1 
Contents 

Director’s Message ........................................................................ 3 

Introduction ................................................................................... 6 

Drug Review................................................................................... 9 

New Drug and Biologic Review.................................................. 9 

Generic Drug Review ................................................................ 18 

Over-the-Counter Drug Review................................................. 22 

Pediatric Drug Development ..................................................... 24 

Maternal Health Team............................................................ 25 

Critical Path Initiative................................................................ 27 

Scientific Research .................................................................... 30 

User Fee Program ...................................................................... 36 

Drug Safety and Quality .............................................................. 37 

Modernizing Drug Safety .......................................................... 39 

Drug Promotion Review............................................................ 44 

Drug Safety Surveillance........................................................... 48 

Drug Recalls and Safety-Based Withdrawals............................ 53 

Compliance Oversight ............................................................... 56 

Drug Quality System ................................................................. 69 

Counterterrorism, Emergency Response ................................... 72 

International Activities................................................................ 74 

President’s Emergency Plan for AIDS Relief............................ 74 

Communications.......................................................................... 80 

Ombudsman Activities .............................................................. 82 

Appendix ...................................................................................... 85 

Glossary of Terms...................................................................... 85 

Internet Resources ..................................................................... 88 

 2 
Director’s Message 

I am happy to present the CDER 2007 Update, which documents the Center for Drug 

Evaluation and Research’s activities and performance across program areas. CDER’s 

continued ability to carry out its mission of protecting and advancing America’s health 

rests squarely on the commitment of our talented and dedicated staff. 

CDER continues to work to assure that medicines are safe, effective and available to the 

public, and to provide clear and easily understandable drug information to health 

professionals, patients and consumers. Our ability to carry out this mission has been 

bolstered by recent legislation. 

On September 27, President George W. Bush signed into law the Food and Drug 

Administration Amendments Act (FDAAA) of 2007. This new law is a significant 

addition to FDA authority. 

FDAAA reauthorized and expanded the Prescription Drug User Fee Act (PDUFA) to 

ensure that CDER has the resources needed to conduct complex and comprehensive drug 

reviews and to provide more resources for drug safety activities. Two other important 

laws were reauthorized; the Best Pharmaceuticals for Children Act and the Pediatric 

Research Equity Act. Both laws encourage more research into developing treatments for 

children. 

A number of our 2007 initiatives were in response to a comprehensive report on the 

nation’s drug safety system that we asked the Institute of Medicine (IOM) to conduct. 

We have taken steps to put many of IOM’s recommendations in place, including 

establishing a new advisory committee to address how we communicate information 

about the efficacy, safety and use of drugs and other FDA-regulated medical products. 

On June 4, 2007, FDA established a Risk Communication Advisory Committee, as 

suggested by IOM and endorsed in the FDAAA. The committee is comprised of 

practitioners and experts in risk communications. These highly-qualified individuals will 

play a vital role in helping us improve our practices, procedures and programs. As a 

result of these efforts, consumers and health-care professionals can make better-informed 

decisions about the risks and benefits of all regulated products. 

Safety First/Safe Use 

When I assumed the role of Acting Director of CDER in October 2007, I announced an 

initiative called Safety First/Safe Use. This initiative builds on authorities and 

opportunities provided by the FDAAA. These authorities further establish our critical role 

in assuring the safe and appropriate use of drugs after they are marketed and gives us 

substantial resources and regulatory tools. Essentially, FDAAA supports our ability to 

manage safety throughout the entire life cycle of pharmaceutical products. 

 3 
We have been tremendously successful in developing a world-class pre-market review 

process. This process enables us to approve safe and effective drugs effectively and 

efficiently without sacrificing the quality of our reviews. Over the past 15 years, 

additional resources and commitments resulting from PDUFA brought unprecedented 

accountability to the new drug review and institutionalized project management, 

prioritization and tracking for pre-market drug review. Now we are going to apply the 

same high standards to managing the post-marketing safety process. 

Safety First refers to steps that strengthen and modernize our internal policies and 

processes to manage significant drug safety issues. Safe Use describes CDER’s mission 

to expand partnerships with other components of the health care system to ensure that 

medicines are used safely and appropriately. 

The specific objectives of Safety First are to: 

• Create and maintain a collaborative, multidisciplinary, team-based approach to 

the review of drug safety. 

• Apply our world class project management skills to make sure we have the same 

focus on and attention to post-market safety issues as we do to drug development. 

• Align our policies and processes to ensure that the most appropriate and bestqualified experts lead or have an equal voice in regulatory decisions. 

• Build the scientific, administrative and technological capacity to carry out the 

provisions of FDAAA and PDUFA IV. 

• Ensure that significant post-market safety issues are our highest priority. 

As we put these changes in place, we will also begin focusing on the longer-term goal of 

influencing the safe and appropriate use of drugs by the healthcare system. The 

preliminary objectives of the Safe Use initiative are to: 

• Develop a cutting-edge pharmacovigilance system for evaluating drug 

performance using electronic health data. 

• Collaborate with stakeholders in the healthcare system to devise effective, 

efficient steps to ensure drugs are used as appropriately as possible, in ways that 

minimize medical errors and manage risks aggressively. 

Critical Path Initiative 

Several years ago, we launched the Critical Path Initiative. This initiative was designed to 

bridge the gap between basic scientific research and the medical product development 

process. It called for a collaborative cross-sector effort to modernize the drug 

development process. 

The Critical Path Initiative has rapidly matured and is now poised to yield benefits. 

Today, we are building on our unique position to work with outside stakeholders to 

identify areas ripe for improvement, and to coordinate, develop and/or disseminate 

solutions to scientific hurdles that are impairing the efficiency of developing and 

evaluating regulated products. 

 4 
Many critical path tools, such as new biomarkers and more informative clinical trial 

designs produce enhanced information about the safety and efficacy of the product. This 

is information that health-care providers can use to tailor therapies to the individual needs 

of patients. 

For example, better methods for selecting patients and assessing their responses during a 

clinical trial can translate directly to better methods of diagnosing and monitoring 

patients in the clinic, and better methods for targeting treatments to the patients who are 

most likely to benefit. Such tools will help bring individualized medicine into the 

physician’s office and help to shape the medical practice of the future. 

Posted descriptions of some of our Critical Path activities are on our Web site. We will be 

adding new activities as they begin to take shape. 

CDER’s initiatives hold the potential to usher in a new era of certainty and predictability 

in the development and performance of products that we regulate. We are extremely 

proud of the work outlined in this CDER 2007 Update. The ultimate beneficiaries of our 

efforts will be the public whom we serve. 

 Janet Woodcock, M.D. 

 5 
Introduction 

Who we are 

The Center for Drug Evaluation and Research is America’s consumer watchdog for 

medicine. Approximately half of us are physicians or other kinds of scientists. We are 

part of one of the nation’s oldest consumer protection agencies—the U.S. Food and Drug 

Administration. The FDA is an agency of the federal government’s Department of Health 

and Human Services. 

Our mission 

CDER promotes and protects public health by ensuring that safe and effective drugs are 

available to Americans. The Food and Drug Administration Act of 1997 affirmed our 

public health protection role, clarified the FDA’s mission and called for the FDA to: 

• Promote the public health by promptly and efficiently reviewing clinical research 

and taking appropriate action on the marketing of human drugs in a timely 

manner. 

 

• Protect the public health by ensuring that human drugs are safe and effective. 

 

• Participate through appropriate processes with representatives of other countries 

to reduce the burden of regulation, harmonize regulatory requirements and 

achieve appropriate reciprocal arrangements. 

• Carry out its mission in consultation with experts in science, medicine and public 

health and in cooperation with consumers, users, manufacturers, importers, 

packers, distributors and retailers of human drugs. 

Our mission was further enhanced on September 27, 2007 when H.R. 3580, the Food and 

Drug Administration Amendments Act (FDAAA) was signed into law. This new law 

represents a significant addition to FDA authority and reauthorized the: 

• Prescription Drug User Fee Act, allowing FDA to fund reviews of new drugs and 

shorten review times. 

• Medical Device User Fee and Modernization Act which allows FDA to make 

significant improvements in the medical device review program. 

• Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act to 

encourage more studies to develop treatments for children. 

 6 
What we do 

We evaluate new drugs for safety and effectiveness before they can be sold. Our 

evaluation, called a review, ensures that the drugs we approve meet our tough standards 

for safety, effectiveness and quality. Once drugs are on the market, we monitor them for 

problems. 

Reviewing drugs before marketing. FDA does not conduct the clinical studies that 

support marketing. A drug company seeking to sell a drug in the United States must 

conduct the studies intended to demonstrate effectiveness and defining the drug’s risks. 

We monitor clinical research to ensure that people who volunteer for studies are 

protected and that the quality and integrity of scientific data are maintained. The 

company then sends us the evidence from these tests to prove the drug is safe and 

effective for its intended use. We assemble a team of physicians, statisticians, chemists, 

pharmacologists and other scientists to review the company’s data and proposed use for 

the drug. If the drug is effective and we are convinced its health benefits outweigh its 

known risks, we approve it for sale. By setting clear standards for the evidence we need 

to approve a drug, we help medical researchers bring safe and effective new drugs to 

American consumers more rapidly. We also review drugs that you can buy over the 

counter without a prescription and generic versions of over-the-counter and prescription 

drugs. 

Watching for drug problems. Once a drug is approved for sale in the United States, our 

consumer protection mission continues. We monitor the use of marketed drugs for 

unexpected health risks. If new, unanticipated risks are detected after approval, we take 

steps to inform the public and change how a drug is used or even remove it from the 

market. We monitor changes in manufacturing to ensure they will not adversely affect 

safety or efficacy. We evaluate reports about suspected problems from manufacturers, 

health-care professionals and consumers. We try to make sure an adequate supply of 

needed drugs is always available to patients who depend on them. 

Monitoring drug information and advertising. Accurate and complete information is vital 

to the safe use of drugs. In the past, drug companies promoted their products almost 

entirely to physicians. More frequently now, they are advertising directly to consumers. 

We oversee advertising of prescription drugs, whether to physicians or consumers. We 

pay particular attention to broadcast ads that can be seen by many consumers. The 

Federal Trade Commission regulates advertising of over-the-counter drugs. 

Advertisements for a drug must contain a truthful summary of information about its 

effectiveness, side effects and circumstances when its use should be avoided. 

 7 
Scientific research. We conduct and collaborate on focused laboratory research and 

testing. This maintains and strengthens the scientific base of our regulatory policymaking and decision-making. We focus on drug quality, safety and performance; 

improved technologies; new approaches to drug development and review; and regulatory 

standards and consistency.

Protecting drug quality. In addition to setting standards for safety and effectiveness 

testing, we also set standards for drug quality and manufacturing processes. We work 

closely with manufacturers to see where streamlining can cut red tape without 

compromising drug quality. To ensure a safe and effective drug supply, we enforce 

federal requirements for drug approval, manufacturing and labeling. When necessary, we 

take legal action to stop distribution of products in violation of these requirements. As the 

pharmaceutical industry has become increasingly global, we are involved in international 

negotiations with other nations to harmonize standards for drug quality and the data 

needed to approve a new drug. This harmonization will go a long way toward reducing 

the number of redundant tests manufacturers do and help ensure drug quality for 

consumers at home and abroad. 

Why we do it 

Our goal is to protect and promote the health of Americans. Protecting consumers 

includes listening to them. We hold public meetings to get expert, patient and consumer 

input into our decisions. We also announce most of our policy and technical proposals in 

advance. This gives members of the public, academic experts, industry, trade 

associations, consumer groups and professional societies the opportunity to comment 

before we make a final decision. In addition, we take part in FDA-sponsored public 

meetings with consumer and patient groups, professional societies and pharmaceutical 

trade associations. These help obtain enhanced public input into our planning and 

priority-setting practices. 

 8 
Drug Review 

New Drug and Biologic Review 

Drug Review Definitions 

• Review and approval times. Review time is time spent examining the application. 

Approval time represents review time plus industry’s response time to our 

requests for additional information. 

• Priority reviews. These products represent significant improvements compared 

with marketed products. We have a goal of reviewing 90 percent of these 

applications within six months. 

• Standard reviews. These products have therapeutic qualities similar to those of 

already marketed products. We have a goal of reviewing 90 percent of these 

applications within 10 months. 

• Actions and filings. An application is filed when we determine it is complete and 

accept it for review. We make a filing decision within 60 days of receiving an 

application. Approval is one of the actions that we can take once an application is 

filed. Another action is seeking more information from the sponsor. There is no 

direct connection between applications filed in one year and actions in the same 

year. 

• Orphan drugs. We administer a program that provides incentives to develop drugs 

for use in patient populations of 200,000 or fewer. Sponsors of orphan drugs 

receive the following inducements: seven-year marketing exclusivity, tax credit 

for the product-associated clinical research, research design assistance from FDA 

and grants of up to $200,000 a year. 

• Accelerated approval. This program makes products for serious or lifethreatening diseases available earlier in the development process by relying on an 

effect on a surrogate end point to predict clinical benefit. An effect of the drug on 

a surrogate end point can be observed significantly sooner than can a long-term 

clinical benefit. Sponsors must perform additional studies to demonstrate longterm clinical benefit. 

• Fast-track development. This program facilitates the development and expedites 

our review of new medicines that demonstrate the potential to address unmet 

medical needs for serious or life-threatening conditions. Fast track emphasizes our 

close, early communication with sponsors. 

• Median times. Our charts show review and approval times as medians. The value 

for the median time is the number that falls in the middle of the group after the 

approval times are ranked in order. It provides a truer picture of our performance 

than average time, which can be unduly influenced by a few very long times. Our 

 9 
guide to understanding median approval time statistics is available at 

http://www.fda.gov/cder/present/MedianAPtime/index.htm. 

• Tentative approval. This program is issued to the drug company when the 

application is approvable prior to the expiration of any patents or exclusivities 

accorded to the reference listed drug product. A tentative approval does not allow 

the applicant to market the product and postpones the final approval until all 

patent or exclusivity issues have expired. 

• New Molecular Entities (NMEs) contain an active substance that has never before 

been approved for marketing in any form in the United States. Because of high 

interest in truly new medicines, we report approvals of NMEs and new biologic 

license applications (BLAs). The charts for all new drug applications (NDAs) and 

all BLAs include NMEs and new BLAs. 

New drug applications 

NDAs are the formal submissions of data that sponsors send us when they are seeking 

approval to market a new drug in the United States. Some NDAs are for NMEs; 

however, NDAs can also be for an active substance previously sold in a different 

form. 

Biologic license applications 

BLAs are the formal submissions of data that sponsors send us when they are seeking 

approval to market a biologic in the United States. A new BLA is an application for a 

biologic that has never been approved for marketing in the United States. 

New Drug and Biologic Review Statistics 

Beginning with 2004, our charts incorporate data on the review of therapeutic biologics 

transferred to us in late 2003. These include: 

• Monoclonal antibodies 

• Cytokines 

• Growth factors 

• Enzymes 

• Other therapeutic immunotherapies 

Additional review statistics are available at http://www.fda.gov/cder/rdmt/default.htm. 

 10 
Approval totals in 2007 

• 78 drugs and biologics

o 76 drugs 

o 2 biologics 

• 18 truly new medicines

o 16 drug NMEs 

o 2 new biologic NMEs 

• 13 tentative NDA approvals

o 10 priority PEPFAR new combinations 

o 3 standard tentative approvals 

• 8 total orphan condition approvals 

o 7 new drugs or biologics 

 -4 priority reviews of new drugs (including 3 NMEs) 

 -1 priority review of a new biologic 

 -3 standard reviews of new drugs 

o 4 new or expanded uses for orphan conditions 

 -2 priority reviews for drugs 

 -2 standard reviews for drugs 

Priority new drugs and biologics 

• 23 approvals

o 22 drugs 

o 1 biologic 

• Median review time: 6.0 months 

• Median approval time: 6.0 months 

• 24 filings 

• 35 actions 

 11 
Priority NDA & BLA Approvals

Median times, approvals

6.26.46.26.46.16.16.06.06.06.013.819.17.77.76.06.06.06.06.06.06.06.0

20

22

23 21

29

14

11

10

28

25

20

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

15

30

Approvals

Median FDA review time Median total approval time Number approved

Priority NDAs & BLAs

Filings, actions, approval percentages

32 35 46 43 41 27 18 26 42 36 27 31 21 7 19 293118 26 2438 35

66%

57% 54% 55%

49% 37% 61%

54%

69% 61% 65%

0

25

50

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year *Includes therapeutic BLAs

(A filing in one year may lead to actions or approval in subsequent years)

Number

0%

50%

100% Percent

Filings Actions Percent of actions that are approvals

Priority new molecular entities and new biologics 

• 8 approvals

o 7 Drug NMEs 

o 1 new BLA 

• Median review time: 6.0 months 

• Median approval time: 6.0 months 

• 10 filings 

 12 
Priority NME & New BLA Approvals

Median times, approvals

6.46.76.26.26.36.96.06.06.06.013.816.36.76.76.06.06.06.06.06.06.06.0

8

16

19

9 7 7

9

21

15 10

9

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

12

24

Approvals

Median FDA review time Median total approval time Number approved

Priority NMEs & New BLAs

Filings

7 10

16 1717

10 5

15 1414 16

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes therapeutic BLAs

(A filing in one year may lead to actions or approval in subsequent years)

Number

Standard drugs and biologics 

• 55 approvals (all NDAs) 

o Median review time: 10.2 months 

o Median approval time: 10.4 months 

• 86 filings 

• 125 actions 

 13 
Standard NDA & BLA Approvals

Median times, approvals

14.718.712.012.012.013.812.012.012.014.012.715.311.915.411.912.911.813.112.013.010.210.4

80

55

101

65

55

78

56

67

58

90

58

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

60

120

Approvals

M edian FDA review time M edian total approval time Number approved

Standard NDAs & BLAs

Filings, actions, approval percentages

92200871531011478719788143791548913975162821079015886125

51% 44%

37%

56% 54%

40% 39% 44% 42% 42% 51%

0

150

300

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year *Includes therapeutic BLAs

(A filing in one year may lead to actions or approval in subsequent years)

Number

0%

50%

100% Percent

Filings Actions Percent of actions that are approvals

Standard new molecular entities and new biologics 

• 10 approvals (all NMEs) 

• Median review time: 12.9 months 

• Median approval time: 12.9 months 

• 26 filings 

 14 
Standard NME & New BLA Approvals

Median times, approvals

14.415.012.313.414.016.315.419.915.719.012.515.913.823.116.024.715.823.012.513.712.912.9

5

17 18

14

30 16

10

12 15

12

10

0

15

30

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

20

40

Number

Median FDA review time Median total approval time Number approved

Standard NMEs & New BLAs

Filings

17

26 19 16 13 12

25

12

22 25 28

0

20

40

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

 *Includes therapeutic BLAs

(A filing in one year may lead to actions or approval in subsequent years)

Number

New or Expanded Use Review 

Applications for a new or expanded use, often representing important new treatment 

options, are formally called efficacy supplements to the original new drug application. 

We have a goal of reviewing standard supplements in 10 months and priority 

supplements in six months. 

Approval totals 

• 127 reviews of drugs and biologics 

• 119 reviews of drugs 

• 8 reviews of biologics 

Priority new or expanded uses (efficacy supplements) 

• 36 approvals

 15 
o 33 reviews of drugs 

o 3 reviews of biologics 

• Median review time: 7.6 months 

• Median approval time: 6.0 months 

• 42 actions 

Priority New or Expanded Use Approvals

Median times, approvals

4.44.46.06.06.06.06.06.06.06.06.06.06.06.06.06.06.06.06.06.06.07.5

48

39 36

36

4

13

9

18

6

19

21

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

25

50

Approvals

Median FDA review time Median total approval time Number approved

Priority New or Expanded Uses

Actions, approval percentages

52 52 42

7

13 19 23 10

36

33 64

86%

100%

78%

60%

53%

47%

57%

64%

75% 69%

75%

0

40

80

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Actions

0%

50%

100%Percent

Actions Percentage of actions that are approvals

Standard new or expanded uses (efficacy supplements) 

• 91 approvals

o 86 reviews of drugs 

o 5 reviews of biologics 

• Median review time: 10.0 months 

• Median approval time: 11.8 months 

 16 
• 109 actions 

Standard New or Expanded Use Approvals

Median times, approvals

11.912.011.912.011.011.310.010.010.711.310.010.010.010.010.010.010.010.09.99.910.011.8

91

105 98 99

110

133

85

111 116

88

104

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

80

160

Approvals

Median FDA review time Median total approval time Number approved

Standard New or Expanded Uses

Actions, approval percentages

171 133 109

178 161

237

182 203

160 165 182

83%

74%

61%

57%

62% 61%

53% 56%

42%

64%

69%

0

150

300

1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*

Calendar year

*Includes BLAs for therapeutic biologics

Actions

0%

50%

100%Percent

Actions Percentage of actions that are approvals

 17 
Generic Drug Review 

Generic drugs are not required to repeat the extensive clinical trials used in the 

development of the original, brand-name drugs. For many products such as tablets and 

capsules, generics must show bioequivalence to the brand-name reference listed drug. 

This means that the generic version must deliver the same amount of active ingredient 

into a patient’s bloodstream over the same time period as the brand-name reference listed 

drug. 

The rate and extent of absorption of a drug is called its bioavailability. The 

bioavailability of the generic drug is compared to that of the brand-name drug. If the 

bioavailability of the two is similar, the drugs are bioequivalent. 

Brand-name drugs are subject to the same bioequivalency tests as generics when their 

manufacturers reformulate them. 

Generic drug 2007 approvals 

We had 683 approval actions with 495 fully approved and 188 tentatively approved 

generic drug products in calendar year 2007. This included a substantial number of 

products that represent the first time a generic drug was available for the brand-name 

product. 

The median statistic for total approval time showed an increase this year due, in part, to 

the high numbers of new applications for the last two years. We have made several 

changes to improve the efficiency of our generic drug review process in order to try to 

keep up with the dramatic increase in applications. These efforts will continue. 

• 495 generic drugs 

• Median approval time 19.26 months 

• 188 tentative approvals 

• 882 receipts 

 18 
Generic Drug Approvals

Median times, approvals

15.7 16.4 17.5 19.3 18.0 18.2 18.1 18.3 17.0 19.3 18.6

495

371

380

263

321

244 234

186

225

273

344

0

18

36

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Months

0

200

400

600

Number

Median approval times Number of generic approvals

Tentative vs. full approval 

The difference between a full approval and a tentative approval is that the final approval 

of these applications is delayed due to an existing patent or exclusivity on the innovator 

drug product. The FDA review of an application that is tentatively approved requires the 

same amount of work as a review that results in a full approval. Tentative approvals are 

displayed in our approvals chart only when they are converted to full approvals. 

Tentative approvals key to affordable, worldwide AIDS relief 

Tentative approval is a key regulatory mechanism to support the availability of drugs for 

the President’s Emergency Plan for AIDS Relief. 

Generic Drug Tentative Approvals 

73 63

101 95 108

164

188

56 4040 61

0

90

180

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

 19 
Generic Drug Applications Received

320 392 479

635

777 828 882

330 345 365 296

0

500

1,000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Applications received (w orkload in future years)

Notable 2007 generic drug approvals 

• Alendronate tablets. Used to treat certain types of osteoporosis and Paget’s 

disease. 

• Carvedilol tablets. A beta blocking agent used to treat congestive heart failure and 

hypertension. 

• Cetirizine tablets. An antihistamine for treatment of various allergic conditions. 

• Granisetron tablets. For the prevention and treatment of nausea or vomiting 

related to cancer therapy and postoperative nausea and vomiting. 

• Irinotecan injection. Used for treatment of colon and rectal cancer. 

• Zolpidem Tablets. Used for the short-term treatment of insomnia. 

Generic drug review efficiencies 

The dramatic increase of generic drug applications makes it imperative that we process 

applications more efficiently. Our steps to improve our processes and to improve the 

content and completeness of generic drug applications include: 

• The Generic Initiative for Value and Efficiency which focuses on using 

existing resources to help FDA modernize and streamline the generic 

approval process. 

• Question-based Review to assist sponsors in providing information that 

demonstrates their understanding of the manufacture of the product. 

• Posting bioequivalence information, including data tables, information 

about laboratory tests and necessary studies. 

• Focused hiring which increase staff in critical review components. 

 20 
• Holding joint meetings and workshops with academia and industry to 

improve knowledge of the submission process and quality of applications. 

• Encouraging electronic submission of applications. 

Reducing hurdles to generic drug availability 

We expedite the review of applications that, at the time of submission, represent the first 

generic application for an innovator product that had no patent or exclusivity protection. 

We are working to implement recently passed legislation aimed at reducing certain delays 

in acting on generic drug applications. 

 21 
Over-the-Counter Drug Review 

How we regulate OTC drugs 

Although many drugs are approved for OTC use through the new drug review process, 

other OTC medicines are regulated under the OTC drug review process. This process 

relies on published monographs created by public rule making. We publish monographs 

that establish acceptable ingredients, doses, formulations and consumer labeling for OTC 

drugs. Products that conform to a final monograph may be marketed without prior FDA 

clearance. FDA maintains an online library of all OTC monographs which can be found 

at http://www.fda.gov/cder/otcmonographs/rulemaking_index.htm. 

In 2007, we approved one new drug application for first-time over-the-counter sale, eight 

prescription-to-OTC switches and one new strength. 

OTC approval statistics 

• 1 first-time OTC 

• 8 Rx-to-OTC switches 

• 1 new strength 

OTC New Approvals & New Uses

6

1

5

13

8

1 7

3

1

5 9

5

13

8 8

2 3

1

1 3

0

12

24

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

New approvals or Rx-to-OTC switches New uses

First-time OTC:

• Orlistat 60 mg (Alli) capsules for weight loss in overweight adults, 18 years and 

older, when used along with a reduced-calorie, low-fat diet and exercise program. 

 22 
Rx-to-OTC Switches:

• Cetirizine HCl 5 mg/pseudoephedrine HCl 120 mg (Zyrtec-D) tablets for the 

temporary relief of symptoms of hay fever or other upper respiratory allergies: 

runny nose, sneezing, itchy, watery eyes, itching of the nose or throat, and nasal 

congestion in adults and children 12 years of age and older. 

• Cetirizine HCl 1 mg/ml (Children’s Zyrtec Allergy) syrup for the temporary relief 

of symptoms of hay fever or other upper respiratory allergies: runny nose, 

sneezing, itchy, watery eyes, itching of the nose or throat in adults and children 2 

years of age and older. 

• Cetirizine HCl 1 mg/ml (Children’s Zyrtec Hives Relief) syrup for the relief of 

itching due to hives (urticaria) in adults and children 6 years of age and older. 

• Cetirizine HCl 5 mg and 10 mg (Children’s Zyrtec Allergy) chewable tablets for 

the temporary relief of symptoms of hay fever or other upper respiratory allergies: 

runny nose, sneezing, itchy, watery eyes, itching of the nose or throat in adults 

and children 6 years of age and older. 

• Cetirizine HCl 5 mg and 10 mg (Children’s Zyrtec Hives Relief) chewable tablets

for the relief of itching due to hives (urticaria) in adults and children 6 years of 

age and older. 

• Cetirizine HCl 5 mg and 10 mg (Zyrtec Allergy) tablets for the temporary relief of 

symptoms of hay fever or other upper respiratory allergies: runny nose, sneezing, 

itchy, watery eyes, itching of the nose or throat in adults and children 6 years of 

age and older. 

• Cetirizine HCl 5 mg and 10 mg (Hives Relief) tablets for the relief of itching due 

to hives (urticaria) in adults and children 6 years of age and older. 

• Omeprazole 20 mg delayed-release tablets for the treatment of frequent heartburn 

in adults 18 years of age and older. 

New Strength:

• We approved a new 20 mg famotidine strength formulation of Pepcid AC 

chewable tablet for the treatment or prevention of meal-induce heartburn, acid 

indigestion and sour stomach for adults and children 12 years of age and older 

replacing the old 10 mg strength chewable tablet. 

 23 
Pediatric Drug Development 

President Bush signed into law the FDA Amendments Act of 2007 in September. This 

law reauthorizes and amends the Best Pharmaceuticals for Children Act of 2002 (BPCA) 

and the Pediatric Research Equity Act of 2003 (PREA). Both laws encourage more 

research into developing treatments for children. Some highlighted changes to BPCA and 

PREA are: 

• Authorization to establish an internal review committee. The Pediatric Review 

Committee will review requests for waivers and deferrals, review pediatric 

assessments and pediatric plans prior to approval and pediatric written requests 

prior to issuance. 

• The clinical, clinical pharmacology and statistical reviews are to be made public 

for applications submitted in response to both PREA and BPCA. 

• Adverse event reporting now affects both PREA and BPCA. The review of 

reports has been modified to occur one year after labeling is approved. 

Pediatric Research Equity Act. In 2007, CDER granted 86 waivers and 32 deferrals. 

There were 32 applications with PREA requirements fulfilled. As of June 2007, there 

have been nine PREA-related labels identified and posted. Since FDAAA, there were 

seven pediatric assessments approved, six deferrals and 23 waivers granted. 

Pediatric Review Committee. In 2007, there were 23 CDER products reviewed by the 

committee. 

Pediatric exclusivity. We issued 20 on-patent written requests and one off-patent. 

During 2007, there were 14 exclusivity determinations, 13 of which were granted 

exclusivity and 17 labels with new pediatric information approved. 

Improved safety, dosing information. The failure to produce drugs in dosage forms that 

can be taken by young children—such as liquids or chewable tablets—can deny children 

access to important medications. As a result of pediatric testing under BPCA, we now 

have 15 drugs with new pediatric formulations and seven drugs with recipes in their 

labels to provide directions for the pharmacist to compound an age-appropriate 

formulation. 

Public disclosure. We have posted 83 summaries of the medical and clinical 

pharmacology reviews responsive to BPCA 2002. These summaries are located at 

http://www.fda.gov/cder/pediatric/Summaryreview.htm. 

Adverse events reporting. Seventy-seven drugs have been presented to the Pediatric 

Advisory Committee. The law mandates review of all adverse event reports for a oneyear period after pediatric exclusivity is granted. 

2007 pediatric exclusivity statistics 

• 20 written requests issued 

 24 
• 17 pediatric exclusivity labeling changes granted 

• 14 exclusivity determinations made 

Pediatric Drug Development

12 17 23 20 23 17 15 18 14

11

12 19 15 25 25 14 17

98

45

69

21 24 19

10 22 20

3

0

60

120

1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Number

Pediatric exclusivity determinations Pediatric exclusivity labeling changes Written requests issued

Maternal Health Team 

The Maternal Health Team mission is to increase knowledge about the safe and effective 

use of medicines during pregnancy and breast-feeding. We encourage research in this 

area and provide scientific guidance to industry and FDA reviewers. When more 

information about medicine use during pregnancy and breastfeeding becomes available, 

we work with FDA reviewers and drug manufacturers to update medicine labels. 

Women who are pregnant or breast-feeding often need to use prescription and/or overthe-counter medicines. During pregnancy, treating a disease or condition with a medicine 

may be safer for the woman and her baby than not treating the condition. It is important 

that health-care providers and pregnant women have the information they need to make 

the best medicine choices. Breastfeeding offers many health benefits to mother and baby, 

and these benefits should be considered along with the possible risks of infant exposure 

to medicine through breast milk. 

In 1997, FDA started reviewing the pregnancy and breast-feeding sections of prescription 

medicine labels and the regulations that describe how the label is written and the 

information it must include. Based on feedback from government agencies, medical 

experts, clinicians and the public, FDA developed a new format for pregnancy and 

breast-feeding sections of medicine labels that will be presented to the public for 

comment as a proposed rule in the Federal Register. 

 25 
Scientific guidance 

• Determining the appropriate dose of a drug for pregnant women. In 2004, we 

published draft guidance for industry that provides a basic framework for 

designing, conducting and analyzing pharmacokinetic and pharmacodynamic 

studies in pregnant women. 

• Evaluating study results on approved drugs when used during pregnancy. In 

2005, we issued our final guidance for FDA reviewers about evaluating the 

effects of medicines on the growing fetus. 

• Lactation studies in women. In 2005, we published draft guidance for industry 

describing a basic framework for designing, conducting and analyzing clinical 

lactation studies. We reviewed public comments received in response to this 

publication and held an Advisory Committee Meeting on November 29, 2007 to 

obtain expert advice. 

• Pregnancy exposure registries. In 2002, we published a final guidance for 

industry that provides advice on how to establish a registry that prospectively 

monitors outcomes of pregnancies in women exposed to a specific drug. The 

Maternal Health Team is updating this guidance to clarify recommendations on 

reporting of major and minor congenital malformations, nonteratogenic endpoints, 

patient recruitment procedures and control group considerations. 

 26 
Critical Path Initiative 

Our role in the Agency’s Critical Path Initiative is to stimulate and facilitate a national 

effort to modernize the scientific processes through which a potential human drug or 

therapeutic biologic is transformed from a discovery or proof of concept into a medical 

product. 

Despite recent innovations, many serious and life-threatening diseases still lack effective 

treatments. In our view, the scientific tools needed to develop medical products have not 

kept pace with the rapid advances in product discovery. As a result, fewer of the sound 

ideas spawned in medical laboratories are producing safe and effective treatments. 

Because of our unique vantage point, we can work with companies, patient groups, 

academic researchers and other stakeholders to coordinate, develop and help disseminate 

solutions to scientific hurdles that are impairing the efficiency of medical product 

development. 

Critical Path Progress in 2007 

Developing Critical Path Opportunities Document for Generic Drugs 

In May of 2007, we released Critical Path Opportunities for Generic Drugs. This 

document identifies key opportunities to improve standards and methods to evaluate 

bioequivalence for locally acting drugs. It also helps increase understanding of the 

manufacturing controls needed to produce complex pharmaceutical formulations with 

consistently high quality. 

Improving warfarin dosing 

Because there is wide variation in patient response to this blood thinning drug that may 

lead to severe consequences of under- or over-dosing, we are involved in two projects. 

• We relabeled warfarin in August 2007 to recommend that prescribers consider 

testing for genetic variants of enzymes that alter the body’s ability to 

metabolize or respond to warfarin. In parallel, we approved the first warfarin 

sensitivity test, which detects these genetic variants. 

• We are developing dosing models that may lead to safer initial dosing for 

warfarin. 

Examining the genetic basis of adverse events 

In 2007, the Serious Adverse Events Consortium, a nonprofit partnership among several 

leading pharmaceutical companies, the FDA and academic institutions, launched initial 

research programs designed to identify genetic markers that may help predict which 

individuals are at risk for serious drug-related adverse events. Two areas of initial focus 

will address drug-related liver toxicity and a rare but serious drug-related skin condition 

called Stevens-Johnson Syndrome. 

 27 
Advancing biomarker qualification 

The Predictive Safety Testing Consortium is a collaboration of the CPath Institute, 17 

pharmaceutical industry partners and FDA. One goal of this consortium is to validate the 

predictive value of new preclinical biomarkers of toxicity and qualify their use in specific 

regulatory contexts. In 2007, a set of biomarkers of nephrotoxicity were submitted to 

FDA for qualification through a pilot process. They were evaluated at the agency to 

understand evidentiary standards and metrics associated with the qualification of novel 

biomarkers. 

In addition, we are collaborating with a public-private research partnership tasked with 

discovering, developing and qualifying new biological markers to support new drug 

development, preventive medicine and medical diagnostics. The Biomarker Consortium 

includes representation from the Foundation for the National Institutes of Health, FDA, 

Centers for Medicaid and Medicare Services, NIH and the pharmaceutical, 

biotechnology, diagnostics and medical device industries. 

Identifying indicators of cardiac toxicity 

FDA and Mortara Instruments, a manufacturer of electrocardiographic equipment, are 

working to create a repository for digital ECGs and a suite of tools to enable their 

efficient review. FDA invited sponsors to upload digital ECGs directly to the repository, 

where they are made immediately available to the reviewers. Currently, the warehouse 

contains more than one million ECGs. In addition to supporting our mission to evaluate 

the effects of drugs on the heart, the repository is an important research resource for 

future studies to identify improved predictors of cardiovascular risks related to use of 

medications. 

In a second phase of this effort, FDA and an academic research center founded the 

Cardiovascular Safety and Research Consortium to coordinate and support research 

projects involving the warehouse. 

Developing guidances on advanced clinical trial design 

We began developing guidance to facilitate innovations in study design and analysis 

related to end of Phase 2a meetings, adaptive trial designs and non-inferiority trial 

designs. 

Developing tools for product characterization and manufacturing 

understanding 

The industrialization challenges posed by the demands of physical product design, 

characterization, scale-up and manufacturing are often little understood outside of FDA 

and the pharmaceutical manufacturing communities. Many product failures during 

development are ultimately attributable to problems relating to the transition from 

laboratory prototype to industrial product. To improve predictability in this area, it is 

crucial that FDA has both improved technical standards—tests, procedures and reference 

materials—and improved methods for design, characterization and product manufacture. 

 28 
A number of studies in these areas were initiated to respond to critical manufacturing 

science questions. 

Pharmacogenomics, personalized medicine 

The Critical Path recognizes the importance of pharmacogenomics and encourages its use 

in drug development. Pharmacogenomics allows health-care providers to identify 

differences in people’s drug-risk-response profiles and predict the best possible treatment 

options for them. 

In 2007, FDA continued laying the groundwork for incorporating pharmacogenomics in 

our regulatory reviews and into clinical practice. Our activities included: 

• Issuing a Draft Companion Guidance to the Pharmacogenomics Guidance on 

Recommendation for the Generation and Submission of Genomic Data. 

• Publishing Guiding Principles for Joint FDA EMEA Voluntary Genomic Data 

Submission Briefing Meetings.

• Posting on our genomics Web site Valid Genomic Biomarkers in Drug Labels. 

• Co-authoring Guidelines and Recommendations for Laboratory Analysis and 

Application of Pharmacogenetics to Clinical Practice.

• Initiation of Part 2 of the Microarray Quality Control initiative to identify 

sources of variability in genomic classifiers derived from microarray gene 

expression and genome-wide association study data.

• Receiving 12 additional voluntary genomic data submissions from industry.

More information is at http://www.fda.gov/cder/genomics. 

 29 
Scientific Research 

We advance the scientific basis of regulatory practice by developing, evaluating or 

applying the best, most appropriate and contemporary scientific methods to regulatory 

testing paradigms. We provide scientific support for reviewer training, regulatory 

decision making and the development of regulatory policy. 

We focus on creating a tighter scientific linkage between non-clinical and clinical studies, 

enhancing methodology for assuring product quality, building databases for improved 

drug development and review and providing regulatory support through laboratory 

testing. 

Linking non-clinical and clinical studies 

• Biomarkers for organ damage. We are identifying, evaluating and 

establishing relevant protein biomarkers in blood in both animal models and 

in humans. These will help detect the very earliest damage that can be caused 

by certain drugs to the heart, kidney, immune system and liver. 

• Biomarkers for inflammation. To enhance safety within broad segments of 

patient populations and enable safe development of new drug classes, we are 

working on the identification and elucidation of associated serum biomarkers 

and mechanisms responsible for the development of vascular inflammation in 

specific organ systems. 

• Medicinal plants, herbs. We established scientific research capabilities in the 

analyses of medicinal plant and herbal products. 

• Imaging drug targets. We continue to explore noninvasive imaging 

technology to extend our long-standing interest in the application of accurate 

dose-concentration-response principles by viewing drugs and their actions 

directly at the level of the drug target, rather than indirectly via plasma 

concentrations. 

• Better use of exposure-response data. We are developing a standardized 

approach for using exposure-response information to help evaluate the risks 

and benefits of drug therapies and recommending dose adjustments in special 

populations. 

• Pediatric pharmacokinetics. We are developing a pediatric population 

pharmacokinetics study design template to facilitate implementation of sparse 

sample strategies in pediatric drug development. 

 30 
Biotechnology research 

We evaluate therapeutic biotechnology product submissions as well as carry out scientific 

research related to biologics regulatory issues. 

• Immune responses. We review many submissions aimed at inhibiting 

unwanted immune responses, such as autoimmune diseases or rejection of 

transplanted organs, or aimed at enhancing desired immune responses, such as 

those against infections or cancer. To facilitate review of such immunologyrelated submissions, we study the mechanisms by which immune cells are 

activated, suppressed or channeled from one kind of active response to 

another. 

• Metabolic pathways. We study the mechanisms by which various regulated 

products induce their intended effects, as well as unintended adverse effects. 

Our investigations also examine various normal and pathogenic pathways that 

are targeted by regulated agents. 

Our research enhances the ability of our scientist/regulators to evaluate risks and benefits 

of biotech products, to advise industry on difficult regulatory problems, such as potency 

assays, and to develop hands-on expertise in the modern technologies used by sponsors of 

biotech products. 

Informatics and computational safety analysis 

• Cancer toxicity predictive software. Our cooperative research and 

development agreements with several commercial software developers have 

resulted in the development and marketing of new computer software to 

predict the cancer-causing potential of chemicals based on their molecular 

structure. The software makes use of our extensive rodent carcinogenicity 

database without compromising proprietary information. 

• Safe starting dose models. We have successfully developed computer models 

to estimate the safe starting dose for clinical trials of drugs based on their 

molecular structure. The current method for estimating the starting dose is 

highly inexact and requires the use of multiple safety factors because it is 

based exclusively on an extrapolation from animal toxicity studies. We have 

begun studies to validate the new method. 

How our scientific research helps us 

Scientists at our own labs in Bethesda and White Oak, Maryland, and St. Louis, Missouri, 

perform research that helps us: 

• Understand how pharmaceutical products are developed and manufactured to 

ensure quality and safety. 

• Study specific characterizations and properties of pharmacological products in 

order to make sound scientific and regulatory decisions. 

 31 
• Set standards for specific products based on scientific evaluation. 

• Develop appropriate methodology for complex and novel products. 

• Determine how best to label products. 

• Address various public health issues. 

• Study new technology to determine regulatory requirements. 

Evaluation of new technologies 

We conduct targeted research to understand how new technologies will affect future 

regulatory decision making. 

For example, we are evaluating how microarrays that can identify thousands of genes or 

proteins rapidly and at the same time could improve the interface between drug 

development and regulatory practice. 

Microbiology 

We assess product sterility, maintenance of product safety and the microbiological 

controls used by firms for drug development and manufacturing. 

Our microbiology review assures the safety of sterile and non-sterile products through 

scientific evaluation and communication with the industry and assures consistency 

through guidance documents. 

We promote the development of uniform and practical test methods and criteria for our 

own use and through the U.S. Pharmacopoeia and the International Conference on 

Harmonization.

We have a new program to advance rapid microbiology test methods. 

Research to support regulatory decision making 

Numerous issues arise in the routine review of drug products which require us to conduct 

some research in order to make scientifically informed decisions regarding the marketing 

of a product, including its labeling. 

The research often serves to provide scientific justification for policy development and 

enforcement actions. The research conducted in our labs covers the broad spectrum of our 

responsibilities, including: 

• Application review. Reviewers will work with researchers to resolve specific 

questions having to do with a specific product before finalizing decision to 

approve. For example, we performed basic laboratory tests that encouraged 

manufacture of Prussian blue as a treatment of people exposed to harmful 

levels of radioactive materials and poisons and for counter-terrorism agents. 

• Regulatory policy. Reviewers, research staff and researcher-reviewers will 

also generate research activities to determine appropriate regulatory policy. 

Examples include altered stability and performance of split tablets and 

filtration of biologics to remove viral contamination. 

 32 
• Product testing. Our scientists test marketed products when there is a question 

of safety or quality, such as the delivery characteristics of a metered dose 

inhaler to make sure they meet standards. 

• New technology. Our researchers help us understand new technologies and 

determine how they will fit into the regulatory scheme. Examples include drug 

delivery systems using nanoparticles, the toxicity of nanomaterial and the 

validation of new test methods. 

• Manufacturing. We conduct research on various aspects of manufacturing to 

better understand a product’s critical attributes and how they affect product 

quality and product lifecycle. Examples include the ability of critical product 

attributes to stimulate an immune response and the impact of adhesion 

variability on transdermal patches. 

• Formulation changes. We determine how certain changes in formulation, such 

as different inactive ingredients, affect the safety, efficacy and quality of 

products. 

• Process analytical technologies. We research various techniques for process 

analytical technology, including new spectroscopy methods for characterizing 

tablets and future follow-on biologics. 

• Mechanism of action. We research the mechanisms of action of a given 

product. This knowledge is critical for designing the bioactivity and potency 

test that is required for all biologics as well as in biomarker development. 

• Biomarkers. We are developing potential safety and efficacy biomarkers to 

help understand how products can be better employed. 

Counterterrorism biotechnology research 

We have used congressionally mandated special funding to initiate research in several 

areas relevant to counterterrorism. Our scientists are studying: 

• Microarray technologies, which could assist in identifying infectious 

biowarfare agents. 

• Non-specific immune boosters, which could provide transient protection 

against such agents. 

• Monoclonal antibodies as neutralizers of biological toxins. 

• Various strategies to defend against anthrax. 

• Development of Anthrax Toxin assays for assessment of potential therapies. 

 33 
By establishing a core of scientists experienced in several areas of bioterrorism, these 

projects anticipate high-priority regulatory submissions likely to require rapid sciencebased evaluation. 

Scientific collaborations 

We collaborate on scientific projects in an effort to leverage our knowledge and 

experience with others because a single institution or firm lacks the resources to conduct 

some types of research. We have a number of collaborative projects that are being done 

under: 

• Cooperative research and development agreements. 

• Material transfer agreements. 

• Involvement with various non-profit collaboration groups such as the National 

Institute for Pharmaceutical Technology and Education and the Product 

Quality Research Institute. 

• Work with academic organizations such as the University of Delaware and 

Purdue University. 

Collaborations bring together experts representing industry, academia and government 

and cover a wide array of scientific and regulatory issues related to pharmaceutical 

products. These collaborations help us maintain the high level of science necessary to 

ensure that all products are safe and effective and of high quality. A number of the 

Critical Path Initiatives, such as the Biomarker Consortium, are also being done through 

these collaborations. 

Pharmaceutical analysis 

We collaborate with other organizations to ensure the availability of high quality 

standards and calibration materials. We collaborated with state pharmacy boards to 

evaluate Internet pharmaceuticals. We evaluated the quality of a select group of the mostoften-ordered pharmaceutical products from foreign Internet suppliers. 

Laboratory support 

• We assessed several technologies for rapid identification of drug products and 

raw materials to guard against counterfeit products. We applied near infrared, 

Raman, Isotope ratio mass spectrometry to the problem of distinguishing 

between production sources of active pharmaceutical ingredients and finished 

dosage forms. 

• We developed methodology to better characterize nasal spray products. We 

evaluated a new aerodynamic particle size analyzer. 

• We evaluated instrumentation for the determination of particle size and 

particle size distribution for cyclosporin drug products. 

 34 
• We are developing physicochemical methods to assess quality changes in 

liposomal drug products. 

• We developed methods to evaluate quality attributes of drug products and raw 

materials by chemical imaging. These properties include polymorphic form, 

hydration state, stability and purity. 

 35 
User Fee Program 

Americans deserve timely access to potentially lifesaving new drugs as soon as possible 

once they are proven safe and effective. The Prescription Drug User Fee Act of 1992 

received its second five-year extension in 2002, known as PDUFA III. This 

reauthorization helps us ensure that we have the staff and resources to review 

applications promptly, and get safe, effective new drugs into the hands of the people who 

need them. The reauthorization also allows user fees to support some safety activities, 

both during development and for newly approved medicines. The current user fee law 

maintains our high review performance goals, includes increased consultations with drug 

sponsors and provides for earlier feedback on their submissions. 

User fee performance 

Under legislation authorizing us to collect user fees for drug reviews, we agreed to 

specific performance goals for the prompt review of submissions. 

• We met or exceeded almost all our performance goals for the fiscal year 2006 

receipts. 

• We are on track to meet or exceed most user-fee performance goals for the 

fiscal year 2007. 

Continuous marketing application pilot programs 

Under PDUFA III, we are assessing the value of both early review of parts of marketing 

applications and of more extensive feedback to sponsors during their development 

programs. Two pilots for continuous marketing applications apply to drugs and biologics 

in our fast track program: 

• Pilot 1 allows applicants to submit predefined portions of their marketing 

applications called reviewable units before submitting the completed 

application. Each reviewable unit has a six-month goal for issuing a discipline 

review letter. In 2007, we did not meet our performance goal for reviewable

unit submissions. 

• Pilot 2 allows us to enter into agreements with sponsors for frequent scientific 

feedback and interactions during the clinical trial phase of product 

development. As of Sept. 30, 2007, there were nine development projects 

entered in the Pilot 2 program. 

More information is available at www.fda.gov/cder/pdufa/CMA.htm. 

 36 
Drug Safety and Quality 

Monitoring Drug Safety 

We monitor the use of marketed drugs for new or emerging information about the health 

risks of these products. As risks are detected, we inform the public and health-care 

providers so they will have the latest information when making prescribing and use 

decisions. In addition, we develop policies, guidance and standards for drug labeling, 

current manufacturing practices, clinical and laboratory practices and industry practices. 

Our goal is to ensure the greatest benefits of drug therapies while minimizing their risks. 

Advertising and Drug Information 

It is critical to receive accurate information to ensure the appropriate use of drugs. We 

regulate the information that comes with an over-the-counter drug. Previously, drug 

companies promoted their products almost exclusively to physicians. Now companies 

advertise directly to consumers. We oversee advertising of prescription drugs, whether to 

physicians or consumers, by ensuring that drug advertisements and other promotional 

materials are truthful and balanced. Drug advertisements must contain an accurate 

summary of information about a drug’s effectiveness, side effects and circumstances 

when its use should be avoided. 

Protecting drug quality and safety 

We also set standards for drug quality and manufacturing processes. We enforce federal 

requirements for drug approval, labeling, and manufacturing to ensure a safe and 

effective drug supply. As the pharmaceutical industry has become increasingly global, we 

cooperate with other nations to harmonize standards for drug quality and approval. We 

base decisions to approve a drug—or to keep it on the market if new safety findings 

surface—on a careful balancing of risk and benefit. We also consider the tools we have to 

help minimize the risks to patients from a drug’s use. As all drugs have risks, we tolerate 

higher risks for drugs that treat serious and life-threatening conditions that have no or few 

treatment options. We consider many issues both in approving a drug as well as 

monitoring it after approval including: 

• Who will be using the drug and how it will be used? 

• Will the drug be used by older people or children? 

• Will it be used with other medications leading to side effects from 

interactions? 

• Will it be administered by a physician, or will consumers be able to buy it 

over the counter? 

• How serious and common are the drug’s side effects compared to the 

seriousness of the disease being treated? 

 37 
Comprehensive oversight of drug safety 

Our professional staff spends about one-half their time addressing safety issues, 

including: 

• Watching for problems once we approve a drug. 

• Overseeing clinical trials. 

• Evaluating new therapies and new or expanded uses for existing therapies to 

balance risks against expected benefits. 

• Overseeing manufacturing, distribution and promotional activities. 

• Preventing medication errors by evaluating proposed proprietary names, 

labeling and packaging. 

• Developing proactive risk management strategies both before and after 

approval. 

Types of Risks from Medicines 

The practical size of premarketing clinical trials means that we cannot learn everything 

about the safety of a drug before we approve it. A degree of uncertainty always exists 

about the risks of drugs. This uncertainty requires our continued vigilance, along with 

that of the industry, to collect and assess data during the post-marketing life of a drug. 

Categories of medicine risks include: 

• Product quality defects. These are controlled through good manufacturing 

practices, monitoring and surveillance. 

• Known side effects. Predictable adverse events are identified in the drug's 

labeling. These cause the majority of injuries and deaths from using medicines. 

Some are avoidable, and others are unavoidable. 

• Avoidable. In many cases drug therapy requires an individualized treatment plan 

and careful monitoring. Other avoidable side effects are known drug-drug 

interactions. 

• Unavoidable. Some known side effects occur with the best medical practice even 

when the drug is used appropriately. Examples include nausea from antibiotics or 

bone marrow suppression from chemotherapy. 

• Medication errors. The drug is administered incorrectly or the wrong drug or dose 

is administered. 

• Remaining uncertainties. In addition to rare events occurring in about 1 in 10,000 

persons, these include long-term effects and unstudied uses and populations. 

 38 
Modernizing Drug Safety 

We take very seriously our response to safety-related issues raised by consumers, health 

professionals and academic researchers. We use emerging science and technology to 

develop better tools for our drug safety program. We are strengthening the drug safety 

system with three key efforts in science, communications and operations. 

Strengthening the science of drug safety 

• We are developing scientific approaches to detecting, understanding, predicting 

and preventing adverse events. 

• We are developing and incorporating quantitative tools in the assessment of 

benefit and risk. 

• We are conducting a pilot program to review the safety profiles of selected new 

molecular entities on a regular basis. 

Improving communications 

• We are conducting a comprehensive review of current public communication 

tools and developing a comprehensive risk communication strategic plan. 

• We conducted focus group testing with consumers and pharmacists of our risk 

communication tools. 

• We issued a guidance document, “Drug Safety Information-FDA’s 

Communication to the Public,” in March 2007 which describes our current 

approach to communicating drug safety information to the public. 

• We plan to conduct assessments of the effectiveness of specific risk minimization 

action plans. 

• We established a new advisory committee to help improve communication of 

drug risks to the public. 

Improving operations and management 

• We have engaged external management consultants to help us develop a 

comprehensive strategy for improving organizational culture. 

• We made specific organizational and management changes to increase 

communications among review and safety staff. We have pilot programs to 

involve safety experts in the application review process. 

• We have a central tracking system that enables staff to track the progress and 

outcome of safety evaluations. 

 39 
• We created an associate center director position for safety policy and 

communication, and elevated the Office of Surveillance and Epidemiology to 

report directly to the center director. 

• We are improving the use of advisory committees, including making the selection 

process of committee members more transparent. 

Our response to Institute of Medicine (IOM) report 

We requested in 2005 that the Institute of Medicine convene an expert panel to assess the 

U.S. drug safety system and to make recommendations to improve risk assessment, 

surveillance and the safe use of drugs. The IOM report, The Future of Drug Safety: 

Promoting and Protecting the Health of the Public, recognizes specific progress and 

reform already underway and makes substantive recommendations about additional steps 

to improve our drug safety program. 

In January 2007, we completed our review of the IOM recommendations and issued a 

response to each of the recommendations. One example of the more than 40 

improvements underway is our Risk Communication Advisory Committee (RCAC) 

comprised of highly qualified individuals who are mostly academicians, several of whom 

are familiar with the perspectives of patients, consumers and health-care professionals. 

Recommendations from RCAC will play a vital role in helping people understand and 

appropriately respond to our health messages. This understanding will significantly 

bolster our capacity to protect and promote public health. 

Drug Safety Communication Channels 

We use a broad range of methods to communicate drug safety information to the public. 

Some of our most common forms of communications are: 

• Professional labeling for prescription drugs. Summary of essential information 

needed for the safe and effective use of a drug by health-care providers. 

• Patient-directed labeling for prescription drugs (patient package inserts and 

Medication Guides). Summary of essential information needed for safe and 

effective use of the drug by patients. 

• Over-the-counter “Drug Facts” labeling. Summary of essential information 

needed for the safe and effective use of a drug by consumers. 

• Public health advisory. Information and advice regarding an emerging drug 

safety issue or other important public health information targeted to the general 

public. 

• Patient information sheet. Concise summary in plain language of the most 

important information about a particular drug. Includes an alert when appropriate 

to communicate an important and often an emerging drug-safety issue to patients, 

consumers, lay caregivers and interested members of the general public. 

 40 
• Health-care professional sheet. Concise summary of an important, and often 

emerging, drug safety issue, with background information about the detection of 

the issue and points to consider for clinical decision-making by health-care

professionals. 

• Alerts on patient information and health-care professional sheets. Summary of 

an important and, often, emerging drug-safety issue. Alerts are tailored to the 

needs of the primary target audience for each type of information sheet. Healthcare professionals, patient, consumers, lay caregivers and interested members of 

the general public require this information. 

Prescription drug information 

We strive to make prescription drug information more useful and available by using: 

• Revised format for prescription drug labeling. Our January 2006 final regulation 

amends the content and format of information in professional labeling for 

prescription drugs, commonly called the package insert. The new label provides 

the most important information about new and recently approved prescription 

drugs and new uses in a format that is better understood, easily accessible and 

easier for physicians to remember. 

• DailyMed public database of drug information. The National Library of Medicine 

will provide an up-to-date electronic repository of all medication labeling so that 

physicians will have easy access to the latest labeling. 

• Electronic submission of drug labeling. This allows physicians to quickly search 

and access specific information they need before prescribing a treatment. 

Medication guides 

Medication guides are printed information sheets dispensed with some prescription 

medicines to help patients avoid serious adverse events. 

We require medication guides when we determine that any or all of these apply: 

• The information is necessary to prevent serious adverse effects. 

• Patient decision-making should be informed by information about a known 

serious side effect. 

• Patient adherence to directions for using a product is essential to its effectiveness. 

 41 
Public health advisories and early communications in 2007 

We issued 16 public health advisories and early communications to alert health-care 

providers and consumers about: 

• The dangers, including death, of using topical anesthetics for cosmetic 

procedures. 

• A study that was stopped early because interferon gamma 1b did not help 

idiopathic pulmonary fibrosis patients. 

• Patients who receive erythropoiesis-stimulating agents may have a higher chance 

of serious and life-threatening side effects including death. 

• Pergolide being withdrawn from the market due to the potential for heart valve 

damage. 

• Zelnorm being withdrawn from the market due to the chance of heart attack and 

stroke. 

• Caution using cough and cold products in children under 2 years of age, and the 

need to properly measure liquids and follow label directions. 

• The possibility of heart problems in patients taking proton-pump inhibitors, 

omeprazole and esomeprazole. Later data showed that the risk of heart problems 

was not confirmed. 

• The increased risk of morphine overdose in infants of nursing mothers taking

codeine who are rapid metabolizers. 

• The report of a death of a patient with cystic fibrosis who inhaled colistimethate, 

an antibiotic made for intravenous use, that was compounded by a pharmacy. 

• Reports of deaths and life-threatening side effects in patients who incorrectly used 

buccal fentanyl tablets. 

• The possibility of an association between the use of bisphosphonates, drugs used 

to treat osteoporosis and atrial fibrillation. 

• Results of a study that showed patients who receive the antibiotic cefepime may 

be at increased risk for death compared to patients who receive similar antibiotics. 

• Reports of suicidal thoughts, aggressive and erratic behavior, and drowsiness in 

patients who have taken varenicline. 

• Important information on the safe use of the fentanyl transdermal system to 

minimize the possibility of life-threatening side effects and death. 

 42 
Podcasts of public health advisories 

We are now broadcasting audio versions of our public health advisories. Our advisories 

are short, to the point, fact-based and provide emerging safety information about drugs. 

In 2007, we produced 12 podcasts. These audio advisories serve as an alternative to 

finding this information on our Web site, reading about it in the newspapers or hearing 

about it from patients. 

Patient Safety News Broadcasts of public health advisories and early 

communications 

FDA Patient Safety News is a televised series for health-care personnel, carried on 

satellite broadcast networks aimed at hospitals and other medical facilities across the 

country. It is also available on FDA’s website. The subjects of some stories are the 

emerging safety information about drugs described in our public health advisories and 

early communications. 

 43 
Drug Promotion Review 

Information about a drug available to physicians and consumers is critically important for 

its safe use. We ensure that drug advertisements and other promotional materials are 

truthful and balanced. We operate a comprehensive program of education, voluntary 

compliance, surveillance and enforcement for drug advertising and promotion. 

Surveillance of drug promotion activities 

Drug advertising and promotion must be truthful, fairly balanced and not misleading. 

When we find advertising and promotion that is not, we issue two types of letters to 

ensure compliance with our regulations. These are advisory comments when a company 

requests review of draft promotional materials and regulatory letters resulting from our 

surveillance. 

Regulatory letters citing violations 

We issued 20 regulatory action letters to companies for prescription drug promotions 

determined to be false, misleading, lacking in fair balance of risks and benefits or that 

promoted unapproved uses. These were either untitled letters for general violations or 

warning letters for more serious or repeat violations. Examples of promotional violations 

include promotion at a Pharmacy & Therapeutics Committee, Internet sites, e-mails, plus 

traditional materials such as journal advertisements, sales brochures and TV ads. 

Launch campaign advisory letters 

When requested, we review advertisements and other promotional materials before drug 

companies launch marketing campaigns that introduce new drugs or new indications or 

dosages for approved drugs. In 2007, we issued 129 advisory letters to companies 

regarding their promotional materials for launch campaigns. 

Other advisory letters 

We issued 391other advisory letters to the industry regarding proposed promotional 

pieces, both professional and consumer directed. We also issued 135 other types of 

correspondence to the pharmaceutical industry, such as letters of inquiry, closure letters 

or acknowledgement letters. 

Drug promotion letters in 2007 

In 2007, we issued 714 letters concerning drug promotion. These were: 

• 59 letters citing violations 

o 20 initial 

o 39 follow-up 

• 655 other drug promotion letters 

o 129 launch campaigns 

 44 
o 526 others 

Drug Promotion Letters Citing Violations

154 158

115

80 71

29 25 20

91 79

56

37 34

9 17 39

22 23 29

33 31 48

0

125

250

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Initial letters Follow-up letters

Drug Promotion Letters

539 399 350 276 178 186 185 129

773

515 597 465 510 526

184 158 197

571

470 466

0

600

1200

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Launch campaign advisory letters Other letters

Direct-to-consumer promotion 

We are conducting research to help develop policy for our oversight of direct-toconsumer advertising. Data from our studies as well as those conducted by consumer 

groups and other entities shows that direct-to-consumer ads may encourage some patients 

to seek care for under treated conditions. This often results in patients obtaining treatment 

for serious medical conditions of which they were unaware. However, physicians and 

consumers have expressed concerns that direct-to-consumer ads may not always provide 

a balanced view of the benefits and risks of a product. 

 45 
FDA Amendments Act of 2007 

On September 27, 2007 the FDA Amendments Act of 2007 became law. The act 

modifies the Food, Drug and Cosmetic Act to specifically address direct-to-consumer 

prescription drug advertising for the first time. It contains provisions that will change 

existing requirements for direct-to-consumer prescription drug advertisements and the 

authority FDA has to oversee this area. 

For example, the act gives FDA new authority to require submission of direct-toconsumer television drug advertisements for review before the ads are aired publicly. It 

also gives FDA authority to seek civil monetary penalties against companies who run 

false or misleading direct-to-consumer prescription drug advertisements. The act further 

requires that the statement of risks in broadcast direct-to-consumer advertisements for 

prescription drugs be presented in a clear, conspicuous and neutral manner, and that print 

direct-to-consumer drug advertisements include information on how to report adverse 

drug events to FDA. CDER is working actively to meet its mandate under the various 

direct-to-consumer drug advertising provisions of the law in the time frames expected. 

This act also reauthorized the Prescription Drug User Fee Act (PDUFA) for five more 

years, through fiscal year 2012. It created a new voluntary user fee program for review of 

direct-to-consumer prescription drug television advertisements. Under this new program, 

the pharmaceutical industry would have paid user fees when they voluntarily submitted 

draft prescription drug television advertisements to CDER or CBER for advisory review. 

These fees would have enhanced CDER and CBER resources for certain prescription 

drug promotional review activities. However, the Consolidated Appropriations Act of 

2007 failed to provide FDA with the authority to collect user fees for this new program, 

and as a result it was not able to commence. 

Ongoing Direct-to-consumer promotion research 

We continue work on three studies to help find the best way or ways to present 

information in the “brief summary,” the page of risk information in a print ad: 

• Purpose. The first study will concern the purpose of the brief summary—how do 

people use it and what topics do they find most useful. This study is underway 

and we expect to have data collected for this study by September 2008. 

• Content. The second study will address content issues in the brief summary, 

including the amount of common side effect information and the inclusion of 

numerical context. 

• Format. The third study will examine format issues, such as graphics, layout and 

font. We expect to have data collected for these two studies by the fall 2008. 

We have designed research to investigate the role of distraction in broadcast television 

ads. CDER will explore the collective role of the audio, textual and visual portions of the 

ad in the understanding of the risk and benefit information in ads. This study was 

 46 
published in the Federal Register for comment in August 2007. After extensive revision 

and external peer review, the second comment period is expected to commence by 

summer 2008. 

New Direct-to-consumer research 

We are developing a new study that will investigate the communication of effectiveness 

information on the main advertising page of print advertisements. By varying the 

presentation of this information, we will determine which manipulations bring consumers 

closer or farther away from an independent physician assessment of the effectiveness of 

the drug product in actual practice. This multi-phase study is in early development. 

Direct-to-consumer promotion letters 

Percentage of Drug Promotion Letters

Concerning DTC Ads

31% 44%

19% 24% 22% 27% 34% 26%

27% 30% 20%

0%

50%

100%

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Percentage of all letters

We issued guidance on direct-to-consumer broadcast advertisements in 1997. Since then, 

the number of letters addressing direct-to-consumer promotion, and the percentage of the 

total letters addressing promotion, have been: 

• 2007: 188 (26%) 

• 2006: 150 (20%) 

• 2005: 203 (30%) 

• 2004: 217 (27%) 

• 2003: 254 (34%) 

• 2002: 188 (27%) 

• 2001: 190 (22%) 

• 2000: 215 (24%) 

• 1999: 247 (19%) 

• 1998: 282 (44%) 

• 1997: 240 (31%) 

 47 
Drug Safety Surveillance 

We evaluate the safety of drugs available to American consumers using a variety of tools 

and disciplines. We maintain a system of post-marketing surveillance and risk assessment 

programs to identify adverse events that did not appear during the drug development 

process. We monitor adverse events such as adverse drug reactions, drug-drug 

interactions and medication errors. 

We have access to commercial databases that contain non-patient-identifiable 

information on the actual use of marketed prescription drugs in adults and children. These 

resources augment our ability to determine the public health significance of adverse event 

reports. 

As we discover new knowledge about a drug’s safety profile, we make risk assessments 

and decisions about the most appropriate way to manage any new risk or new perspective 

on a previously known risk. Risk management methods may include new labeling, drug 

names, packaging, “Dear Health Care Practitioner” letters, education or special risk 

communications, restricted distribution programs or product marketing termination. 

Population-based drug safety evaluation 

We have established several contracts that give us access to population-based data 

resources. This enables us to evaluate the use and safety of newly marketed drugs in real 

world settings. The databases we work with provide healthcare data on more than 20 

million persons in the United States in different geographic areas and include special 

populations, such as children and pregnant women. We also work with a database from 

the United Kingdom that provides electronic medical record data on nearly 10 million 

persons receiving their health care from a general practitioner. 

We use these databases to: 

• Evaluate the extent of drug exposure in the population and the levels of potential 

risk that may be associated with that exposure. 

• Provide a mechanism for collaborative investigations to test hypotheses, 

particularly those arising from suspected adverse reactions reported to us. 

• Enable our rapid access to U.S. population-based data sources to examine patterns 

of care and their impact on the safe use of drugs. 

CDER is developing a guidance on best practices for pharmacoepidemiologic studies of 

drug safety issues using electronic healthcare data. FDA entered into collaborations with 

the Veterans Health Administration, the Centers for Medicaid & Medicare, and the 

Agency for Health Care Research Quality to enable access to their large databases to look 

at drug effects and evaluate drug safety signals. 

 48 
Data mining 

Our safety evaluators and epidemiologists routinely use data mining software for 

quantitative analysis of drug safety data. Using data mining for drug-event signal 

generation increases our awareness and understanding of trends and patterns in adverse 

drug reactions. In 2007, CDER began a pilot project between Office of Surveillance and 

Epidemiology and Office of New Drug’s Division of Cardiovascular and Renal Products 

to increase post-marketing data mining surveillance of all products within this division. 

Adverse Event Reporting System 

A powerful drug safety tool is the Adverse Event Reporting System, known as AERS. 

This computerized system combines the voluntary adverse drug reaction reports from 

MedWatch and the required reports from manufacturers. These reports can often be 

signals that there may be a potential for serious and unrecognized drug-associated events. 

When a signal is detected, further testing of the hypothesis is undertaken using various 

epidemiological and analytic databases, previously published studies or other instruments 

and resources. AERS features both paper and electronic submission options with 

international compatibility. 

In 2007, we received 482,155 reports of suspected drug-related adverse events from the 

MedWatch program and from the postmarketing 15-day and periodic safety reports 

submitted by manufacturers: 

• 23,033 MedWatch reports directly from health-care providers and consumers. 

• 230, 922 manufacturer 15-day reports for adverse events that are both serious and 

unexpected (not in the approved labeling). 

• 228,200 manufacturer periodic reports for adverse events that are both serious 

and expected or non-serious. 

Adverse Event Reports

212,978 247,607 278,266 266,978 285,107

322,691 370,898 423,031464,068 471,679482,155

0

200,000

400,000

600,000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Calendar year

Direct (MedWatch) 15-day Periodic

 49 
Report types 

• Direct reports to MedWatch. An individual, usually a health-care practitioner, 

notifies us directly of a suspected serious adverse event. 

• 15-day (expedited) reports. Manufacturers report adverse events that are both 

serious and unexpected as soon as possible but within 15 days of discovering the 

problem. 

• Manufacturer periodic reports. These report all other adverse events, such as 

those that are not serious and that are already described in the product’s labeling. 

These reports are submitted quarterly for the first three years of marketing and 

annually there after. 

Adverse event electronic submissions 

Electronic submission of adverse event reports permits more timely receipt and 

evaluation at a considerable cost savings for both the FDA and industry. In late 2007, 40 

sponsors submitted their 15-day reports electronically, and 11 submitted periodic adverse 

event reports electronically. 

Since electronic submissions began in 2000 for 15-day reports and in 2001 for periodic 

reports, the number of electronic submissions has grown tremendously each year. Our 

initiative to encourage electronic reporting continues to make progress and remains a 

high priority. 

We provide useful information on electronic adverse event reports at 

http://www.fda.gov/cder/aerssub/default.htm. 

MedWatch 

Safety Information and Voluntary Adverse Event Reporting 

We administer the MedWatch program that helps promote the safe use of drugs by: 

• Rapidly disseminating new safety information on the internet and providing email listserve and RSS feed notification to health professionals, institutions, the 

public and our MedWatch partner organizations, consisting of professional 

societies, health agencies and patient and consumer groups. 

• Providing a mechanism for health professionals and the public to voluntarily 

report serious adverse events, product quality problems, medication use errors and 

therapeutic failure and inequivalence for CDER-regulated drugs and therapeutic 

biologics. Reports can be filed by mail, fax, telephone or online at 

www.fda.gov/medwatch/report.htm. 

• Educating health professionals― both practitioners and students― and consumers 

about the importance of recognizing and reporting serious adverse events and 

 50 
product problems, including medication errors. Our education program includes 

Internet outreach, speeches, articles and exhibits. We also offer a video selflearning module, "FDA MedWatch and Patient Safety", at:

www.connectlive.com/events/fdamedwatch/

Individual health-care professionals and consumers can sign up for our GovDelivery 

e-mail notification service, which now has over 92,000 subscribers. We also have 160 

MedWatch partner organizations who work with MedWatch to promote FDA's drug 

safety program. In 2007, these individuals and groups received: 

• 102 safety alerts for drugs and therapeutic biologics. 

• 25 to 70 safety-related labeling changes for drugs each month, these include 

important changes to boxed warnings, warnings, contraindications, precautions 

and adverse reaction sections, and new or updated patient labeling information, 

medication guides and patient package inserts. 

Medication Error Prevention 

We review proposed brand names, labels, labeling and packaging to help prevent 

medication errors in prescribing, dispensing or administering drug products. To ensure 

the safe use of drugs we avoid brand names that look or sound like the name of existing 

products. 

We review about 2,000 post-marketing reports of medication errors each month. About 

half are due to error-prone labeling such as similar looking labels and labeling, poor 

package design, confusing instructions for use and confusing names. We investigate the 

causes and contributing factors of these errors and recommend revisions to the label, 

labeling and/or packaging of these products to avert further error. 

In January 2007, we conducted a public workshop to explore how labels on intravenous 

drug products could be designed to minimize medication errors and to define the 

limitations faced by the different stakeholders. The workshop was an opportunity to hear 

from all stakeholders in order to gain a better understanding of the medication error 

issues they face and the challenges they have in making changes to improve patient 

safety. 

Drug Shortages 

We work to help prevent or alleviate shortages of medically necessary drug products. 

Drug shortages occur for a variety of reasons including manufacturing difficulties, bulk 

supplier problems and corporate decisions to discontinue drugs. 

Because drug shortages can have significant public health consequences, we work with 

all parties involved to make sure all medically necessary products are available within the 

United States. 

 51 
Drug shortage program aids counterterrorism effort 

Utilizing data obtained from manufacturers and distributors, our drug shortage program 

provides supply and production information in response to federal government requests 

in relation to counterterrorism efforts. 

We have a Web site that lists current drug shortages, describes efforts to resolve them and 

explains how to report them. The site is at www.fda.gov/cder/drug/shortages. We have an 

e-mail address to provide the public a communication tool for drug shortage information 

at DrugShortages@cder.fda.gov. 

 52 
Drug Recalls and Safety-Based Withdrawals 

Recalls 

In some cases, a drug product must be recalled due to a problem occurring in the 

manufacture or distribution of the product that may present a significant risk to public 

health. These problems usually, but not always, occur in one or a small number of 

batches of the drug. In other cases, a drug is determined to be unsafe for continued 

marketing and must be withdrawn completely. 

Manufacturers or distributors usually implement voluntary recalls in order to carry out 

their responsibilities to protect the public health when they need to remove a marketed 

drug product that presents a risk of injury to consumers or to correct a defective drug 

product. A voluntary recall of a drug product is more efficient and effective in assuring 

timely consumer protection than an FDA-initiated court action or seizure of the product. 

It should be noted that FDA has statutory authority to recall biologics and devices but not 

drugs. There are occasions where FDA has requested a recall and the company has 

refused. In those instances, FDA may decide to pursue an appropriate regulatory action. 

Drug recalls in fiscal year 2007 

• 136 over-the-counter drugs 

• 851 prescription drugs 

Drug Recalls

248 176

352 401

240

851

34 88

72 156

72 71

101

121

136

254 316 354

248 215

88

83

100

400

700

1000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Fiscal year

Prescription Over-the-counter

How we coordinate drug recalls 

We coordinate drug recall information, assist manufacturers or distributors in developing 

recall plans, and coordinate the preparation of health hazard evaluations with medical 

officers in the review divisions to determine the risk posed to the public by products 

being recalled. Recall actions are classified in accordance with the level of risk. We 

participate in determining recall strategies based upon the health hazard posed by the 

product and other factors including the extent of distribution of the product to be recalled. 

We determine the need for public warnings and assist the recalling firm with public 

 53 
notification about the recall. We also work with our field offices to conduct follow-up 

inspections where needed to investigate the reasons for the recall in order to mitigate the 

opportunity for reoccurrence. 

Number of recalls by fiscal year 

Different factors can affect the number of recalls in any one year. For example, one firm 

had more than 100 recalls in 2005, which caused a significant increase for that fiscal 

year. In 2007, one repacker caused over 670 recalled products. This event caused 2007 to 

be the highest year for recalls that CDER has recorded. 

Top reasons for drug recalls in fiscal year 2007 

• Correctly labeled product in incorrect package 

• Temperature abuse 

• Subpotent (single-ingredient drugs) 

• Chemical contamination 

• Impurities/degradation products 

• Failed USP dissolution test requirements 

• Labeling illegible 

• Marketed without an approved New Drug Application/abbreviated New Drug 

Application 

• Lack of assurance of sterility 

• Label mix-up 

• Stability data does not support expiration date 

• Microbial contamination of non-sterile products 

Safety-Based Drug Withdrawals 

In some cases, there is an intrinsic property of a drug that makes it necessary to withdraw 

the drug from the market for safety reasons. Because there has been concern expressed 

that sponsor user fees might have affected FDA decisions, the rates of withdrawal before 

and after user fees have been compared. The rates of safety-based withdrawals of new 

molecular entities are similar for the period before we collected user fees and for the 

period, beginning Oct. 1, 1992, after we began to collect user fees. The time periods are 

based on when we received an application rather than when we approved it. Beginning 

Oct. 1, 2003, approvals include new therapeutic biologics. Applications exempt from user 

fees are also counted. 

 54 
Safety-Based Withdrawals

NMEs approved Jan. 1, 1971, to March 31, 2007

BLAs approved Oct. 1, 2003, to March 31, 2007

3.3%

3.6%

0%

2%

4%

Pre-PDUFA (16/488) PDUFA (13/363)

Receipt periods (withdrawals/approvals)

Percentage

No safety-based drug withdrawals in 2006 

There were no market withdrawals of drugs or biologics for safety reasons in calendar 

year 2006. 

Safety-based drug withdrawals in 2007 

As of Aug. 1, 2007, there were two market withdrawals of NMEs for safety reasons: 

• Pergolide, approved in 1988, a drug used to treat Parkinson’s disease, was 

voluntarily removed from the market because of the risk of serious damage to 

patients’ heart valves. 

• Tegaserod maleate, approved in 2002, a treatment for irritable bowel 

syndrome, was voluntarily discontinued from marketing on March 30, 2007, 

due to cardiovascular risk findings. While the manufacturer continued to study 

the drug, we announced a program to allow access to the drug by adult women 

under age 55 who are identified by their physicians as appropriate candidates 

for the drug. 

 55 
Compliance Oversight 

We provide comprehensive regulatory coverage of the production and distribution of 

drug products. We manage inspection programs designed to minimize consumer 

exposure to defective drug products. We have three basic strategies to meet this goal: 

• Evaluate the findings of inspections that examine the conditions and practices in 

plants where drugs are manufactured, packed, tested and stored. 

• Monitor the quality of finished drug products in distribution, through sampling 

and analysis. 

• Monitor drug products to ensure that they comply with applicable approval and 

labeling requirements. 

We identify, evaluate and analyze inspection findings for trends in deficiencies. We 

publish guidances to assist drug manufacturers and distributors in gaining a better 

understanding of our regulations. We communicate the expectations of compliance 

through outreach programs. We review and evaluate for regulatory action all reports of 

FDA inspections of foreign drug manufacturing facilities. We determine which 

manufacturers are acceptable to supply active pharmaceutical ingredients or finished drug 

products to the U.S. market. 

Risk-based surveillance sampling of drugs 

We monitor the quality of the nation’s drug supply through surveillance and sampling of 

foreign and domestic finished dosage forms and bulk shipments of active ingredients. 

The drug products surveyed are selected according to a risk-based strategy that targets 

products with the greatest potential to harm the public health. FDA district offices 

conduct follow-up inspections to determine the cause of sample failures and to assure 

corrective action by the firms. 

Criteria for risk-based sampling 

• Microbial/endotoxin concerns. 

• Stability concerns. 

• Sterility issues. 

• Dissolution issues. 

• Impurities/contaminants. 

• Product quality history. 

• Counterfeit drugs. 

• History of violations. 

Misbranded drugs, unapproved drugs, and unsubstantiated claims 

We often encounter misbranded, unapproved, and fraudulent products that make 

unsubstantiated claims. Consumers may use these products inappropriately. They may 

use a fraudulent product for treating a serious disease in place of an approved treatment, 

or they may delay the use of a proper treatment in favor of a fraudulent remedy. 

Fraudulent products may also contain toxic compounds or other hazardous substances 

that have the potential to cause serious illness, injury or even death. For these reasons, 

 56 
products that are unapproved, mislabeled, fraudulent, or make unproven claims may pose 

a significant health risk. 

Protecting consumers from unapproved, misbranded or fraudulent drugs 

We protect consumers from unapproved, mislabeled, fraudulent or hazardous products. 

We locate and identify these products on the Internet and other outlets, and we take steps 

to prevent their sale and to remove them from the market. These steps include issuing 

enforcement letters and pursuing enforcement actions, such as seizures of violative 

products and injunctions against firms and individuals. We also work with other federal 

agencies to coordinate enforcement action against firms and individuals who violate 

federal law. 

We may also take steps to warn the public about unapproved, misbranded and fraudulent 

products. These steps include issuing press releases and MedWatch alerts to warn 

consumers about the potential health risks associated with these products. For example, in 

2007: 

• We issued a warning letter to a firm that marketed several transdermal vitamin 

therapy products for the prevention and treatment of diseases such as cancer, heart 

disease, osteoporosis and diabetes. 

• We also continued to take enforcement actions against firms that marketed 

products promoted as dietary supplements for treating erectile dysfunction and 

enhancing sexual performance, and containing potentially harmful undeclared 

prescription drug ingredients. Additionally, we continued our efforts to warn 

consumers about these illegal products by issuing press releases, consumer alerts, 

articles in consumer oriented publications, and posting information on the FDA 

website. 

Compounded drugs 

We generally defer to state authorities regarding the regulation of traditional pharmacy 

compounding. Traditional pharmacy compounding involves a pharmacist’s customizing 

of reasonable quantities of drugs in response to a practitioner’s prescription for an 

individual patient with medical needs that cannot be met by FDA-approved drugs. 

Some pharmacies, however, manufacture and distribute compounded drugs in a way that 

goes beyond traditional pharmacy practice. These pharmacies may make large quantities 

of unapproved copies of FDA-approved, commercially available drugs when there is no 

medical need to do so. They may also make these drugs in advance of receiving valid 

prescriptions. We hold pharmacies that manufacture drug products under the guise of 

pharmacy compounding to the same federal legal requirements as drug manufacturers. 

Furthermore, some pharmacies compound drugs that are contaminated, dangerously weak 

or strong. Of special concern are the compounding of sterile and more complex dosage 

forms, such as extended-release drugs, as mistakes in their preparation often lead to 

serious defects and patient injury. Our steps to protect the public from these products 

 57 
include issuing enforcement letters, referring complaints to state authorities and 

providing support when states ask. We also pursue enforcement actions, such as seizure 

of violative products and injunctions against firms and responsible individuals.

Compounding enforcement in 2007 

• We warned a firm to stop manufacturing and distributing thousands of doses of 

unapproved inhalation drugs under the guise of compounding. In a letter to the 

firm, we identified a range of serious concerns including inadequate quality 

control, concerns about potency and compounding copies of FDA-approved 

drugs.

• We sent a warning letter to a repacker of active pharmaceutical ingredients (APIs) 

that was distributing the API domperidone for use in pharmacy compounding. 

FDA is concerned with the public health risks associated with domperidone. 

Domperidone is not an ingredient in any FDA-approved drug. FDA does not 

sanction its use in pharmacy compounding and will not exercise its enforcement 

discretion with respect to compounded drugs containing domperidone. 

• We warned a firm to stop manufacturing and distributing thousands of doses of 

injectable drugs under the guise of compounding. FDA inspection revealed that 

the firm received over 70 adverse event reports associated with the use of its 

betamethasone injectable drug. In a letter to the firm, we identified a range of 

serious concerns including inadequate quality control, concerns about potency, 

and compounding copies of FDA-approved drugs. 

Drug Imports 

We take steps to assure that drugs imported or offered for import into the United States 

are approved, when required, and do not pose a safety hazard to consumers. 

These steps include: 

• Preventing entry of products that have been removed from the U.S. market for 

safety reasons. 

• Implementing controls over the importation of drugs, such as human growth 

hormone, which may pose unique risks to consumers who obtain them outside the 

legitimate drug distribution system. 

Drugs sold without required applications 

We identify drugs that are marketed without an approved application. The marketing of 

products that lack required FDA approval may present safety risks and threatens the U.S. 

drug development and approval process, as well as the over-the-counter drug monograph 

system. 

We estimate that there are several thousand illegally marketed drug products in the 

United States, comprised of several hundred unique molecules. In June 2006, we issued a 

guidance document, Marketed Unapproved Drugs—Compliance Policy Guide, that 

 58 
clearly articulates our expectation that manufacturers of products requiring FDA approval 

submit applications to show that their products are safe and effective. 

The guidance outlines our enforcement policies aimed at efficiently and rationally 

bringing all such drugs into the approval process and protecting the public health without 

imposing undue burdens on consumers or unnecessarily disrupting the market. It also 

creates incentives for manufacturers of marketed, unapproved drugs to seek approval of 

their products, a process essential to ensuring that physicians prescribe and patients take 

drug products that are safe, effective, properly manufactured and accurately labeled. 

Unapproved drug actions 

In 2007 we took action against the following classes of unapproved drugs: 

• Trimethobenzamide suppository drug products, used to treat nausea and vomiting in 

adults and children but lacking evidence of effectiveness. 

• Products containing ergotamine, which are used to treat vascular headaches, including 

migraines. Most of the companies, in addition to marketing these products without 

FDA approval, omitted from the drugs’ labeling critical warnings regarding the 

potential for serious, possibly fatal, interactions with certain other drugs. 

• Timed-release drug products containing guaifenesin, which are commonly used to 

relieve cough symptoms. These products lack assurance, through the FDA approval 

process, that the product releases its active ingredients safely and effectively over the 

entire time in which the product is intended to work. 

• Prescription drug products containing hydrocodone, a narcotic widely used to treat 

pain and suppress coughs. The action did not affect other hydrocodone formulations, 

which have FDA approval. 

By comparing agency data with a number of private drug data files, we have improved 

our ability to accurately identify unapproved drug products in the U.S. market. This 

enhances our ability to develop a rational strategy for bringing all such drugs into the 

approval process and protecting the public health. 

Regulation of OTC drugs 

The formulation of OTC drugs and the information that accompanies them or is displayed 

with them is critical to their safe use. 

Approved drug applications and OTC drug monographs define acceptable formulations 

and the consumer labeling and promotional statements for drugs sold over-the-counter. 

We monitor the statements that accompany these products along with their formulations 

to make sure that they comply with the appropriate application or final monograph. We 

also monitor the formulations, labeling and promotional materials associated with overthe-counter drugs marketed without an approved application or final monograph, 

 59 
including fraudulent drugs, and take enforcement actions against these products where 

necessary. 

● We issued warning letters to two prominent firms marketing OTC topical 

antimicrobials with unsubstantiated claims not covered by FDA’s OTC drug 

review and without an approved application. Given the extensive advertising and 

promotion of one such product for use by school children, we issued a press 

release to alert consumers to the violative nature of that product. 

● Following reports of consumer confusion and/or overdose involving several 

leading brand name and private-label OTC cough-cold drug products packaged 

with dosage delivery cups, we found that the markings on the cups were 

inconsistent with the labeled dosage directions. We engaged in discussions with 

the three manufacturers of these products and all initiated nationwide recalls to 

consumers. 

Assessing Data Quality, Research Risks 

When obtaining data about the safety and effectiveness of drugs, sponsors rely on highquality laboratory studies and human volunteers to take part in clinical studies. Protecting 

volunteers from research risks is a critical responsibility for us and all involved in clinical 

trials. 

We perform on-site inspections to protect the rights, safety and welfare of volunteers and 

verify the quality and integrity of data submitted for our review. We inspect domestic and 

foreign clinical trial study sites; institutional review boards; sponsors, monitors, and 

contract research organizations; laboratories that obtain data; and sites performing 

bioequivalence studies in humans and preclinical studies in animals. 

Our programs to protect volunteers are challenged by increases in the number of clinical 

trials; the number of sites participating in each clinical study; the types and complexity of 

products undergoing testing; and the increased number of trials performed in countries 

with less experience and limited or no standards for conducting clinical research. 

Sponsors and clinical investigators protect volunteers by ensuring that: 

• Clinical trials are appropriately designed and conducted according to good 

clinical practices. 

• Research is reviewed and approved by an institutional review board. 

• Informed consent is obtained from participants. 

• Ongoing clinical trials are actively monitored. 

• Special attention is given to protecting at-risk populations, such as children 

and the mentally impaired. 

 60 
We require sponsors to disclose financial interests of clinical investigators who conduct 

studies for them. This helps identify potential sources of bias in the design, conduct, 

reporting and analysis of clinical studies. 

Inspections for data quality, research risks in 2007 

We conducted 767 inspections in 2007: 

• 369 U.S. clinical investigators 

• 104 foreign clinical investigators 

• 103 institutional review boards 

• 23 sponsors, monitors, or contract research organizations 

• 46 non-clinical laboratories 

• 122 in-vivo bioequivalence studies 

The top five deficiencies found during inspections of clinical investigators in 2007 were: 

• Failure to follow the protocol 

• Failure to keep adequate and accurate records 

• Failure to account for the disposition of study drugs 

• Failure to report adverse events 

• Problems with the informed consent form 

International inspections of clinical research 

We conducted 104 inspections of clinical research in 28 countries in 2007. 

We participate in international efforts to strengthen protections for human volunteers 

worldwide and encourage clinical investigators to conduct studies according to the 

highest ethical principles. This includes our work with the International Conference on 

Harmonization. 

Compliance actions in 2007

The Bioresearch Monitoring Program issued 15 warning letters in 2007: ten to clinical 

investigators, three to institutional review boards, one to a GLP facility, and one to a 

bioequivalence testing facility. We also initiated the disqualification process for five 

clinical investigators due to repeated or deliberate violations of the regulations or the 

submission of false information to the sponsor or FDA. 

 61 
Bioresearch Monitoring Council 

The Bioresearch Monitoring Council was established to coordinate activities and update 

the program across the five centers in FDA. The Council is composed of representatives 

of the five centers, Office of Regulatory Affairs (ORA) and the Office of Chief Council, 

and is conducted under the auspices of the Critical Path Program. The Division of 

Scientific Investigations is an active member of the Council. We participate on working 

groups that are charged with updating the compliance policy guides, guidances for 

clinical investigators, rewriting regulations for the bioequivalence program and the 

clinical testing of investigational products not conducted under an investigational new 

drug application. We also participated in the development of guidance for institutional 

review boards and a guidance regarding questions about the need and application of 

required information. 

We participate as instructors in training courses for ORA investigators for bioresearch 

monitoring inspections, both at the introductory level and in advanced courses. The 

courses provide a review of the relevant regulations for each of the five bioresearch 

monitoring programs, case study review and evaluation and updates on program policies. 

Internet resources 

More information on data integrity and patient safety is at 

http://www.fda.gov/cder/offices/dsi/index.htm. 

Drug Registration and Listing System 

We maintain a database of human drug products in commercial distribution in the United 

States and all the domestic and foreign establishments involved in their manufacture, 

repackaging or re-labeling. The Drug Registration and Listing System provides a 

searchable database for: 

• Manufacturers of a specific product. 

• Products manufactured by a specific firm. 

• Products with a specific ingredient or dosage form. 

• Foreign manufacturers in a specific country. 

This information helps us administer many key programs, including: 

• Postmarketing surveillance. 

• User fee assessments. 

• Counterterrorism and emergency response. 

• Monitoring of drug shortages and availability. 

• Identification of products marketed without an approved application. 

 62 
• Identification of sites for use in our risk-based inspections for good manufacturing 

practices and adverse drug events. 

• Identification of drugs marketed in violation of the law for use in public alerts and 

enforcement actions. 

• In conjunction with commercial databases, identification of marketed unapproved 

drugs. 

Under the FDAAA, an electronic system will replace the current system of submitting 

paper forms for registration and listing. 

Drug Registration and Listing System statistics for 2007 

• 14,500 establishment registration forms processed. 

• 43,200 drug product listing forms processed. 

• approximately 19,500 inquiries answered. 

Manufacturing Plant Inspections 

FDA field offices conduct inspections of domestic and foreign plants that manufacture, 

test, package and label drugs. Before a drug is approved, FDA investigators must 

determine if data submitted in the firm’s application are authentic and if the plant is in 

compliance with good manufacturing practices. After a drug is approved, FDA conducts 

periodic inspections to make sure a firm can consistently manufacture the product with 

the required quality. We develop compliance programs to guide the investigators in 

conducting these inspections, and we identify facilities that are high priority for 

inspection based on their identified risk potential. We provide guidance to explain our 

current thinking on certain scientific and technical issues. 

Prioritizing sites for inspection 

Our 2004 white paper, Risk-Based Method for Prioritizing CGMP Inspections of 

Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking Model, creates a formal risk 

ranking of manufacturing plants by using an analytical process to: 

• Pose a risk question. 

• Identify potential hazards and risks. 

• Characterize factors that can be used as variables for quantifying risk. 

• Mathematically combine the variables to yield an overall risk score. 

This program continues to be refined and improved by better evaluation of the risk 

factors available to us. For example, we added adverse experience reports data to the 

model in addition to the many data sources already being used. This allows us to 

maximize our limited resources by focusing our field force on those sites that most affect 

product quality and safety. 

 63 
Good manufacturing practice enforcement 

We have acted under our regulatory enforcement program to address products not 

manufactured under current good manufacturing practice regulations. We provide expert 

technical support that employs science and risk-based principles in applying these 

regulations. As a result, many corrections are achieved voluntarily or through 

administrative means. Some corrections, though, require the involvement of the judiciary 

system. Notable 2007 actions include: 

• An inspection of a large repackaging firm uncovered violations whereby some 

products were mislabeled and some products could have been contaminated by 

residues from other products packaged using the same equipment. Although the 

firm recalled many products, FDA officially warned the firm about the 

importance of implementing promised corrections due to the large scope of their 

operations—distributing to 47 states and over a 1.4 million patients—and to 

provide notice should future regulatory action be necessary. 

• A manufacturer of highly-potent drugs was warned to improve their equipment 

cleaning procedures to prevent cross-contamination, and of the importance of 

organizing operations and drug storage areas to reduce the chance for mix-ups. 

The firm was also cautioned about the need to properly design and monitor their 

sterile product filling room. 

• A large manufacturer of transdermal drugs was warned about the need to establish 

a scientifically-sound product specification and of the importance of monitoring 

all product specifications from batch-to-batch. The firm recalled batches that 

were not performing well and that were associated with complaints by consumers 

and health-care practitioners. 

• Despite promised corrections, FDA warned a manufacturer of generic prescription 

drugs about the importance of properly documenting and investigating laboratory 

deviations and unusual test results. 

Domestic drug plant inspections 

In fiscal year 2007, FDA field office inspections included: 

• 289 preapproval inspections in support of: 

o 145 new drug applications 

o 177 generic drug applications 

• 1,119 current good manufacturing practice inspections

For these, we approved 15 actions: 

o 1 seizure 

o 14 warning letters 

• 67 medical gas inspections

We reviewed 67 medical gas inspections and approved two warning letters. 

 64 
Biologics license inspections 

Our experts conduct preapproval inspections in support of biologics license applications 

and supplements to them. In fiscal year 2007, there were: 

• 10 domestic inspections 

• 2 foreign inspections 

In other work to ensure the quality of biologics, we reviewed: 

• 90 supplements for facilities that did not require an inspection 

• 23 annual reports 

We held 43 meetings with industry. 

Foreign drug inspections 

There were a total of 333 inspections. Of these, 208 were PAI/GMP; 89 were PAI only; 

24 were GMP; 6 were therapeutic drug product (GMP); and 6 were for cause inspections 

in 2007. 

Council for Pharmaceutical Quality 

FDA formed a Council for Pharmaceutical Quality in 2005. The Council oversees policy 

development and implementation, including the ongoing implementation of internal 

quality management systems relating to drug quality regulations. 

Through our active participation in this program, we have provided the Pharmaceutical 

Inspectorate advanced training on risk-based approaches to inspections, modern quality 

systems and the legal and scientific application of good manufacturing practice 

regulations to manufacturing operations. We certified the first class of these highly 

trained investigators and are preparing for the next class. 

Outreach on Drug Manufacturing 

We published one final and two draft guidance documents that explain our current 

thinking on certain scientific and technical areas. Guidance documents that were issued to 

communicate proactively FDA's cGMP (current Good Manufacturing Process) 

expectations to the pharmaceutical industry include: 

• “Testing of Glycerin for Diethylene Glycol.” This final guidance alerts 

pharmaceutical manufacturers, pharmacy compounders, repackers and suppliers to 

the potential public health hazard of glycerin contaminated with diethylene glycol 

(DEG), a poison. FDA has received and continues to receive (most recently in 

October 2006) reports about fatal DEG poisoning of consumers who ingested 

medicinal syrups, such as cough syrup or acetaminophen syrup, that were 

manufactured with DEG-contaminated glycerin. This guidance provides 

 65 
recommendations that will help pharmaceutical manufacturers, repackers, and other 

suppliers of glycerin, and pharmacists who engage in drug compounding, avoid the 

use of glycerin that is contaminated with DEG and prevent incidents of DEG 

poisoning. 

• “The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 - Good 

Manufacturing Practice (CGMP).” This draft guidance is intended to aid drug 

manufacturers (including ancillary testing laboratories) in the use of mechanical 

calibration as an alternate approach to the use of calibrator tablets in calibrating an 

apparatus used for dissolution testing. This guidance provides references to 

information on critical tolerances that should be achieved with mechanical 

calibration. 

• “Q10 Pharmaceutical Quality System.” This draft ICH (International Conference on 

Harmonization) document establishes a new ICH tripartite guideline describing a 

model for an effective quality management system for the pharmaceutical industry, 

referred to as the Pharmaceutical Quality System. ICH Q10 describes one 

comprehensive approach to an effective pharmaceutical quality system that is based 

on International Organization for Standards concepts, includes applicable GMP 

regulations, and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 

“Quality Risk Management.” ICH Q10 is a model for a pharmaceutical quality 

system that can be implemented throughout the different stages of a product lifecycle. 

The content of ICH Q10 that is additional to current GMP requirements is optional.

External Inquiries Program 

We communicate our policies and guidance through our External Inquiries Program. 

Through this program, we coordinate receipt, assignment and response to a large number 

of foreign and domestic inquiries. Topics ranging from policy issues to current good 

manufacturing practice questions are covered. In fiscal year 2007, we provided responses 

to 667 external inquiries. 

Drug Quality Surveillance Systems 

Our reporting tools help us rapidly identify significant health hazards and quality 

problems associated with the manufacturing and packaging of medicines. Problems that 

may affect a medicine’s safety, purity or potency may occur during manufacturing, 

processing, packing, labeling, storage or distribution. 

We evaluate reports and FDA field inspections to identify specific firms with 

manufacturing quality problems with the most potential impact on public health. We 

target these candidates for inspection and further product sampling and laboratory 

analysis. We recommend appropriate corrective actions based upon our analysis of the 

findings. We may take enforcement action in some cases. 

 66 
Drug Quality Reports 

Types of reports 

• Drug Quality Reporting System. Through MedWatch, we receive reports from 

consumers and health-care professionals of observed and suspected product 

quality defects. Our central reporting system assists us in evaluating and 

prioritizing these data to identify potential manufacturing quality problems and 

industry trends. 

• Field Alert Reports. Applicant holders are required to promptly notify FDA 

district offices about possible quality and labeling problems that may represent a 

safety hazard. Experts in FDA district offices evaluate the reports and conduct 

further investigations when needed. 

• Biological Product Deviation Reports. Licensed manufacturers are required to 

report any event associated with the manufacturing of a therapeutic biological that 

may affect its safety, purity or potency. 

Drug Quality Reports

2,020 2,125 2,469 2,800 2,846 3,064 2,864 2,332

3,311

296 281

299

413 447 374 325

311

318

43 4 25

15

27

0

2,000

4,000

1999 2000 2001 2002 2003* 2004* 2005* 2006* 2007*

Fiscal year

*BPDR program received in fiscal year 2003

MedWatch drug quality reports Field alerts Biologic product deviation reports

 

 67 
2007 Reported Drug Quality Defects

Contamination 10%

Labeling 5%

Tampering 1%

Packaging 27%

Other 1%

ADR, 12%

Mixup 2%

Formulation/potency 

42%

Postmarketing Adverse Event Reporting Compliance 

We monitor the pharmaceutical industry’s processing of adverse event reports. A firm’s 

procedures for collection, evaluation and submission of reports may affect the transfer 

and quality of safety data available for analysis. Our surveillance of industry is based 

upon the risks associated with specific drug products and specific data processing 

procedures. 

Risk-based inspections 

We inspect drug firms’ adverse event reporting based upon risk criteria associated with 

specific drug products and corporate performance. These include newly marketed drugs, 

emerging safety signals, previous violations and corporate transitions. 

In fiscal year 2007, our field investigators inspected 77 domestic and seven foreign firms 

to assess compliance with our regulations for adverse event reporting. We sent two firms 

official notification that they had significant uncorrected deficiencies. We were able to 

work with 34 firms to obtain voluntary correction of deficiencies identified by our 

monitoring. 

Outreach and education 

In addition to our inspectional program for adverse event compliance, we improve safety 

reporting through educational presentations to industry. Our educational activities include 

formal presentations at global industry meetings and training for FDA field investigators. 

These activities provide industry with a direct opportunity to expand its understanding of 

reporting requirements and best practices in drug safety, and alert industry to pending 

regulatory changes. These meetings also serve to expand our own knowledge of 

industry’s worldwide pharmacovigilance activities. 

 68 
Drug Quality System 

Our overhaul of the regulatory and quality control systems for pharmaceutical products 

encourages manufacturers to modernize their methods, equipment and facilities. Our goal 

is to help eliminate both production inefficiencies and undue risks for consumers. Our 

initiative implements improved policies that are making better use of our limited 

resources through more targeted and effective inspections. 

We are improving both our external polices, known as “current good manufacturing 

practices” or cGMPs as well as our internal programs for the review of an application’s 

chemistry, manufacturing and controls sections. Pharmaceutical cGMPs for the 21st 

Century is the umbrella name for this strategic initiative, and more information is 

available at http://www.fda.gov/cder/gmp/. 

Our vision for “desired state” in manufacturing 

The desired goals of regulating manufacturing for both the industry and FDA for all 

products are: 

• Product quality and performance assured by effective and efficient manufacturing 

processes. 

• Product attributes based on mechanistic understanding of how formulation and 

process impact performance. 

• Continuous improvement and continuous real-time assurance of quality enabled. 

• Regulatory policies recognize the level of product and process knowledge. 

New drug quality assessment 

Our chemists have transformed drug quality assessment from a checklist review to a 

scientifically sound, risk-based process. Their mission is to: 

• Assess the critical quality attributes and manufacturing processes of new drugs. 

• Establish quality standards to assure safety and efficacy. 

• Facilitate new drug development. 

Biotechnology product quality assessment 

We are also in the process of implementing the concepts of quality by design for 

biological products. The new process will closely follow the tenets already established 

for new drugs. We are in the process of designing a similar pilot program that will help us 

in developing a process for future submission and review of quality-by-design 

information in biologic license applications. 

 69 
Generic drug quality assessment 

We have developed a question-based review for quality evaluation of generic drug 

applications that is focused on product and process design and understanding. In January 

2007, we fully implemented the initiative. 

• We piloted and discussed the questions to determine how best to ensure that the 

quality-by-design applications would be beneficial both to the sponsors and to us 

in addressing quality-by-design concerns. 

• We posted on the internet two models of the quality overall summary portion of 

an application and a frequently asked questions document to help generic drug 

sponsors implement quality by design and prepare high quality applications. 

• We offered industry three workshops on how to prepare an effective quality 

overall summary and a generic drug basics course. We and the generic drug 

industry have held numerous teleconferences and Webcast meetings to discuss the 

progress of question-based review and to explain our expectations. 

Focus on key product attributes for safety, efficacy 

Our chemists are now focusing on critical pharmaceutical quality attributes and their 

relevance to safety and efficacy. These include chemistry, pharmaceutical formulation, 

stability, manufacturing processes, bioavailability and product performance. Our longterm goals are to: 

• Emphasize quality by design in the evaluation of critical aspects of 

pharmaceutical quality. 

• Have a strong focus on manufacturing science. 

• Integrate review and inspection functions. 

• Use modern statistical methodologies. 

Quality-by-design pilot program 

We have a formal pilot program under which pharmaceutical companies can voluntarily 

submit new drug applications that apply quality-by-design principles and demonstrate 

their product knowledge and process understanding. 

This scientific information—more relevant than found in a traditional submission—will 

enable us to: 

• Perform a risk-based assessment of product quality and process performance. 

• Consider an applicant’s proposal for regulatory flexibility in setting product 

specifications and post-approval changes. 

• Better understand information that is available for better assessing quality of 

products. 

 70 
Workshop explores drug quality system 

We have held several scientific workshops for industry to explore how we can achieve 

the new drug quality system. We worked with industry scientists to: 

• Identify scientific training gaps that must be filled for the successful 

implementation of the new system. 

• Obtain industry input on building a scientific, risk-based regulatory system that 

maintains high quality and facilitates continuous improvement. 

• Help determine how to best use information from the pharmaceutical 

development phase in the industrialization phase. 

• Identify the roles and responsibilities for industry and us in the new system. 

• Propose ways to reduce the number of post-marketing supplements. 

Process analytical technology 

The Pharmaceutical cGMPs for the 21st Century Initiative stresses the need to apply 

more scientific and engineering knowledge to regulatory decision making and to the 

evaluation of manufacturing processes. The goal is to improve upon the overall efficiency 

and effectiveness of manufacturing processes and to enhance product quality. We have 

looked closely at manufacturing science to develop recommendations for improvements. 

One of the areas that we are focusing on is the Process Analytical Technologies Initiative. 

The capability to use process analytical technologies encourages manufacturers to be 

innovative and to apply state-of-the-art quality assurance methodologies to their 

manufacturing processes. Process analytical technologies incorporate assessment of a 

product’s characteristics in real-time and feed that information back into process control 

systems that maintain the desired state of product quality throughout manufacturing. 

We received a number of applications and manufacturing supplements in 2007 that 

incorporated process analytical technology into their manufacturing processes. More 

information on process analytical technologies can be found at 

http://www.fda.gov/cder/OPS/PAT.htm.

 71 
Counterterrorism, Emergency Response 

We pursue an aggressive and proactive approach to our role in helping prepare the nation 

for terrorist events, emerging health threats and emergency response to natural and manmade crises, including: 

• Assuring the availability of safe, effective and quality medicines during a crisis. 

• Addressing issues on procurement, packaging, labeling, use, storage and shelf-life 

extension of products in the Strategic National Stockpile (SNS). 

• Utilizing regulatory mechanisms to provide emergency access to new therapies 

and to approved therapies used in novel ways. 

• Working to protect the nation’s drug supply from attack or deliberate 

contamination. 

• Leveraging with other federal agencies to answer scientific questions about 

treatments for emerging health threats and terrorist events. 

• Preparing ourselves to continue operations during a crisis. 

Emergency Preparedness and Response 

• CDER assisted in the development of the content for the "Radiation Event 

Medical Management" website available through the National Library of 

Medicine, at http://remm.nlm.gov. This is an internet-based diagnostic and 

treatment toolkit designed for health care providers, primarily physicians, who 

may have to provide medical care during a radiation incident. 

• We played an extensive role in the October 2007 Top Officials 4 (TOPOFF 4) 

counterterrorism exercise, facilitating the issuance of notional emergency use 

authorizations for radiation countermeasures. More than 50 CDER participants 

played a role in the exercise. 

• CDER’s Office of Counterterrorism and Emergency Coordination established 

emergency coordinator positions and an emergency operations center to give the 

Center around-the-clock emergency management capability. 

Facilitating medical countermeasure development 

• We finalized our work with the Centers for Disease Control and Prevention on the 

ongoing human trials of gentamicin in plague in Africa. We continue to work with 

the National Institute of Allergy and Infectious Diseases and the U.S. Army 

Medical Research Institute of Infectious Disease on monkey studies of 

gentamicin, ciprofloxacin, levofloxacin, ceftriaxone and doxycycline in 

pneumonic plague. 

 72 
• FDA announced the SNS labeling rule in the Federal Register on Friday, 

December 28, 2007. The interim final rule provides flexibility in labeling 

requirements for FDA-regulated medical products in the SNS. CDER’s Office of 

Counterterrorism and Emergency Coordination participated in drafting this rule 

and is CDER’s point of contact for SNS issues. 

• CDER is fully engaged with HHS’s Public Health Emergency Medical 

Countermeasure Enterprise (PHEMCME) 

(http://www.hhs.gov/aspr/barda/phemce/index.html). The Enterprise’s mission is 

to define and prioritize requirements for public health emergency medical 

countermeasures; integrate and coordinate research, early- and late-stage product 

development and procurement activities addressing the requirements; and set 

deployment and use strategies for medical countermeasures held in the SNS. 

CDER subject matter experts served on the PHEMCE Biological, Chemical, and 

Radiological/Nuclear Working Groups and helped draft requirements papers for 

medical countermeasures. 

Pandemic influenza preparedness 

• We participated in several departmental and agency working groups and task 

forces to develop strategic plans for response to an influenza pandemic. The FDA 

Pandemic Influenza Preparedness Strategic Plan was posted in March 2007 and is 

available at http://www.fda.gov/oc/op/pandemic/strategicplanupdate03_08.html. 

• CDER approved a supplemental new drug application for Tamiflu® (oseltamivir 

phosphate) Capsules that provides for an extension of the expiration dating from 

five years to seven years for 30 mg, 45 mg, and 75 mg dosage forms. 

Counterterrorism guidances published in 2007 

• The draft Guidance for Industry Smallpox (Variola) Infection: Developing Drugs 

for Treatment or Prevention, http://www.fda.gov/cder/guidance/7423dft.pdf, was 

issued November 2007. 

• Emergency Use Authorization of Medical Products, 

http://www.fda.gov/oc/guidance/emergencyuse.html, was issued July 2007. This 

FDA guidance explains policies for authorizing the use of an unapproved medical 

product or unapproved use of an approved medical product during a declared 

emergency involving a heightened risk of attack on the public or U.S. military 

forces, or a significant potential to affect national security. 

 73 
International Activities 

To meet our responsibilities to United States citizens we must increasingly look, think 

and act globally. We participate in harmonization committees and are involved in 

bilateral and multilateral efforts to leverage scientific and financial resources with other 

nations. This avoids duplication of effort and allows focus on high-risk areas. 

President’s Emergency Plan for AIDS Relief 

The president’s $15 billion plan for AIDS relief around the world has a special focus on 

15 countries hardest hit by the HIV epidemic. It targets three specific areas related to 

HIV/AIDS: 

• Prevention of HIV transmission. 

• Treatment of AIDS and associated conditions. 

• Care, including palliative care, for HIV infected-individuals and care for orphans 

and vulnerable children. 

We are encouraging manufacturers to submit applications for fixed-dose combination and 

co-packaged versions of previously approved antiretroviral therapies. Tentative approval, 

whether for a new drug application or a generic drug application, will be the regulatory 

mechanism by which low-cost versions of innovator drugs sold in the developed world 

will become eligible for purchase under the emergency plan. Our tentative approval

means that a drug meets our standards for safety, efficacy and quality, but that existing 

patents or exclusivity prevent them from being sold in the United States. 

We have an expedited review process to ensure that the United States could provide safe, 

effective and affordable quality drugs to developing countries. We encouraged U.S. and 

foreign firms who were developing generic drugs to treat HIV disease to apply under the 

president’s plan. To meet the plan’s approval timelines, our generic drug reviewers 

implemented many process changes, including a rolling review approach. Our average 

review time for these applications has been six months. We lack information about most 

clinical laboratories and manufacturing sites associated with the products seeking 

approval under the emergency plan. Therefore, we are engaged in outreach activities, 

manufacturer assistance, inspections and postmarketing monitoring. 

15 countries in the President’s plan 

• Botswana 

• Cote d’Ivoire 

• Ethiopia 

• Guyana 

• Haiti 

• Kenya 

• Mozambique 

• Namibia 

• Nigeria 

• Rwanda 

 74 
• South Africa 

• Tanzania 

• Uganda 

• Vietnam 

• Zambia 

As of December 20, 2007, 58 generic drugs were eligible for purchase under the 

president’s plan. We had fully approved four generic drug products and tentatively 

approved another 54. More information is available at www.fda.gov/oia/pepfar.htm. 

Information-Sharing Agreements 

With enhanced cooperation among regulators around the world, FDA has entered into 

international agreements in which we play a critical implementation role. Below is a 

growing list of regulatory partners worldwide with whom we can pursue more open 

dialogue on emerging issues as well as exchange routine information on scientific review, 

policy development and enforcement. 

Countries: 

• Australia 

• Belgium 

• Canada 

• Denmark 

• European Union 

• France 

• Germany 

• Ireland 

• Israel 

• Japan 

• Mexico 

• Netherlands 

• Singapore 

• Sweden 

• Switzerland 

• South Africa 

• United Kingdom 

Organizations: 

• European Medicines Agency (EMEA) 

• World Health Organization (WHO) 

 75 
Examples of our agreements 

Japan and Australia 

We routinely exchange recall information about products of interest to Japan and 

Australia and communicate emerging enforcement activities of mutual interest. We 

continue to collaborate with our counterparts regarding site inspection information. With 

limited inspection resources of our own, we increasingly depend on foreign regulatory 

inspections and incorporate their findings into a risk-based program for future 

inspections. 

European Medicines Agency 

This agreement establishes a basis for exchanging confidential information with the 

European agency primarily responsible for approving drugs. It permits our review and 

compliance staff to share important information about pending approvals, post-marketing 

surveillance and enforcement actions concerning products and facilities under the 

European agency’s oversight. Implementation, to be phased in, includes activities to build 

understanding and mutual confidence in one another’s systems. 

Mexico and Canada 

FDA is working jointly with our North American neighbors to develop information 

exchange arrangements about drug manufacturing facilities in each of our countries and 

to share information about product recalls that may impact our consumers. Our recent 

contributions to this long-standing effort have been vital in moving this relationship in a 

mutually beneficial direction. Exchanges of product recalls, emerging compliance issues 

and site-specific information have already begun. An agreement with Canada provides 

for the exchange of information about pending approvals, post-marketing surveillance 

and enforcement actions. 

Switzerland 

The working arrangement with Switzerland began several years ago and has continued to 

progress steadily. The present agreement addresses the need for protection of confidential 

information and provides for the exchange of information about marketing approval 

decisions, post-market surveillance, policy developments and compliance or enforcement 

activities of mutual interest. Progress in implementing this arrangement includes the 

exchange of technical staff and training opportunities as well as inspection information. 

Successful joint inspections have helped foster mutual confidence and improve 

communications. 

 76 
International regulators forums 

Over the years, CDER has been privileged to host many of our international colleagues 

interested in learning about our drug review process. In September 2005, the CDER 

Forum for International Drug Regulatory Authorities was established for the exchange of 

drug regulatory information between CDER and its counterpart agencies in other 

countries. Offered every spring and fall, it provides information about the U.S. drug 

regulatory processes in an organized and integrated manner. It explains the role of CDER 

as well as the science, technology, regulations and processes used to do our work.

The fifth forum was offered in October 2007. As of that date, we had provided 

information about the U.S. drug regulatory processes to 171 regulators from 50 countries. 

Our materials are posted on the Internet so participants can share what they have learned 

with their colleagues; www.fda.gov/cder/audiences/iact/forum/degault.htm . 

Assuring International Trade Quality 

While the globalization of pharmaceutical commerce brings the benefits of modern drugs 

to citizens worldwide, it poses many challenges to us and regulators in foreign countries. 

We share with them a common interest in ensuring our citizens have access to safe, 

effective and high quality products and are protected from counterfeit drugs and terrorist 

threats. 

Drug exports

Export certificates attest that U.S. drug products are subject to inspection by FDA and are 

manufactured in compliance with current good manufacturing practice. These certificates 

enable American manufacturers to export their products to foreign customers and foreign 

governments. The demand for certificates remains high due to expanding world trade, 

ongoing international harmonization initiatives and international development 

agreements. 

Drug imports

Agency resources are particularly focused on counterfeit drugs and counterterrorist 

activities. We work to: 

• Enforce the law. With FDA’s field force, we enforce legal requirements 

determining which drug products may be imported by manufacturers, distributors 

and consumers. 

• Identify and interdict illegal drugs. We take steps to ensure that imported drugs 

are not counterfeit, unapproved, adulterated or misbranded and that they meet 

applicable legal requirements relating to safety and effectiveness. 

• Improve technology. Along with the pharmaceutical and advanced technology 

industries, the states and other federal agencies, we are monitoring the 

development and implementation of track and trace technology that will enhance 

anti-counterfeiting measures by providing real-time monitoring of a drug product 

through the U.S. drug distribution system. 

 77 
Foreign inspections 

• 289 preapproval inspections in support of: 

o 145 new drug applications 

o 177 generic drug applications 

• 238 current good manufacturing practice inspections 

For most foreign inspections, both a cGMP and a preapproval inspection take place and 

are counted twice, once under each inspection program. We reviewed 208 inspection 

reports for foreign establishments to ensure compliance with good manufacturing 

requirements and to determine capability of producing drugs named in applications. 

Regulatory actions included five warning letters, two untitled letters, four import alerts 

and several regulatory meetings. 

Export certificates 

Export Certificates Issued

4,491 5,207

6,420

7,724

5,509

4,544 4,762 4,378 4,382 3,973 4,197

0

3,500

7,000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Fiscal year

We issue export certificates that verify drug products being exported: 

• Were freely marketed in the United States. 

• Were in compliance with U.S. laws and regulations. 

• Met certain national or international standards, such as quality standards. 

• Were free of specific contaminants. 

Harmonization 

Harmonization—making the drug regulatory processes more efficient and uniform—is an 

issue that is important not only to Americans, but to drug regulatory agencies and 

pharmaceutical companies throughout the world. The International Conference on 

Harmonization of Technical Requirements for Registration of Pharmaceuticals for 

Human Use (ICH) has worked to bring together government regulators and drug industry 

experts from innovator trade associations in the European Union, Japan and the United 

States. 

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We are leading FDA's collaboration with the ICH. This work is making new drugs 

available with minimum delays not only to American consumers but also to patients in 

other parts of the world. 

The drug regulatory systems in all three regions share the same fundamental concerns for 

the safety, efficacy and quality of drug products. Before ICH, many time-consuming and 

expensive technical tests had to be repeated in all three regions. 

The ICH goal is to minimize unnecessary duplicate testing during the research and 

development of new drugs. The ICH process results in guidance documents that create 

consistency in the requirements for product registration in the three regions. 

Harmonized guidances 

We publish International Conference on Harmonization documents as guidances to 

industry at on the topics of drug safety, efficacy and quality. These guidances may be 

found at: www.fda.gov/cder/guidance/index.htm. 

Common Technical Document 

The ICH Common Technical Document allows data in the same format to be submitted 

to drug review authorities in all three ICH regions. Specifications for electronic 

submission of the CTD, known as the eCTD, were completed in 2002. More information 

is on the ICH Web site at www.ich.org. 

Electronic Common Technical Document 

Electronic submissions using the eCTD can be used to submit all applications and related 

submissions such as promotional materials and adverse events. Among other things, the 

eCTD allows reviewers to: 

• Create an up-to-date, cumulative table of contents for the entire application at any 

time. 

• Access any electronic submission from a single screen. 

• Download files so submissions can be used even when the reviewer is off the 

network. 

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Communications 

Our present and future mission remains constant: to ensure that drug products available to 

the public are safe and effective. Our yardstick for success will always be protecting and 

promoting the health of Americans.

Getting consumer input 

Protecting consumers means listening to them. We consult with the American public 

when making difficult decisions about the drugs that they use. We hold public meetings 

about once a week to get expert, patient and consumer input into our decisions. We also 

announce most of our policy and technical proposals in advance. This gives members of 

the public, academic experts, industry, trade associations, consumer groups and 

professional societies the opportunity to comment before we make a final decision. In 

addition, we take part in FDA-sponsored public meetings with consumer and patient 

groups, professional societies and pharmaceutical trade associations. These help us obtain 

enhanced public input into our planning and priority-setting practices. 

Public participation 

• We confer with panels of outside experts in science, medicine and public health in 

meetings open to the public. 

• We assure that patient representatives are included on advisory committees 

considering medicines for HIV, AIDS, cancer and other serious disorders. 

• We analyze public comments on proposed new rules, and we seek and receive 

comments on our guidances to industry. 

We held public meetings and participated in scientific workshops to both present 

information and gather a wide variety of viewpoints on major scientific and regulatory 

issues, including: 

• 23 advisory committee meetings. 

• Three public workshops. 

• Six public meetings. 

Stakeholders in drug review, drug quality and safety 

We work closely with many organizations on issues of public health and safety, 

including: 

• Consumers, patients and their organizations 

• Scientific and professional societies 

• Industry and trade associations 

• Universities, hospitals and health-care professionals 

• Federal, state and local government agencies 

• Foreign governments 

Consumer, industry outreach 

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• Trade press. We responded to over 1,700 telephone and e-mail requests from the 

specialized press for the pharmaceutical industry. 

• General information requests. We answered nearly 40,000 telephone inquiries, 

about 67,017 e-mails and 789 letters from consumers, health professionals and 

industry. We responded to all phone calls and e-mails within 48 hours and letters 

within 30 days. 

• Support to FDA field offices. We had over 800 requests from FDA field offices 

for information. 

• Videoconferencing. We held 229 domestic and foreign videoconferences for 

academia, industry and associations. 

• Compliance information requests. We responded to nearly 6,400 compliance 

inquiries and concerns from drug sponsors, clinical investigators, institutional 

review boards, industry, consumers, advocacy organizations and other 

government agencies. 

Outreach for revised Rx drug labeling format 

Our 2007 requirement provides that labels for new and recently approved prescription 

drugs and new uses be presented in a format that is better understood, more easily 

accessible and more memorable for physicians. Our communications efforts included: 

• Produced and launched a web-based continuing educational module for healthcare professionals. 

• Published an article in Pharmacy Today, a publication of the American 

Pharmacists Association (APhA). APhA is the largest association of pharmacists 

in the United States. The Pharmacy Today publication is circulated to over 

144,000 pharmacists. 

Transparency of policies, decisions 

• Regulations. We published one final regulation and we sought public comment on 

two proposed rules. 

• Guidances. We published eight guidances for industry that explain our position on 

best practices in scientific and technical areas. We published another 21 in draft 

form seeking public comment. 

• Manual of Policies and Procedures. To foster transparency of our operations, we 

publish our internal operating policies and procedures on the Internet. We added 

32 new and revised documents in 2007. 

• Freedom of Information requests. We responded to 3,498 requests under the 

Freedom of Information Act. 

Public education programs 

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Our programs educate and empower consumers to make wise choices about their 

medications. Our messages, which reached 200 million Americans last year, include 

information on: 

• Antibiotic resistance 

• Benefits vs. risks of medication use 

• Buying drugs from outside the United States 

• Buying prescription drugs online 

• Using medicines safely in children 

• Counterfeit drugs 

• Generic drug quality 

• Medicines and the elderly 

• Misuse of prescription pain relievers 

• Over-the-counter medicine labels 

• Sedating medicines and driving 

These are available at 

http://www.fda.gov/cder/drug/DrugSafety/drugSafetyConsumer.htm. 

Internet updates 

We have more than 25,000 subscribers to our service that provides daily e-mail updates 

of new content on our Web site and more than 24,000 subscribers to our weekly e-mail 

updates. In 2007, there were 24,913,978 sessions: 273,552,280 page views and 

670,008,349 hits on the CDER Web site. To subscribe, visit 

http://www.fda.gov/cder/cdernew/listserv.html. 

Ombudsman Activities 

Our ombudsman office serves as a portal for consumers, regulated industry and small 

businesses to, among other things: 

• Comment on our programs and actions. 

• Obtain formal and informal dispute resolution. 

• Seek general information on product development and regulation. 

• Report adverse drug experiences. 

Consumers, law firms, and the pharmaceutical industry can contact our ombudsman’s 

office by fax, phone, postal mail and electronic mail. Beginning in March, the 

ombudsman instituted a different tracking system for phone calls and electronic mail. 

Therefore, the phone and email data presented below reflect contacts and activities from 

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March through December 2007 and the numbers for fax and regular mail encompass the 

full calendar year. 

In total, the ombudsman received 660 communications, the vast majority (94%) of which 

came via electronic mail and phone. In many instances, several emails or phone calls 

were exchanged per case. Follow up correspondences were not counted for this report. 

Examples of cases and allegations from the Pharmaceutical Industry, Law Firms, 

Consultants, and Public or Private Research Institutions our ombudsman handled 

included: 

• Regulatory jurisdiction. 

• Generic drug decisions. 

• Review delays. 

• Whistle blower’s informing about unethical clinical research conduct. 

• Lengthy response times to Citizen Petitions and Suitability Petitions. 

• Import/Export issues. 

• Enforcement actions taken on marketed drugs that do not have FDA approval. 

• Freedom of Information Act requests. 

• New drug approval or nonapproval. 

• Unlawful promotional activities by competitors. 

Examples of cases and allegations from consumers and health care professionals our 

ombudsman handled included: 

• Reporting of drug adverse events and medication errors. 

• Drug costs and insurance problems. 

• Drug shortages. 

• Complaints from consumers about their doctors. 

• Personal importation of drugs not lawfully marketed in the United States. 

• Study protocol violations as reported by study participants. 

• Generic drug does not seem to work the same as the brand drug. 

• Oxycontin abuse and pleas to remove it from the market. 

• Misleading product websites. 

• Albuterol inhalers. 

Jurisdictional Issues 

Many times it is not readily apparent where in FDA a proposed product will be reviewed 

and regulated. Our ombudsman is our jurisdiction officer and a member of the steering 

committee that advises FDA’s Office of Combination Products that coordinates 

intracenter jurisdictional issues. 

This calendar year, our ombudsman responded to hundreds of informal jurisdiction 

questions from within and outside FDA and put forth CDER’s position on 44 requests for 

designation. Most of the designations were drug/device combinations. More information 

about jurisdictional issues can be found at www.fda.gov/oc/combination/ . 

 83 
Outreach Efforts 

The CDER ombudsman’s office conducted outreach to explain its functions including 

product jurisdiction and dispute resolution at several internal and external venues. The 

office also created an informative website for use by CDER employees. 

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Appendix 

Glossary of Terms 

Drug Definitions 

We regulate drugs used to treat, prevent or diagnose illnesses. However, drugs include 

more than just medicines. For example, fluoride toothpaste, antiperspirants, dandruff 

shampoos and sunscreens are all considered “drugs.” You can buy some drugs in a store 

without a prescription, while others require a doctor’s prescription. Some are available in 

less-expensive generic versions. 

Prescription drugs 

Prescription medicines must be administered under a doctor’s supervision or 

require a doctor’s authorization for purchase. There are several reasons for 

requiring a medicine be sold by prescription: 

• The disease or condition may be serious and require a doctor’s 

management. 

• The medicine itself may cause side effects that a doctor needs to monitor. 

• The same symptoms may be caused by different diseases that only a 

doctor can diagnose. 

• The different causes may require different medicines. 

• Some medicines can be dangerous when used to treat the wrong disease. 

Over-the-counter drugs 

You can buy over-the-counter drugs without a doctor’s prescription. You can 

successfully diagnose many common ailments and treat them yourself with 

readily available OTC products. These range from acne products to cold 

medications. As with prescription drugs, we closely regulate OTC drugs to ensure 

that they are safe, effective and properly labeled. 

Generic drugs 

A generic drug is a chemical copy of a brand-name drug. There are generic 

versions of both prescription and over-the-counter drugs. Generic drugs approved 

by the FDA have the same therapeutic effects as their brand-name counterparts, 

often at much lower cost. 

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Drug Review Definitions 

• Review and approval times. Review time is time spent examining the application. 

Approval time represents review time plus industry’s response time to our 

requests for additional information. 

• Priority reviews. These products represent significant improvements compared 

with marketed products. We have a goal of reviewing 90 percent of these 

applications within six months. 

• Standard reviews. These products have therapeutic qualities similar to those of 

already marketed products. We have a goal of reviewing 90 percent of these 

applications within 10 months. 

• Actions and filings. An application is filed when we determine it is complete and 

accept it for review. We make a filing decision within 60 days of receiving an 

application. Approval is one of the actions that we can take once an application is 

filed. Another action is seeking more information from the sponsor. There is no 

direct connection between applications filed in one year and actions in the same 

year. 

• Orphan drugs. We administer a program that provides incentives to develop drugs 

for use in patient populations of 200,000 or fewer. Sponsors of orphan drugs 

receive the following inducements: seven-year marketing exclusivity, tax credit 

for the product-associated clinical research, research design assistance from FDA 

and grants of up to $200,000 a year. 

• Accelerated approval. This program makes products for serious or lifethreatening diseases available earlier in the development process by relying on an 

effect on a surrogate end point to predict clinical benefit. An effect of the drug on 

a surrogate end point can be observed significantly sooner than can a long-term 

clinical benefit. Sponsors must perform additional studies to demonstrate longterm clinical benefit. 

• Fast-track development. This program facilitates the development and expedites 

our review of new medicines that demonstrate the potential to address unmet 

medical needs for serious or life-threatening conditions. Fast track emphasizes our 

close, early communication with sponsors. 

• Median times. Our charts show review and approval times as medians. The value 

for the median time is the number that falls in the middle of the group after the 

approval times are ranked in order. It provides a truer picture of our performance 

than average time, which can be unduly influenced by a few very long times. Our 

guide to understanding median approval time statistics is available at 

http://www.fda.gov/cder/present/MedianAPtime/index.htm. 

• Tentative approval. This program is issued to the drug company when the 

application is approvable prior to the expiration of any patents or exclusivities 

 86 
accorded to the reference listed drug product. A tentative approval does not allow 

the applicant to market the product and postpones the final approval until all 

patent or exclusivity issues have expired. 

• New Molecular Entities (NMEs) contain an active substance that has never before 

been approved for marketing in any form in the United States. Because of high 

interest in truly new medicines, we report approvals of NMEs and new biologic 

license applications (BLAs). The charts for all new drug applications (NDAs) and 

all BLAs include NMEs and new BLAs. 

New drug applications 

NDAs are the formal submissions of data that sponsors send us when they are seeking 

approval to market a new drug in the United States. Some NDAs are for NMEs; 

however, NDAs can also be for an active substance previously sold in a different 

form. 

Biologic license applications 

BLAs are the formal submissions of data that sponsors send us when they are seeking 

approval to market a biologic in the United States. A new BLA is an application for a 

biologic that has never been approved for marketing in the United States. 

 87 
Internet Resources 

CDER Drug and Biologic Approval Reports 

You can find reports on drug and biologic approvals at 

http://www.fda.gov/cder/rdmt/default.htm

Generic drug Web site 

You can find information about our generic drug program at 

http://www.fda.gov/cder/ogd/. 

OTC drug Web site 

Information for consumers, manufacturers and health-care professionals about OTC 

drugs can be found at http://www.fda.gov/cder/offices/otc/default.htm. The Web site 

includes details about how we regulate OTC drugs. We also include information to help 

ensure safe use of OTC drugs, including information about pain relievers, reporting 

adverse drug events, and the use of nonprescription cough and cold medicines in 

children. 

Critical Path 

The FDA’s comprehensive Web site on the Critical Path is at 

http://www.fda.gov/oc/initiatives/criticalpath/. Reports available on the site include those 

on: 

• Generic drugs

• Opportunities initiated during 2006 

• The opportunities report 

• The list of 76 opportunities 

• The original 2004 report and analysis 

The site also includes information on meetings and workshops. 

Counterterrorism and Emergency Response 

We provide the most current information on medical countermeasures and vaccines, plus 

advice on purchasing and taking medication, at 

http://www.fda.gov/cder/drugprepare/default.htm. 

Public Health Advisories 

Links to our Public Health Advisories, early communications, and associated information 

are at http://www.fda.gov/cder/news/pubpress.htm.

 88 
Medication Guides 

A list of products with Medication Guides is available at 

http://www.fda.gov/cder/Offices/ODS/medication_guides.Htm. 

Podcasts

Our audio advisories can serve as an alternative to finding this information on our Web 

site, reading about it in the newspapers or hearing about it from patients. More 

information is at http://www.fda.gov/cder/drug/podcast/default.htm. 

Patient Safety News 

Patient Safety News segments are available at 

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/index.cfm. The subjects of some 

stories are the emerging safety information about drugs described in our public health 

advisories and early communications. 

Medication Errors 

Our comprehensive site on medication errors is at 

http://www.fda.gov/cder/drug/MedErrors/default.htm. 

Adverse Event Reporting 

You can learn more about the Adverse Event Reporting System at 

http://www.fda.gov/cder/aers/default.htm.

MedWatch 

• You can find the latest medical product safety information at 

http://www.fda.gov/medwatch/. 

• You can sign up for immediate e-mail or RSS feed notification of MedWatch

safety information at http://www.fda.gov/medwatch/elist.htm. 

• You can access a video self-learning tutorial FDA MedWatch and Patient Safety 

at http://www.connectlive/events/fdamedwatch. You will learn more about why 

your voluntary reporting to MedWatch is critical to our safety surveillance efforts, 

how we use your reports to make drugs safer and how you can receive new, 

timely safety information from us that results from your reports. 

Drugs@FDA

Drugs@FDA—the most frequently used application on the FDA Web site—has official 

information about FDA approved brand-name and generic drugs such as: 

• Approved and tentatively approved drug products. 

 89 
• The regulatory history of an approved drug. 

• Labels for approved drug products. 

• All drugs with a specific active ingredient. 

• Generic drug products for a brand-name drug product. 

• Therapeutically equivalent drug products for a brand-name or generic drug 

product. 

• Consumer information for drugs approved during the last 10 years. 

To use Drugs@FDA, go to our home page (http://www.fda.gov/cder) and click on 

“Drugs@FDA.” 

User Fees 

Our user fee Web site is http://www.fda.gov/cder/pdufa/default.htm and has links to 

PDUFA: 

• Legislation 

• Federal Register documents 

• Guidances

• Letters 

• Performance reports 

 

 90