragedies such as thalidomide and elixir 

sulfanilamide. What lessons should we take from those prior episodes, and how do they 

relate to the legislation under consideration and to the off-label communications issue 

more broadly? 

5. We heard testimony regarding the risk of clinical decisions as a result of scientific 

infonuation provided directly to prescribers without FDA intetmediation. What is the 

proper role of fDA in regulating information as a means of encouraging prescribers to 

make therapy selection decisions that aeeord with the agency's view of patient care? 

6. Assuming there is agreement regarding the utility of independent FDA review of 

manufacturer information before it is shared with prescribers, what are the costs 

associated with the delay that would accompany FDA's review? 

The Honorable Frank Pallone, Jr. 

Dangers of Expanding Scientific Exchange 

In your testimony you provided a number of examples of past instances where 

manufacturers have settled with the federal government over inappropriate off-label promotion. 

However, you noted importantly that many of these examples were not manufacturers spreading 

falsehoods, but rather providing anecdotal benefits from uncontrolled cases, flawed observational 

studies, or selectively presenting only favorable studies. 
176 


The proposed discussion draft offered by Representative Griffith would create a 

"scientific exchange safe harbor" which would allow a manufacturer to engage in 

communication as long as that communication is not advertising or promotional in nature, is 

supported by competent and reliable scientific evidence, provides contextual information about 

the data presented, and discloses that such information is not in the labeling and that the 

unapproved use has not been found to be safe and enective. 

Ql: Does the criteria outlined in Rep. Griffith's discussion draft guard against some of 

the bad behavior you note in your testimony, such as the anecdotal evidence from 

uncontrolled case series, unbalanced study data, or favorable presentation of 

literature? If not, what further safeguards would be necessary to protect against 

such behaviors? 

Q2: Both of the proposed discussion drafts that were the focus of the hearing include 

disclaimers that intend to make clear that the drug or device has not been proven 

to be safe and effective or to clarify the differences between the infonnation 

provided and what is included in the labeling. Given your research in this area, do 

you believe the inclusion of such disclaimers in the discussion draf\s will help to 

clarify for patients and providers that the information provided is not associated 

with an approved usc or an approved product? 

Off Label Communication with Physicians 

We have heard from some health care providers that under current Food and Drug 

Administration (FDA) guidance and regulations physicians are unable to receive timely access to 

clinical information that could be useful in making patient care decisions. Some have also argued 

that health care providers are trained and able to analyze data to know when a study is 

misleading, or when the data is presented with bias or out of context, making them a skeptical 

audience for manufacturer communication. 

In your testimony, you noted the value of having FDA provide an independent 

assessment of whether a drug or high-risk medical device is safe and effective for its intended 

use, and in fact suggest FDA is an important intermediary for prescribing physicians as not all 

physicians have the time and expertise to scrutinize claims from manufacturers. 

Ql: As a physician yourself, do you believe further legislative safe harbors are needed 

in order to ensure physicians have access to timely and sufficient scientific 

information? And if so, how do we ensure that such safe harbors don't result in 

lhe collection and dissemination of less rigorous data to physicians? 

Q2: Can you discuss further what impact, if any, increased offlabcl communication 

from manufacturers may have on physician behavior? 
177 


Off-Label Promotion and Prescribing Practices 

In response to a question from Congresswoman Schakowsky, you noted that history has 

shown that off-label promotion drives physician practices "in ways that favor the drug being 

promoted, not in ways that favor the overall state of the evidence and the overall state of 

practice." 

Ql: Is there evidence demonstrating that there is a direct association between 

promotional statements and prescribing practices? lf so, please discuss this 

association further. 

Q2; In reviewing the proposed discussion drafts released by Reps. Griffitl1 and 

Guthrie, what further changes are necessary to ensure that the communications 

contemplated under the "scientific exchange safe harbor" and the "preapproval 

information exchange" are not promotional? 

Clinica!Trials.gov 

At the hearing there was a discussion about the utility and effectiveness of 

ClinicalTrials.gov and the availability of clinical trials information for physicians. Ms. House 

commented on the difficulty of patients in finding information about relevant treatments. Ms. 

Khachatourian commented that the frequent delay of publication of clinical trial information also 

makes it difficult for payors to make coverage decisions. 

Ql: How can we better utilize, or improve, Cliniea!Trials.gov to ensw·e that patients 

and physicians have access to timely and useful scientific or medical information 

about medical products? Could such improvements help to a1leviate the need for 

expanding manufacturer communication about unapproved products or uses of 

products? 

2 
178 


GREG WALDEN, OREGON 

CHAIRMAN 

Ms. Linda House 

President 

ONE HUNDRED FIFTEENTH CONGRESS 

FRANK PALLONE, .lA., NEW JERSEY 

RANKING MEMBER 

C!ongress of tue Wniteb ~tates 

:l!}oul:!t of l\epresentatlues 

COMMITIEE ON ENERGY AND COMMERCE 

2125 RAYBURN HousE OFFICE BuiLDING 

WASHINGWN, DC 20515-6115 1:?0:?)2<!5--2927 

!202)22$ 3H<11 

August !7, 20!7 

Cancer SuppOit Community 

734 15th Street, N.W. 

Suite 300 

Washington, DC 20005 

Dear Ms. House: 

Thank you for appearing before the Committee on Energy and Commerce on July 12, 2017, to 

testify at the hearing entitled '"Examining Bipartisan Legislation to Improve the Medicare Program. u 

Pursuant to the Rules of the Committee on Energy and Commerce. the hearing record remains 

open for ten business days to permit Members to submit additional questions for the record, which are 

attached. The fonmt 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 respond to these questions with a 

transmittal letter by the close of business on August 31, 2017. Your responses should be mailed to Zack 

Dareshori, Legislative Clerk, Committee on Energy and Commerce, 2125 Rayburn House Office 

Building, Washington, DC 20515 and e-mailed in Word fonnat to zack.dareshori@mail.house.gov. 

Thank you again for your time and effort preparing and delivering testimony before the 

Conunittee. 

cc: The Honorable Gene Green, Ranking Member, Subcommittee on Health 
179 


The Honorable Michael C. Burgess 

1. We heard testimony as to the need for FDA to act as a "learned intermediary" between 

manufacturers and prescribers with respect to scientific information disseminated under the 

proposed legislation. Would it represent a significant shift in federal medical product regulation 

if the law were to require all manufacturer communications to be reviewed by FDA in advance? 

What is the scope of FDA's authority under current law to substitute its judgment for that of a 

prescriber when it comes to drug and medical device use? 

1 cannot speak specifically to the current regulation. I will say that esc does support 

responsible communication by the manufacturer and also FDA regulation of promotional 

communication. However, adding a requirement that the FDA review all communication 

would create a significant burden on the system that I believe would cause delays in the 

exchange of timely and meaningful information. The question, as written, does not 

differentiate between promotional communication (e.g., print and TV ads) and scientific 

exchange (e.g., sharing the results of a new trial). Imagine being a provider seeing a patient 

who has a rare cancer in your office. You are aware that an investigator worked with a 

manufacturer on an investigator-initiated trial (liT) for that rare cancer. In the model you 

propose, in order for the provider to gain access to the results of that liT, the provider would 

have to wait until the manufacturer cleared their response with the FDA before providing an 

update on the trial. Additionally, in the current system, the FDA may not have results from 

the many IITs performed through the vast investigator network. If the policy outlined above 

were to change, so too would the requirements around reporting, database updating, and 

rapid labeling changes, to name a few. Further, CSC believes that the "learned intermediary" 

should be reframed as a "learned informer" to ensure that patients have comprehensive 

information about their illness and the options available to them. This "learned informer" 

role sits best as a part of the compact that exists between the patient and their providerwho knows the patient's unique scenario better than anyone. 

2. We heard testimony regarding the inability of any manufacturer to provide complete 

information about a new use. It was also suggested that FDA is the only source of complete 

information about the full range of medical product uses. What information does FDA receive 

from manufacturers, adverse event reporting, and other sources, and how does that 

information compare to that data and analysis to which the manufacture has access? 

This question should be directed to the FDA. I will suggest that neither the FDA nor the 

manufacturer has complete information about the full range of medical product uses once 

the product is commercially available. To the extent of my knowledge, the FDA has access to 

the clinical trial datasets, the label submission datasets, and adverse event reporting. I do 

not believe that the FDA has full access to information learned from the liT trials mentioned 

above, as one example. These trials often study novel uses, doses, and administration and 

offer meaningful contributions to the body of evidence generally, but especially for rare 

diseases. 
180 


3. It has been suggested that off-label information might be more useful in some areas of practice 

than in others. How should the subcommittee evaluate that issue, and is there a principled basis 

in the law for making a distinction in the regulation of information dissemination according to 

the nature of the disease area {e.g., rare diseases, oncology) or patient population (e.g., 

pediatrics)? 

To the best of my knowledge, there is no distinction in the regulation. The use of off-label 

information is more effective and likely more prevalent in rare diseases and other scenarios 

where there is high unmet need. The complexity ofthe topic would require a crossfunctional approach led by individuals with deep expertise. If the subcommittee feels it is 

within their frame to evaluate this, it should convene a working group of individuals from 

the FDA, manufacturers, providers, patient groups, and patients to discuss and recommend 

new approaches that work to improve patient outcomes. 

4. We heard testimony regarding the need for FDA to adjudicate "claims" and "promotion" in view 

of prior public health tragedies such as thalidomide and elixir sulfanilamide. What lessons 

should we take from those prior episodes, and how do they relate to the legislation under 

consideration and to the off-label communications issue more broadly? 

It should always remain the role oft he FDA to ensure patient safety. This role has typically 

entailed ensuring that solutions are safe and effective for use. Post-commercialization, this 

focus on safety has primarily centered on toxicity (e.g., side effects and other disease 

related events}. As the environment continues to evolve and personalized medicine 

continues to turn macro-level diseases (e.g., lung cancer) into highly specialized diseases 

(e.g., ALK+ lung cancer), the system and focus need to follow this evolution to embrace 

findings from trials that support evidence-based, real-world data on these highly-specialized 

populations. Regulatory statute and review systems should also evolve to ensure that 

patients and providers have access to sufficient information to make fully informed 

decisions about care and both the safety and efficacy components of the risk/benefit tradeoff. 

5. We heard testimony regarding the risk of clinical decisions as a result of scientific information 

provided directly to prescribers without FDA intermediation. What is the proper role of FDA in 

regulating information as a means of encouraging prescribers to make therapy selection 

decisions that accord with the agency's view of patient care? 

The FDA should ensure that information communicated to providers and patient is 

evidence-based, peer reviewed, and scientifically sound. In the current environment, FDA 

regulation focuses on communicating use directly from more narrow sources including the 

controlled clinical trials performed for product labeling, the actual label itself, and toxicity 

reported through post-marketing surveillance. As has been noted in multiple reports and 

forums, the FDA labels are oftentimes out of date and may not contain information on rare 

disease populations or the highly specialized diseases referenced above, yet there may be 

perfectly safe and meaningful data available through other resources that may never 

become available to patients and clinicians because of the currently regulatory statute and 

FDA limitations. 
181 


6. Assuming there is agreement regarding the utility of independent FDA review of manufacturer 

information before it is shared with prescribers, what are the costs associated with the delay 

that would accompany FDA's review? 

It is difficult to answer this with any level of specificity, but the costs associated with the 

delay that would accompany the FDA review would be directly related to the costs 

associated with the delay in starting treatment for patients. I think about the patient with an 

aggressive cancer where hours matter waiting to hear about a treatment option, or a 

patient with sepsis where seconds and minutes matter waiting to hear about a treatment 

option. Imagine if there is scientifically-validated information to help these patients, 

available in peer-reviewed journals, but these patients have to wait for it to be approved for 

dissemination by the FDA. Instead, imagine a system that would create enforceable 

guardrails to allow immediate dissemination of information to providers and patients as 

soon as the information reaches an acceptable threshold of evidence. 

The Honorable Tony Cardenas 

Ms. House, according to the American Cancer Society, a recent survey has shown that a majority of 

practicing oncologists prescribe drugs off-label to treat cancer. In fact, off-label prescription of drugs has 

become so common for the treatment of cancer that the National Cancer Institute (NCI) has stated, 

"Frequently, the standard of care for a particular type or stage of cancer involve[s] the off-label use of 

one or more drugs." 

1. Can you help us to understand how and why utilizing drugs off-label, including not just for 

different indications but also for novel or unique dosing or routes of administration, can be 

important to the practice of oncology? 

As the environment continues to evolve and personalized medicine continues to turn 

macro-level diseases (e.g., lung cancer) into highly specialized diseases (e.g., ALK+ lung 

cancer), the system and focus need to follow this evolution to embrace findings from trials 

that support evidence-based, real-world data on these highly-specialized populations. One 

example regarding unique dosing is the use of Gemcitabine for the treatment of pancreatic 

cancer. The Gemcitabine label instructs that the treatment should be administered by 30-

minute infusion. There was an early and ongoing hypothesis that administering Gemcitabine 

over a longer period of time (coined fixed-duration infusion) would essentially saturate cells 

with more drug and thus produce higher cell death and prolong patient survival. There was 

also a concern that fixed-duration infusion could increase toxicity. In the years since 

Gemcitabine received its label, studies have been done on hundreds of patients and 

published in peer-reviewed journals (e.g., Journal of Clinical Oncology), yet this information 

might not be available for patients and clinicians to access and the Gemcitabine label will 

likely not be updated to reflect these findings. 

2. What types of data would be most useful during scientific exchange and are there existing best 

practices for distinguishing these data from those in approved labeling? 
182 


As a baseline, all data should be peer-reviewed and/or fully vetted by third party 

independent reviewers. The scientific rigor required for acceptance to journals like the 

Journal of Clinical Oncology, the New England Journal of Medicine, or the Journal of the 

American Medical Association should pass the standard of communication to providers and 

patients. Such communication and data should be clearly indicated as outside the scope of 

the FDA label and supplemental, for use in treatment decision-making conversations 

between providers and patients. 

3. What safeguards need to be developed in order to prevent bad actors from manipulating a 

system of scientific exchange optimized for responsible manufacturers of medical products? 

There should be clear guidance in place- and enforced- to set expectations of the types of 

data which can be shared, how it can be shared, and consequences for violating the 

guidance. Managing to the bad actors at the expense of access to information for 

comprehensive treatment decision-making for the masses seems detrimental to overall 

patient care. 
183 

[Ms. Khachatourian did not answer submitted questions for the 

record by the time of printing.] 


GREG WALDEN, OREGON 

CHAIRMAN 

ONE HUNDRED FIFTEENTH CONGRESS 

FRANK PALLONE, JR., NEW JERSEY 

RANKING MEMBER 

<!ongress of tbe ~ntteb $tates 

j!}ou!:ie of l'eprtsentatibt!:i 

COMMITTEE ON ENERGY AND COMMERCE 

2125 RAYBURN HousE OFFICE Bu:LD!NG 

WASHINGTON, DC 20515-6115 

Ms. Kat Khachatourian 

Vice President 

Qualchoice Health Plan Services 

33820 Weyerhaeuser Way South 

Heron Building, 2nd Floor 

Federal Way, WA 98001 

Dear Ms. Khachatourian: 

Ma)!II'IIY 

M-nanty 

A%'USt 17,2017 

Thank you for appearing before the Committee on Energy and Commerce on July 12,2017, to 

testify at the hearing entitled "Examining Bipartisan Legislation to Irnprove the Medicare Program." 

Pursuant to the Rules of the Committee on Energy and Commerce, the hearing record remains 

open for ten business days to permit Members to submit additional questions for the record, which are 

attached. The format 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 respond to these questions with a 

transmittal letter by the close of business on August 31, 2017. Your responses should be mailed to Zack 

Dareshori) Legislative Clerk, Committee on Energy and Commerce, 2125 Rayburn House Office 

Building, Washington, DC 20515 and e-mnilcd in Word format to zack.dareshori@mail.house.gov. 

Thank you again for your time and effoti preparing and delivering testimony before the 

Committee. 

cc: The Honorable Gene Green, Ranking Member, Subcommittee on Health 

Attachment 
184 


Attachment- Additional Questions for the Record 

The Honorable Michael C. Burgess 

1. We heard testimony as to the need for fDA to act as a "learned intermediary" between 

manufacturers and prescribers with respect to scientific infonnation disseminated under 

the proposed legislation. Would it represent a significant shift in federal medical product 

regulation if the law were to require all manufacturer communications to be reviewed by 

FDA in advance? What is the scope of FDA's authority under current law to substitute 

its judgment for that of a prescriber when it comes to drug and medical device use? 

2. We heard testimony regarding the inability of any manufacturer to provide complete 

information about a new use. It was also suggested that FDA is the only source of 

complete information about the full range of medical product uses. What information 

does FDA receive from manufacturers, adverse event reporting, and other sources, and 

how does that information compare to the data and analysis to which the manufacturer 

has access? 

3. It has been suggested that off-label information might be more useful in some areas of 

practice than in others. How should the subcommittee evaluate that issue, and is there a 

principled basis in the law for making a distinction in the regulation of infmmation 

dissemination according to the nature of the disease area (e.g., rare diseases, oncology) or 

patient population (e.g., pediatrics)? 

4. We heard testimony regarding the need for FDA to adjudicate "claims" and "promotion" 

in view of prior public health tragedies such as thalidomide and elixir 

sulfanilamide. What lessons should we take from those prior episodes, and how do they 

relate to the legislation under consideration and to the off-label communications issue 

more broadly? 

5. We heard testimony regarding the risk of clinical decisions as a result of scientific 

infomJation provided directly to prescribers without FDA intermediation. What is the 

proper role of fDA in regulating infonnation as a means of encouraging prescribers to 

make therapy selection decisions that accord with the agency's view of patient care? 

6. Assuming there is agreement regarding the utility of independent FDA review of 

manufacturer information before it is shared with prescribers, what are the costs 

associated with the delay that would accompany FDA's review? 

The Honorable Frank Pallone, Jr. 

Pre-Approval Communication Safeguards 

The proposed discussion draft offered by Representative Guthrie relating to pre-approval 

communication proposes to allow medical product mannfacturers to share health care economic 

information and scientific infonnation about new indications and new products. I am concerned 

because the discussion draft would include a broad expansion of what can be communicated, 
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while also carving out any of FDA's enforcement authorities, leaving the agency hamstnmg in 

its ability to ensure such communication is truthful and not misleading. 

Q 1: You note in your testimony that there is a need for a minimum set of standards that 

infom1ation shared in a pre-approval context must meet. What principles should such standards 

encompass? For example, what should the minimum levels of evidence be for such 

communication? Further, what standards should be put in place to protect against the sharing of 

non-truthful and misleading information?