45 

Improving Public Health Through Human Drugs 

Center for Drug Evaluation and Research 2002

Report to the Nation 

Improving 

Public Health 

Through 

Human Drugs 

 

U.S. Department of Health and Human Services

Food and Drug Administration 

Center for Drug Evaluation and Research 
46 

CDER 2002 Report to the Nation 

MISSION

The Center for Drug Evaluation and Research promotes and protects public 

health by assuring that safe and effective drugs are available to Americans. 

The Food and Drug Administration Modernization Act of 1997 affirmed 

the center’s 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. 

1 

2 

3 

4 

This report is available on the Internet in Adobe Acrobat Portable 

Document Format and in hypertext markup language. The charts and 

graphs are available as Microsoft PowerPoint slides. The locations are: 

PDF: http://www.fda.gov/cder/reports/rtn/2002/rtn2002.pdf

HTML: http://www.fda.gov/cder/reports/rtn/2002/rtn2002.htm

Slides: http://www.fda.gov/cder/reports/rtn/2002/rtn2002.ppt

Suggested citation: Food and Drug Administration. CDER 2002 Report to 

the Nation: Improving Public Health Through Human Drugs. Rockville, 

Maryland, 20857. 
47 

Improving Public Health Through Human Drugs 

CONTENTS

DIRECTOR’S MESSAGE ............................................................. iii 

INTRODUCTION ...........................................................................1 

2002 HIGHLIGHTS .......................................................................3 

 Improving Innovation in Medical Technology ....................4 

 Pharmaceutical GMPs for the 21st Century ........................4 

 Counterterrorism .................................................................5 

 Scientific Research ..............................................................7 

 Drug Review Team .............................................................8 

1 DRUG REVIEW ........................................................................9 

 New Drug Review .............................................................10 

 New or Expanded Use Review ..........................................15 

 Pediatric Drug Development .............................................17 

 Electronic Submissions .....................................................18 

 Over-the-Counter Drug Review ........................................19 

 Generic Drug Review ........................................................20 

 Assessing Data Quality, Research Risks ...........................23 

 User Fee Program ..............................................................24 

2 DRUG SAFETY AND QUALITY ...............................................25 

 Types of Risks from Medicines .........................................26 

 Drug Safety .......................................................................26 

 MedWatch Outreach and Reporting ..................................28 

 Drug Shortages ..................................................................29 

 Drug Recalls and Withdrawals ..........................................30 

 Drug Promotion Review ....................................................32 

 Drug Product Quality ........................................................34 

 Drug Product Quality Science ...........................................36 

 Export Certificates ............................................................37 

3 INTERNATIONAL ACTIVITIES ...............................................38 

4 COMMUNICATIONS ...............................................................40 

 Where to Find More Information ......................................42 

i 
48 

CDER 2002 Report to the Nation 

Graphs and Charts 

Priority New Drugs ....................................................................10 

Priority New Molecular Entities ................................................11 

Standard New Drugs ..................................................................12 

Standard New Molecular Entities ..............................................13 

New or Expanded Uses ..............................................................15 

Pediatric Drug Development ......................................................17 

Over-the-Counter Drugs ............................................................19 

Generic Drugs ............................................................................21 

Inspections of Clinical Research ................................................23 

Sources of Risk from Drug Products .........................................26 

Post-Marketing Adverse Event Reports .....................................27 

Drug Recalls ..............................................................................30 

Safety-Based NME Withdrawal Percentages .............................31 

Drug Promotion Review ............................................................33 

FDA Inspections of Manufacturing Plants .................................35 

Export Certificates Issued ..........................................................37 

Modular Structure of Common Technical Document ................39 

Average Monthly Use of CDER Internet Site ............................41 

Organizational Chart ..........................................Inside back cover 

ii 
49 

Improving Public Health Through Human Drugs 

iii 

Director’s Message 

Last year, we at the Center for Drug Evaluation and Research worked hard to meet the 

challenge of promoting and protecting the public health. The dedication, creativity and 

expertise of our professional staff, coupled with new authorities and resources, enable us to 

continue to meet this challenge. 

Our new Commissioner has established five strategic areas for the Agency: 

 A strong FDA. 

 Efficient risk management. 

 Patient and consumer safety. 

 Better consumer information. 

 Counterterrorism. 

 In 2002, we took significant steps in each of these areas. 

Strong FDA 

Strong and sound science means our scientists stay on the cutting edge of new technologies. 

Our mission depends more than ever on a solid cadre of experienced physicians, toxicologists, 

chemists, statisticians, mathematicians, project managers and other highly qualified and 

dedicated professionals. The expertise of our professional staff is essential for making our 

regulatory decisions balanced and fair. A committee of our scientists oversees an extensive 

program of training, seminars, case study rounds and guest lectures that helps keep our 

scientists up-to-date on the latest developments in their disciplines and current industry 

practices.

Quality of work life is important in retaining our professional staff, who rated CDER very 

high in the Secretary’s 2002 survey on organizational environment. 

Last year, Congress reauthorized our collection of user fees for drug reviews. The 

reauthorization maintains our rigorous review and drug development goals, places the 

program on a sound financial footing and increases our resources for surveillance of newly 

marketed drugs. The review function for therapeutic biological products will be transferred to 

our center in 2003. Consolidation will strengthen our science base, and we look forward to 

working with, and extend a warm welcome to, our colleagues from the Center for Biologics 

Evaluation and Research. 

Efficient risk management 

Last year, our hard work enabled us to meet nearly all of the demanding application review 

goals of the Prescription Drug User Fee Act. We evaluated many new drugs that offered 

important treatment options for Americans. For example, we approved the first non-sedating 

antihistamine for over-the-counter sale and the first non-stimulating treatment for attention 

deficit/hyperactivity disorder in children. 

However, we are concerned that the approval of truly new drugs is at the lowest level in a 

decade. We have launched an important initiative to remove barriers to innovation in drug 

development. 
50 

CDER 2002 Report to the Nation 

iv 

We are leading an important FDA initiative to facilitate the modernization of American drug 

manufacturing. Use of cutting-edge technology will allow manufacturers to produce highquality drug products with greater efficiency and lower cost. 

Patient and consumer safety 

We continued to enhance our drug safety program to help make sure that drugs are used 

safely once they’re approved. Legislation has given us new authority and resources to 

conduct more rigorous safety monitoring of newly approved drugs in the first few years on 

the market. Last year, we evaluated more than 300,000 adverse event reports. We alerted the 

public to the dangers of importing or buying over the Internet 10 drugs that are marketed in 

this country with special safety restrictions. 

Balanced and fair information is critical to the safe use of medicines. We completed surveys 

of physicians and consumers about direct-to-consumer advertising. About 40 percent of 

patients and about 45 percent of physicians feel DTC advertising encourages information 

seeking about potentially serious medical conditions. We are working on new guidance for 

direct-to-consumer advertising. 

Better consumer information 

We are collaborating with a broad spectrum of groups to improve information for prescribers 

and consumers. Last year, we implemented a mandatory changeover to new, easy-tounderstand labels for medicines sold over the counter. Industry and consumers are 

increasingly turning to our Internet site for important and up-to-date information on our 

regulatory programs and on the drugs they take to improve their health. We have 10 public 

education programs to promote the safe use of medicines. The program to bolster consumer 

confidence in generic drugs has met with particularly outstanding success and acceptance. 

Counterterrorism 

We continue to facilitate development of new drugs and new uses for already approved 

drugs that could be used as medical countermeasures. We amended our regulations so that 

certain human drugs and biologics intended to reduce or prevent serious or life-threatening 

conditions may be approved based on animal evidence of effectiveness when human efficacy 

studies are not ethical or feasible.

The way forward 

As we look to the challenges ahead, we remain steadfast in our commitment to facilitate the 

availability of safe and effective drugs, keep unsafe or ineffective drugs off the market, 

improve the health of Americans and provide clear and easily understandable drug 

information to health professionals, patients and consumers. 

Janet Woodcock, M.D. 

Director 

Center for Drug Evaluation and Research 
1 

Improving Public Health Through Human Drugs 

INTRODUCTION

Who we are 

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

watchdog for medicine. We are part of one of the nation’s oldest consumer 

protection agencies—the Food and Drug Administration. The FDA is an 

agency of the federal government’s Department of Health and Human 

Services. We are the largest of FDA’s five centers, with about 1,800 

employees. Approximately half of us are physicians or other kinds of 

scientists. Many of us have experience and education in such fields as 

computer science, legal affairs and regulatory matters. 

What we do 

Our best-known job is to evaluate new drugs for safety and effectiveness 

before they can be sold. Our evaluation, called a review, makes sure that 

the drugs we approve meet our tough standards for safety, effectiveness and 

quality. We also make sure that you and your doctor will have the 

information you need to use medicines wisely. Once drugs are on the 

market, we monitor them for problems.

Reviewing drugs before marketing. A drug company seeking to sell a drug 

in the United States must first test it. 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 risks, we approve it for sale. We don’t actually 

test the drug when we review the company’s data. By setting clear 

standards for the evidence we need to approve a drug, we help medical 

researchers bring 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 a drug from the market. We also monitor 

manufacturing changes to make sure they won’t adversely affect the safety 

or efficacy of the medicine. We evaluate reports about suspected problems 

from manufacturers, health care professionals and consumers. Sometimes, 

manufacturers run into production problems that might endanger the health 

What is a drug? 

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. 
2 

CDER 2002 Report to the Nation 

of patients who depend on a drug. We try to make sure that an adequate 

supply of drugs is always available. 

Monitoring drug information and advertising. Accurate and complete 

information is vital to the safe use of drugs. Drug companies have 

historically promoted their products directly to physicians. More and more 

frequently now, they are advertising directly to consumers. While the 

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

we oversee the advertising of prescription 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. We are 

monitoring the industry’s voluntary program to provide consumers useful 

information about prescription drugs when they pick up their prescriptions. 

We are watching this program closely to see that it meets its goals for 

quantity and quality of information.

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. 

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.

Conducting applied research. We conduct and collaborate on focused 

laboratory research and testing. Research maintains and strengthens the 

scientific base of our regulatory policy-making 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.

Why we do it 

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 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 proposals in advance. This gives members of the public, 

academic experts, industry, trade associations, consumer groups and 

professional societies the opportunity to comment and make suggestions 

before we make a final decision. In addition, we take part in a series of 

FDA-sponsored public meetings with consumer and patient groups, 

professional societies and pharmaceutical trade associations. These 

stakeholder meetings help us obtain enhanced public input into our 

planning and priority-setting practices. 

Over-the-counter 

drugs 

You can buy OTC 

drugs without a 

doctor’s prescription. 

You can successfully 

diagnose many 

common aliments 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 overthe-counter drugs. 

Generic drugs 

approved by the FDA 

have the same 

therapeutic effects as 

their brand-name 

counterparts. 

The biggest difference 

between a generic drug 

and its brand name 

counterpart is usually 

price. A generic drug 

may be priced 

anywhere between 20 

percent and 75 percent 

of the cost of the 

brand-name version. 
3 

Improving Public Health Through Human Drugs 

2002 HIGHLIGHTS

We are pleased to present our seventh performance report. Our work last 

year offered many Americans new or improved choices for protecting and 

maintaining their health or new ways to use existing products more safely. 

Drug review 

Children and people with cancer, heart disease and other serious conditions 

have benefited from our approvals in 2002. Our workload remained very 

high; however, our experience last year included some concerning trends in 

drug development. The number of filings and approvals of new molecular 

entities, significant new drugs never before approved for marketing in the 

United States, continued to decline to their lowest point in a decade. Our 

statistics for priority drug reviews have also been affected by this trend. 

Last year saw a steep rise in median total approval times for priority new 

drugs and priority new molecular entities. This resulted from the approval 

of drug applications received in previous years coupled with the decrease in 

recent priority submissions. With a smaller pool of recent priority 

applications with short approval times, the submissions from previous years 

dominated the median approval time statistics. 

We met or exceeded most of our obligations to Congress for prompt and 

thorough review of drug applications supported by user fees. 

We approved 78 new drugs, including 17 new molecular entities. We also 

approved 152 new or expanded uses of already approved drugs, an increase 

of 67 percent from the previous year. 

We increased choices for self-care by approving 13 medicines for over-thecounter marketing. This included the first switch of a non-sedating 

antihistamine from prescription only to over-the-counter sale. A mandatory 

changeover to new, easy-to-understand labels for OTCs began last year. 

Our reviews of generic drugs have been prompt and predictable. We 

approved 321 generic equivalents for prescription or over-the-counter 

drugs. Our generic drug education program, specially funded by Congress, 

has been enormously successful, with many organizations reproducing our 

materials at no cost to the government. 

Our effort to protect our citizens and soldiers against chemical, biological 

and nuclear weapons was bolstered last year. We amended our regulations 

to permit us to approve certain countermeasures based on animal studies 

when human efficacy studies are infeasible or unethical. 

Realignments 

Last year, we adjusted 

our organizational 

structure to enhance 

how we use risk 

management principles 

in our operations: 

 With additional 

resources, our postmarket drug safety 

experts have begun to 

contribute their 

insights to the 

premarket review of 

risk management plans 

for new drugs. 

 Our compliance 

operations have 

relocated and 

reorganized. 

Our current 

organizational charts 

are at http://www.fda.

gov/cder/cderorg.htm.

New, reauthorized 

legislation 

Our programs will 

benefit from additional 

authorities and 

resources. 

 The Bioterrorism Act 

of 2002 improves the 

nation’s ability to 

prevent, prepare for 

and respond to 

bioterrorism and other 

public health 

emergencies. 

 The bioterrorism 

law also contained the 

third five-year 

reauthorization of the 

Prescription Drug User 

Fee Act. PDUFA III 

maintains our rigorous 

review and drug 

development goals, 

places us on a sound 

financial footing and 

increases our resources 

for surveillance of 

newly marketed drugs. 

 The Best 

Pharmaceuticals for 

Children Act of 2002 

renewed our authority 

to grant six months of 

marketing exclusivity 

to manufacturers who 

conduct and submit 

pediatric studies in 

response to our written 

requests. It also 

authorizes the federal 

government to contract 

for pediatric studies for 

drugs that lack patent 

protection or other 

marketing exclusivity. 
4 

CDER 2002 Report to the Nation 

Drug safety and quality 

All medicines have risks. With modern, state-of-the-art tools and 

techniques, we are able to detect rare and unexpected risks rapidly and take 

corrective action quickly. We improved our risk-assessment ability by 

gaining access to actual use data. 

Last year, we processed and evaluated more than 320,000 adverse drug 

events. We issued nearly 700 letters to help ensure that the promotion of 

drug products presents a fair balance of risks and benefits and isn’t false or 

misleading. 

Improving Innovation 

We believe we can help speed potentially important new drugs to the 

market by reducing regulatory uncertainty and increasing the predictability 

of product development. We are playing a key role in a broad FDA 

initiative called Improving Innovation in Medical Technology: Beyond 

2002. The initiative is aimed at: 

 Reducing the time and costs of medical product development. 

 Facilitating the introduction of innovative new technologies. 

 Maintaining our traditional high standards of consumer protection. 

We are looking to achieve these goals through new actions in three major 

areas: 

 Identifying the root causes of multiple review cycles and avoiding them 

when possible through early communication and other steps to improve 

the quality of new product applications. 

 Improving the quality and efficiency of the review process by adopting 

a quality systems approach to medical product reviews. 

 Improving the quality of submissions in new and priority product areas 

by providing clearer up-to-date guidance for particular diseases and for 

emerging technologies. 

Our proposals are outlined in a detailed report at http://www.fda.gov/bbs/

topics/NEWS/2003/beyond2002/report.html. The executive summary is at 

http://www.fda.gov/bbs/topics/NEWS/2003/beyond2002/execsumm.html.

Pharmaceutical cGMPs 

Our regulatory and quality control systems for pharmaceutical products 

have become a gold standard for the world; however, the last 

comprehensive revisions to these regulations are nearly a quarter of a 

century old. Last year, we announced a significant new initiative, called

Pharmaceutical cGMPs for the 21st Century, to enhance the regulation of 

International 

activities 

We worked closely with 

our colleagues in Japan 

and the European 

Union on finding ways 

to make the drug 

development process 

more efficient and 

uniform. 

We finalized the 

electronic version of 

the Common Technical 

Document format. The 

CTD can be used for 

seeking approval to 

market new drugs in 

the United States, the 

European Union and 

Japan. 

Communications 

We met almost weekly 

with outside experts on 

difficult scientific and 

public health issues. 

We received valuable 

input from a public 

hearing on risk 

management tools. 

Each month, our 

Internet information 

site averaged 750,000 

visitors and 

13.5 million hits. 

We responded to more 

than 70,000 individual 

requests for 

information. 

We developed public 

education campaigns in 

areas such as new OTC 

drug labels, generic 

drug quality, proper 

drug dosing for 

children and pregnancy 

and drug use. 
5 

Improving Public Health Through Human Drugs 

Pharmaceutical 

reviews to be 

consolidated 

The review of some 

new biologic products 

will be transferred to 

our center in 2003. This 

will enhance the 

efficiency and 

consistency of 

reviewing clinically 

similar products. 

Consolidation will 

strengthen our science 

base, increase 

timeliness of reviews 

and contribute to 

greater uniformity of 

regulations, policies 

and practices involving 

all therapeutics. 

Planned for transfer 

are cytokines, growth 

factors, enzymes and 

interferons—including 

recombinant 

versions—plus proteins 

for therapeutic use that 

are extracted from 

animals or 

microorganisms and 

other therapeutic 

immunotherapies. 

Counterterrorism 

The first therapy for those exposed to a terrorism agent is often a drug. We 

have been taking an aggressive and proactive approach to our role in 

helping prepare the nation for terrorism attacks. These steps include: 

 Assuring the availability of medicines to treat victims of terrorism 

attacks. 

 Leveraging resources with other federal agencies to answer scientific 

questions concerning therapies to treat conditions against terrorism 

agents. 

 Protecting the nation’s drug supply from attack or deliberate 

contamination. 

 Preparing ourselves to continue operations during a crisis. 

We continue to facilitate development of new drugs and new uses for 

already approved drugs that could be used as medical countermeasures. We 

work with other agencies to implement a shelf-life extension program for 

stockpiled drugs for military use. We gather information on drugs that 

might be used in response to an attack, including data on manufacturers, 

bulk suppliers, inventories and lead times for production. 

pharmaceutical manufacturing and product quality and to bring a 21st 

century focus to this FDA responsibility. 

The major goals of the initiative are to make sure that: 

 Public health protection is strengthened by implementing risk-based 

approaches that focus both industry and FDA attention on critical areas 

for improving product safety and quality. 

 The regulatory review program and the inspection program operate in a 

coordinated and synergistic manner. 

 Regulation and manufacturing standards are applied consistently using 

state-of-the-art pharmaceutical science. 

 Innovation in the pharmaceutical manufacturing sector is encouraged. 

 FDA resources are used most effectively and efficiently to address the 

most significant health risks. 

More information on the program, including the concept paper, progress 

reports and announcements of public meetings, is on our Web site at http://

www.fda.gov/cder/gmp/index.htm.

Increased 

counterterrorism 

resources 

We hired additional 

experts in medicine, 

science and regulatory 

affairs dedicated to our 

counterterrorism 

mission. 

We have improved 

coordination and 

communication with 

other federal agencies 

and manufacturers. 

We provide guidance 

and direction for the 

research and 

development of new 

and existing medical 

countermeasures. 
6 

CDER 2002 Report to the Nation 

Counterterrorism notable 2002 achievements 

Animal efficacy rule. We amended our regulations so that certain human 

drugs and biologics intended to reduce or prevent serious or life-threatening 

conditions may be approved based on animal evidence of effectiveness 

when human efficacy studies are not ethical or feasible. The rule—also 

known as the Animal Efficacy Rule or Subpart I—applies when: the 

pathophysiology of the disease and the mechanisms of action of the drug 

are well understood; the efficacy endpoints in the animal trials are clearly 

related to human benefit; the drug effect is demonstrated in at least one 

well-characterized animal species expected to react with a response 

predictive for humans; and data allow selection of an effective human dose. 

We reviewed and, in February 2003, approved pyridostigmine bromide to 

increase survival after exposure to Soman nerve gas poisoning—the first 

use of the rule. 

New drug approval—ATNAA. We approved ATNAA (Antidote 

Treatment—Nerve Agent, Autoinjector) sponsored by the U.S. Army, for 

use as an antidote to nerve agent exposure. Atropine and pralidoxime, the 

two nerve agent antidotes in this combination product, were already 

approved separately. Approval of the combination provided for a single 

injection containing both drugs, thereby allowing for more efficient and 

convenient administration on the battlefield. 

Generic drug approval—potassium iodide. ThyroSafe Tablets, 65 mg, an 

over-the-counter generic drug application, was approved in September 

2002 under expedited review. This thyroid blocking agent for use in 

radiation emergencies is half the concentration of the other approved 

potassium iodide tablets, making it particularly important for use in 

pediatric populations. 

New drug review—Prussian Blue. We completed the review of the data for 

using Prussian Blue to treat exposure to radioactive cesium and thallium. 

We published our findings of safety and efficacy in February 2003 to 

encourage sponsors to submit applications for this indication. 

New drug review—Chelators. We also reviewed all U.S. cases of radiation 

exposure treated with intravenous chelators. Results of this review are 

pending.

Grants announcement, interagency agreement. We announced the 

availability of grants to support clinical trials on the safety and efficacy of 

drug products for the treatment of human plague. We are supporting an 

interagency agreement with the Centers for Disease Control and Prevention 

to fund such studies. 

Contracts. Through FDA’s Office of Women’s Health, we contracted for 

studies on therapies that may be used to treat conditions caused by 

terrorism agents. These studies will enroll special populations such as 

lactating and pregnant women and the elderly. 

Public health 

guidance 

With the results from 

the research on 

doxycycline and 

potassium iodide 

(page 7), we provided 

medical professionals 

and the public 

information on: 

 The palatability and 

stability of doxycycline 

tablets ground and 

mixed in food or 

drinks. 

 Home preparation 

procedures for 

emergency 

administration of 

potassium iodide 

tablets to infants and 

children. Information 

on palatability and 

stability is also 

included. 

Additional information 

was also provided on 

potassium iodide: 

 Frequently asked 

questions about 

potassium iodide for 

use in radiation 

emergencies. 

 A public 

announcement on 

protection of children 

and adults against 

thyroid cancer in case 

of nuclear accident. 

Shelf-life extension 

for drug stockpiles 

Our laboratories 

perform shelf-life 

extension testing for 

drug products 

stockpiled by the 

U.S. military. 

Draft guidance 

We issued a draft 

guidance on developing 

drugs to treat 

inhalational anthrax. 

Counterterrorism 

Internet resources 

Our Internet site 

provides links to the 

most current 

information on drugs 

to prevent or treat 

disease caused by 

terrorism agents, 

including drugs for use 

against anthrax, 

plague, radiation 

emergencies and 

chemical agents; drug 

development of 

counter-terrorism 

products; vaccines; 

pediatric counterterrorism measures; 

and prescribing and 

buying 

countermeasures. 

You can find these 

links at http://www.fda.

gov/cder/drugprepare/

default.htm. 
7 

Improving Public Health Through Human Drugs 

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 nonclinical and clinical studies 

We are identifying, evaluating and establishing improved protein 

biomarkers in blood in both animal models and in humans. These will help 

monitor the very earliest damage that can be caused by certain drugs to the 

heart, kidney, immune system and liver. 

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. 

We conduct targeted research on microarrays, a new technology that can 

identify thousands of genes or proteins rapidly and at the same time. We 

are evaluating how this technology could improve the interface between 

drug development and regulatory practice. 

We confirmed reports of brain toxicity findings in neonatal rats with 

ketamine, an anesthetic widely used in children. Our rapid research resulted 

in the National Toxicology Program undertaking broad ranging non-human 

primate studies to assess better human relevance of these rodent findings. 

Clinical pharmacology 

We established scientific research capabilities in the analyses of medicinal 

plant and herbal products. 

We continue to explore noninvasive imaging technology to extend the our 

long-standing interest in the application of accurate dose-concentrationresponse principles by viewing drugs and their actions directly at the level 

of the drug target, rather than indirectly via plasma concentrations. 

We are developing a standardized approach for using exposure-response 

information for evaluating the risk and benefit of drug therapies and 

recommending dose adjustments in special populations. 

We are developing a pediatric population pharmacokinetics study design 

template to facilitate implementation of sparse sample strategies in 

pediatric drug development. 

Pharmaceutical 

analysis 

We assure that 

analytical methods 

being developed by 

pharmaceutical 

companies are suitable 

for quality assurance 

and regulatory 

purposes. Last year, we 

assessed analytical 

methods for more than 

20 new drugs. 

We collaborate with 

other organizations to 

ensure the availability 

of high quality 

standards and 

calibration materials. 

Other analytical 

methods under 

development last year 

included 

characterization of 

nasal inhalation 

products and complex 

drug substances. 

We tested several 

analytical technologies 

for characterizing 

active pharmaceutical 

ingredients and 

guarding against 

counterfeit product 

marketing. These 

included isotope ratio 

mass spectroscopy, ion 

mobility spectroscopy, 

near infrared and 

Raman spectroscopies. 

We examined Raman 

imaging’s ability to 

determine particle size 

distribution of the 

active ingredient in 

nasal sprays. 

Counterterrorism 

scientific research 

In collaboration with 

the National Institute 

of Allergy and 

Infectious Diseases and 

the Department of 

Defense, we developed 

a monkey model for 

pneumonic plague to be 

used to study a number 

of potential therapies. 

We are also 

collaborating with 

them on a monkey 

model for studies of 

smallpox therapies. 

Some medical 

countermeasures are 

stockpiled in tablet 

form that may be 

difficult to swallow for 

infants, small children 

and others. Two 

examples are 

doxycycline, for postexposure prophylaxis 

for anthrax, and 

potassium iodide, for 

use in emergencies 

involving radioactive 

iodine. We studied the 

stability and palatability of these drugs 

when crushed and 

mixed with different 

foods or drinks. 

We developed an 

exposure-response 

model for 

pyridostigmine, an 

anti-nerve gas agent, to 

extrapolate animal 

efficacy data to a 

human dose regimen. 
8 

CDER 2002 Report to the Nation 

Drug Review Team 

We use project teams to perform drug reviews. Team members apply their 

individual special technical expertise to review applications: 

Chemists focus on how the drug is manufactured. They make sure the 

manufacturing controls, quality control testing and packaging are adequate 

to preserve the drug product’s identity, strength, potency, purity and 

stability. 

Pharmacologists and toxicologists evaluate the effects of the drug on 

laboratory animals in short-term and long-term studies, including the 

potential based on animal studies for drugs to induce birth defects or cancer 

in humans. 

Physicians evaluate the results of the clinical trials, including the drug’s 

adverse and therapeutic effects, and determine if the product’s benefits 

outweigh its known risks at the doses proposed. 

Project managers orchestrate and coordinate the drug review team’s 

interactions, efforts and reviews. They also serve as the regulatory expert 

for the review team and as the primary contact for the drug industry. 

Statisticians evaluate the designs and results for each important clinical 

study. 

Microbiologists evaluate the effects of anti-infective drugs on germs. These 

medicines—antibiotics, antivirals and antifungals—differ from others 

because they are intended to affect the germs instead of patients. Another 

group of microbiologists evaluates the manufacturing processes and tests 

for sterile products, such as those used intravenously. 

Clinical pharmacologists and biopharmaceutists evaluate factors that 

influence the relationship between the body’s response and the drug dose 

and evaluate the rate and extent to which a drug’s active ingredient is made 

available to the body and the way it is distributed, metabolized and 

eliminated. They also assess the clinical significance of changes in the 

body’s response to drugs through the use of exposure-response 

relationships and check for interactions between drugs. 

Scientific training 

for reviewers 

Our systematic, 

internal training 

program is based on 

core competencies, 

learning pathways and 

individual development 

plans. 

 The program grew 

from seven activities 

offered in 1997 to more 

than 40 in science and 

science policy 

 We offer 44 courses 

in job skills, research 

tools, leadership and 

management. 

 Reviewer 

participants increased 

six-fold, from about 

250 in 1997 to 1,500 

currently. 

 Last year, we 

brought in 40 visiting 

professors to talk 

directly to individual 

review divisions about 

critical, new drugrelated research and 

techniques. 

 We collaborate with 

five local universities to 

present special courses. 

Last year we examined 

the effects of drug 

therapy on the heart. 

Advanced 

scientific 

education 

A committee of our 

scientists oversees a 

program of scientific 

training, seminars, case 

study rounds and guest 

lectures. 

This multidisciplinary 

program helps keep 

our scientists up-todate on the latest 

developments in their 

fields and current 

industry practices. 

Quality of work life 

survey 

In a survey conducted 

last year by the 

Department of Health 

and Human Services, 

we did better than both 

FDA and the entire 

department in 13 of 14 

general areas 

important to 

organizational 

performance. 

About three-fourths of 

our scientists and other 

employees reported 

positively on the 

effectiveness of our 

management practices, 

their feelings about the 

organization and the 

effective use of their 

abilities. 
9 

Improving Public Health Through Human Drugs 

1 

DRUG REVIEW

Many Americans benefited from last year’s timely reviews of new 

prescription medicines, over-the-counter medicines and the generic 

equivalents for both. 

We approved 17 new medicines that have never been marketed before in 

this country, known as new molecular entities. We approved 321 generic 

versions of existing drugs. We authorized 13 medicines to be sold over the 

counter without a prescription, and 11 of them can be used by children. 

We met or exceeded 12 of the 14 performance goals for the fiscal year 

2001 receipt cohort, the latest year for which we have full statistics. These 

are goals we agreed to under legislation authorizing us to collect user fees 

for drug reviews. In addition to surpassing all goals for original new drug 

applications, we exceeded all three of the goals for new molecular entities. 

We conducted 487 foreign and domestic inspections that help protect 

volunteers for clinical trials from research risks and validate the quality and 

integrity of data submitted to us. 

Highlights of new medication options for American consumers include: 

 Three new drugs to treat childhood diseases. 

 19 labels with new information for treating children. 

 The first two drugs to treat opiate dependence that can be prescribed in 

an office setting under the Drug Addiction Treatment Act of 2000. 

 Two new drugs to treat cancer. 

 Three new drugs to treat heart disease. 

 Three new drugs to treat infectious diseases. 

 Eight drugs to treat “orphan” patient populations of 200,000 or fewer. 

 The first active ingredient in a nonsedating antihistamine switched from 

prescription only to over-the-counter sale. 

 One new antidote for chemical warfare nerve agents. 

Mission 

We 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. 

Drug approvals 

for 2002 

 78 new drugs 

 17 new 

molecular entities 

 8 orphan new drugs 

 152 new or 

expanded uses for 

already approved drugs 

 13 over-the-counter 

drugs or Rx-to OTC 

switches 

 321 generic 

equivalents 

for prescription 

and over-the counter 

drugs 
10 

CDER 2002 Report to the Nation 

Priority new drugs 

(N=NME)

 Adefovir dipivoxil 

(Hepsera) (N) 

 Atropine and 

pralidoxime chloride 

(ATNAA) 

 Cyclosporine 

(Restasis) 

 Oxaliplatin 

(Eloxatin) (N) 

 Ribavirin (Copegus) 

 Tegaserod maleate 

(Zelnorm) (N) 

 Buprenorphine 

hydrochloride and 

naloxone hydrochloride 

dihydrate (Suboxone) 

New Drug Review 

Review and approval times. Review time represents the time that we spend 

examining the application. Approval time represents our review time plus 

industry’s response time to our requests for additional information. Our 

charts show these times as “medians.” The value for the median time is the 

number that falls in the middle of the group after the numbers 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 or short times. Our 

guide to understanding median approval time statistics is available at http://

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

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. Other actions include seeking more 

information from the sponsor. There is no direct connection between 

applications filed in one year and actions in the same year. Filings provide 

an idea of what the workload in subsequent years will be. 

Orphan drugs 

(N=NME)

 Buprenorphine 

hydrochloride 

(Subutex) 

 Buprenorphine 

hydrochloride and 

naloxone hydrochloride 

dihydrate (Suboxone) 

 Icodextrin 

(Extraneal) (N) 

 Nitazoxanide 

(Alinia) 

 Nitisinone (Orfadin) 

 Secretin (SecreFlo) 

 Sodium oxybate 

(Xyrem) (N) 

 Treprostinil sodium 

(Remodulin) (N) 

Priority new drugs 

 11 approvals 

 Median review time: 

13.8 months 

 Median approval 

time: 19.1 months 

 18 actions 

 16 filings 

Priority NDA Approvals

Median times, approvals

6.06.07.87.86.26.46.26.46.16.16.06.06.06.013.819.1

29

11

20 28

10

20

15

25

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Months

0

15

30

Approvals

Median FDA review time Median total approval time Number approved

Priority NDAs

Actions, filings*, approval percentages

3124442635324627433141212771816

57% 61%

37%

49%

65% 54%

66% 48%

0

25

50

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

*A filing in one year may lead to several actions or an approval in subsequent years.

Number

0%

50%

100%

Percent

Actions Filings Percent of actions that are approvals
11 

Improving Public Health Through Human Drugs 

New molecular entities. Seventeen of the new drugs we approved were new 

molecular entities, and seven received priority reviews. NMEs contain an 

active substance that has never before been approved for marketing in any 

form in the United States. 

Priority new drugs. We took 18 actions on priority new drug applications, 

of which 11 were approvals. These drugs represent significant 

improvements compared with marketed products. We have a goal of 

reviewing 90 percent of these applications within six months. 

Standard new drugs. We took 154 actions on standard new drug 

applications, of which 67 were approvals. These drugs have therapeutic 

qualities similar to those of already marketed products. We have a goal of 

reviewing 90 percent of these applications within 10 months. 

Orphan drugs. Eight of the approvals were for “orphan” uses in patient 

populations of 200,000 or fewer. Sponsors of such products receive 

inducements that include seven-year marketing exclusivity, tax credit for 

the product-associated clinical research, research design assistance by FDA 

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

Priority new 

molecular entities 

 7 approvals 

 Median review time: 

13.8 months 

 Median approval 

time: 16.3 months 

 10 filings 

Priority NME Approvals

Median times, approvals

6.06.07.79.66.46.76.26.26.36.96.06.06.06.013.816.3

7 7

9 9 9

18 16

19

0.0

12.0

24.0

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Months

0

10

20

Approvals

Median FDA review time Median total approval time Number approved

Priority NMEs

Filings*

161617151415510

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

*A filing in one year may lead to several actions or an approval in subsequent years.

Number

Filings

Older applications 

dominate statistics 

for priority reviews 

Last year saw a steep 

rise in median total 

approval times for 

priority NDAs and 

NMEs. 

This was a statistical 

artifact caused by the 

approval of a number 

of older applications 

remaining from the 

1999 and 2000 receipt 

cohort coupled with a 

significant decrease in 

the number of priority 

applications received in 

2001 and 2002. 

With a smaller pool of 

recent priority 

applications with short 

approval times, the 

remaining “tail” of 

submissions for earlier 

years dominated the 

median approval time 

statistic. 

 Nitazoxanide 

(Alinia) (N) 

 Nitisinone (Orfadin) 

(N) 

 Sodium oxybate 

(Xyrem) (N) 

 Treprostinil sodium 

(Remodulin) (N) 

Priority new drugs

(continued; N=NME)
12 

CDER 2002 Report to the Nation 

Notable 2002 new drug approvals 

Last year’s approvals benefited people with cancer, HIV infection, heart 

disease and other disorders. 

People with cancer 

Oxaliplatin for injection (Eloxatin) is used with infusional 5-FU/LV to treat 

cancer of the colon or rectum in patients whose disease has recurred or 

progressed during or within six months of completion of first-line therapy. 

Fulvestrant (Faslodex) is for the treatment of hormone receptor-positive 

metastatic breast cancer in postmenopausal women with disease 

progression following anti-estrogen therapy. 

People with gastrointestinal disorders 

Tegaserod maleate (Zelnorm) is the first drug approved for the short-term 

treatment of women with irritable bowel syndrome whose primary bowel 

symptom is constipation. The medicine is the first agent in a new class of 

drugs called serotonin-4 receptor agonists (5HT4 agonist) developed to 

target the gastrointestinal tract. 

Standard new 

drugs 

 67 approvals 

 Median review time: 

12.7 months 

 Median approval 

time: 15.3 months 

 154 actions 

 87 filings 

Standard NDAs

Actions, filings*, approval percentages

18592225902009215387147101197871438915487

51% 45% 42% 37% 40% 39% 44% 36%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

*A filing in one year may lead to several actions or an approval in subsequent years.

Number

0%

50%

100%

Percent

Actions Filings Percent of actions that are approvals

Standard NDA Approvals

Median times, approvals

16.218.715.117.814.715.012.012.012.013.812.012.012.014.012.715.3

67

102 101

65 55

78

56 67

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Months

0

60

120

Approvals

Median FDA review time Median total approval time Number approved

Reasons for 

approval delays 

studied 

We examined reasons 

for approval delays on 

first cycle reviews for 

standard and priority 

new molecular entities 

in 2000 and 2001. 

Standard NMEs: 

 Safety issues 

(38 percent) 

 Efficacy issues 

(21 percent) 

 Manufacturing 

facility issues 

(14 percent) 

 Labeling issues 

(14 percent) 

 Chemistry, 

manufacturing, and 

controls issues 

(10 percent) 

 Submission quality 

(3 percent) 

Priority NMEs: 

 Chemistry, 

manufacturing and 

controls issues 

(46 percent) 

 Safety issues 

(27 percent) 

 Efficacy issues 

(18 percent) 

 Manufacturing 

facilities issues 

(9 percent) 
13 

Improving Public Health Through Human Drugs 

People with heart disease 

Eplerenone (Inspra) treats high blood pressure both alone and in 

combination with other antihypertensive therapies. The drug works by 

selectively blocking aldosterone, a hormone that plays a role in regulating 

electrolyte and water balance. 

An imaging agent, dimyristoylphosphatidylcholine and perflexane (Imagent 

Kit for the Preparation of Perflexane Lipid Microspheres), can help in the 

diagnosis of heart disease. It is intended for use in patients with suboptimal 

ultrasound images of the heart. It helps distinguish between normal and 

abnormal heart structure and motion, two primary indicators of cardiac 

health. 

Olmesartan medoxomil (Benicar) treats high blood pressure. 

People with pulmonary hypertension 

Treprostinil sodium (Remodulin) is a continuous subcutaneous infusion for 

the treatment of pulmonary arterial hypertension, a disease in which blood 

pressure in pulmonary arteries rises to life-threatening levels. The orphan 

priority drug received accelerated approval. 

New molecular 

entities 

 Adefovir dipivoxil 

(Hepsera) 

 Aripiprazole 

(Abilify) 

 Atomoxetine 

hydrochloride 

(Strattera) 

 Dimyristoylphosphatidylcholine and 

perflexane (Imagent 

Kit for the Preparation 

of Perflexane Lipid 

Microspheres) 

 Eletriptan 

hydrobromide (Relpax) 

 Eplerenone (Inspra) 

 Ezetimibe (Zetia) 

 Fulvestrant 

(Faslodex) 

 Icodextrin 

(Extraneal) 

 Nitazoxanide 

(Alinia) 

 Nitisinone (Orfadin) 

 Olmesartan 

medoxomil (Benicar) 

 Oxaliplatin 

(Eloxatin) 

 Sodium oxybate 

(Xyrem) 

 Tegaserod maleate 

(Zelnorm) 

 Treprostinil sodium 

(Remodulin) 

 Voriconazole 

(Vfend) 

Standard new 

molecular entities 

 10 approvals 

 Median review time: 

12.5 months 

 Median approval 

time: 15.9 months 

 13 filings 

Standard NME Approvals

Median times, approvals

15.917.814.615.114.415.012.313.414.016.315.419.915.719.012.515.910

17 18

30

19

35

14

16

0.0

12.0

24.0

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Months

0

20

40

Number

Median FDA review time Median total approval time Number approved

Standard NMEs

Filings*

3429242822122513

0

20

40

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

*A filing in one year may lead to several actions or an approval in subsequent years.

Number

Filings
14 

CDER 2002 Report to the Nation 

Office-based 

addiction 

treatment 

Buprenorphine 

hydrochloride (Subutex) 

and the combination of 

buprenorphine and 

naloxone (Suboxone) 

treat opiate addiction 

by preventing 

symptoms of 

withdrawal from 

heroin and other 

opiates. 

These orphan drugs 

are the first treatments 

of opiate dependence 

that can be prescribed 

in an office setting 

under the Drug 

Addiction Treatment 

Act of 2000. 

People needing dialysis 

Icodextrin (Extraneal) is a peritoneal dialysis solution that expands 

patients’ options for effective fluid management in home-based peritoneal 

dialysis, a form of kidney dialysis. 

Infectious diseases 

Adefovir dipivoxil (Hepsera) is the first nucleotide analogue to be approved 

for the treatment of chronic hepatitis B. 

Voriconazole (Vfend) is a triazole antifungal agent indicated as the primary 

treatment for acute invasive aspergillosis and as a salvage treatment for rare 

but serious fungal infections. It is available in both oral and intravenous 

formulations. 

Ribavirin (Copegus), in a new formulation, received a priority review for 

treatment of hepatitis C. 

People with mental illness 

Aripiprazole (Abilify), which is administered as a once-daily oral tablet, 

was shown in clinical studies to provide significant improvements in both 

the positive and negative symptoms of schizophrenia. 

People with neurological disorders 

Sodium oxybate (Xyrem), an oral solution, is the first drug approved for the 

treatment of cataplexy, a sudden loss of muscle tone associated with 

narcolepsy. The medicine is a Schedule III controlled substance. 

Eletriptan hydrobromide (Relpax) acts on blood vessels and sensory nerve 

endings to relieve the symptoms of migraine attacks. 

Pediatric uses 

Atomoxetine sodium (Strattera) is the first major new treatment for 

attention-deficit/hyperactivity disorder in three decades. The drug works to 

prolong the presence in the brain of the chemical norepinephrine, which is 

involved in regulating attention and impulsivity levels. It provides full-day 

relief of symptoms without causing insomnia in most children and adults. It 

is the first drug approved to treat the condition in adults. 

Nitazoxanide (Alinia), a priority orphan approval, is the first oral 

suspension medicine specifically approved for the treatment of diarrhea 

caused by two parasitic infections, cryptosporidiosis and giardiasis in 

children 1 to 11 years old. In compromised children, these infections have 

been associated with malnutrition and impaired growth. 

Nitisinone (Orfadin), a priority orphan approval, is used to treat hereditary 

tyrosinemia type I, a life-threatening metabolic disorder that affects fewer 

than 100 children the United States. The disease, which results from the 

lack of an enzyme to break down the amino acid tyrosine, usually results in 

progressive liver disease and liver cancer. 

Internet resources 

for drug review 

statistics 

Other drug review 

statistics are available 

on our Web site at 

http://www.fda.gov/

cder/rdmt/default.htm.

Notable 2002 new drug approvals (continued)

Chemical warfare 

antidote 

Atropine and 

pralidoxime chloride 

(ATNAA), sponsored by 

the U.S. Army, is for 

use as an antidote to 

nerve agent exposure 

(page 6).

People with eye 

disease 

Cyclosporine (Restasis), 

in a new ophthalmic 

emulsion formulation, 

received a priority 

review for treatment of 

moderate to severe 

inflammation of the 

eye’s cornea and to 

restore and maintain 

normal tear secretion 

and surface integrity of 

the eye. 
15 

Improving Public Health Through Human Drugs 

Orphan new or 

expanded uses 

 Imatinib mesylate 

 Secretin 

Priority efficacy 

supplement 

reviews 

 Alosetron 

hydrochloride 

 Anastrozole 

 Argatroban 

 Clopidogrel 

bisulfate 

 Clozapine 

 Imatinib mesylate 

 Irbesartan 

 Lansoprazole 

 Latanoprost 

ophthalmic solution 

 Linezolid 

 (3 approvals) 

 Losartan potassium 

 Pravastatin 

 Secretin 

 (2 approvals) 

 Tamoxifen citrate 

 Vinorelbine tartrate 

 Zoledronic acid 

New or expanded 

uses (efficacy 

supplements) 

 152 approvals 

 Median review time: 

10.0 months 

 Median approval 

time: 10.0 months 

 19 priority reviews 

 2 orphan uses 

 273 actions 

New or Expanded Use Approvals

Median times, approvals

14.216.012.313.911.911.911.711.810.210.410.010.010.111.310.010.0

152

91 134 97 118

124

69 108

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Months

0

80

160

Approvals

Median FDA review time Median total approval time Number approved

New or Expanded Uses

Actions, approval percentages

185196189173184205213273

56%

43% 37%

57%

53% 65%

72%

60%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Actions

0%

50%

100%

Percent

Actions Percentage of actions that are approvals

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. The new and expanded use review 

statistics on this page include figures for both priority and standard 

applications. Priority and standard application review performance will be 

reported separately in the future to reflect better their different review 

goals. 

Notable 2002 new or expanded use approvals 

Anastrozole (Arimidex Tablets) is for adjuvant treatment of postmenopausal 

women with hormone receptor positive early breast cancer. 

Argatroban (Argatroban Injection), an anticoagulant, is for use in patients 

undergoing heart catherizations and have or are at risk for developing 

heparin-induced decreases in the number of blood platelets. 
16 

CDER 2002 Report to the Nation 

Clopidogrel bisulfate (Plavix), a blood thinner, is now approved to treat 

acute coronary syndrome. 

Clozapine (Clozaril) can be used to treat patients with schizophrenia or 

schizoaffective disorder who are at risk for emergent suicidal behavior. 

Imatinib mesylate (Gleevec) is for treatment of gastrointestinal stromal 

tumor, which affects about 5,000 people in the United States each year. It is 

a tumor that generally arises within the stomach or intestinal tract and 

metastasizes within the abdomen or the pelvis. The drug was first approved 

in May 2001 for treatment of Philadelphia chromosome positive chronic 

myeloid leukemia. 

Irbesartan (Avapro) and losartan potassium (Cozaar) can be used to treat 

kidney damage in people with Type 2 diabetes. Both belong to a class of 

high blood pressure drugs known as angiotensin II receptor blockers. 

Latanoprost ophthalmic solution (Xalatan) is for the reduction of 

intraocular pressure in patients with open-angle glaucoma or ocular 

hypertension. 

Secretin (SecreFlo for Injection), used for secretin stimulation testing, 

received two approvals for identification of pancreatic disorders. 

Zoledronic acid (Zometa) is for the treatment of patients with multiple 

myeloma and patients with documented bone metastases from solid tumors, 

in conjunction with standard therapy. 

Priority pediatric labeling changes 

When studying approved drugs in children, sponsors often learn new 

information about the drug’s safety and the doses that should be used. An 

efficacy supplement changes the labeling information to reflect the new 

discoveries, even if there is not a new or expanded use. Consistent with the 

mandate in the Best Pharmaceuticals for Children Act, these pediatric 

supplements received priority reviews last year: 

 Lansoprazole (Prevacid), a treatment for gastric reflux disease, has 

updated labeling for children 1 to 11 years old. 

 Linezolid (Zyvox), first in a new class of antibiotics, is for treating 

infections in children, including those caused by some antibiotic 

resistant organisms. 

 Pravastatin (Pravachol) is for the treatment of an inherited form of 

high cholesterol in children 8 years old and older. 

 Tamoxifen citrate (Nolvadex) labeling contains new information on 

pediatric studies for girls 2 to 10 years old with McCune-Albright 

syndrome. 

Irritable bowel 

syndrome 

treatment 

reintroduced 

Alosetron hydrochloride 

(Lotronex), a treatment 

for diarrheapredominant irritable 

bowel syndrome in 

women that had been 

withdrawn for safety 

reasons in 2000, was 

reintroduced with 

limited distribution and 

a risk management 

plan (page 31). The 

regulatory mechanism 

for reintroduction was 

a priority efficacy 

supplement.

Other pediatric 

exclusivity priority 

reviews 

Vinorelbine tartrate 

(Navelbine) is a cancer 

treatment, and 

pediatric clinical trials 

are now described in 

the labeling. 
17 

Improving Public Health Through Human Drugs 

Conditions with 

approved pediatric 

labeling 

 Abnormal heart 

rhythms 

 Allergies 

 Anesthesia and 

sedation 

 Asthma 

 Atopic dermatitis 

 Attention deficit/

hyperactivity disorder 

 Diabetes mellitus 

(Type 1 and Type 2) 

 Gastroesophageal 

reflux 

 High blood pressure 

 High cholesterol 

 High eye pressure 

 HIV infection 

 Infectious diseases 

 Juvenile rheumatoid 

arthritis 

 Low levels of 

calcium associated with 

severe kidney disease 

 Obsessive 

compulsive disorder 

 Pain 

 Seizures 

 Severe recalcitrant 

nodular acne 

Pediatric Drug Development 

Last year, we approved 19 labeling changes for pediatric uses. Also, we 

approved three new molecular entities (page 14).

As of April 1, 2003, we had received 328 proposed pediatric study requests 

from manufacturers, issued 272 written requests, made 84 exclusivity 

determinations and added pediatric use information to 50 labels. 

The Best Pharmaceuticals for Children Act of 2002 renewed our authority 

to grant six months of additional marketing exclusivity to manufacturers 

who conduct and submit pediatric studies in response to our written 

requests. It also allows us to collect user fees for reviewing these pediatric 

supplements and mandates a six-month priority review for a pediatric 

supplement submitted in response to a written request. 

The law also authorizes the National Institutes of Health to contract for 

pediatric studies for drugs that lack patent protection or other marketing 

exclusivity, referred to as “off-patent” drugs. In consultation with us, the 

NIH obtained input from outside pediatric experts to identify the priority 

off-patent drugs for which pediatric studies are needed. A list of 12 of these 

drugs was published in January 2003, and contracts for testing them will 

publish later in 2003. 

Pediatric exclusivity has helped us uncover important dosing and safety 

information, such as drug effects on growth, to help healthcare providers 

use drugs to treat children more confidently. The absence of pediatric 

testing and labeling poses significant risks for children. Children may be 

exposed to ineffective treatment through underdosing. Inadequate dosing 

information exposes children to the risk of adverse reactions without the 

benefit of efficacy; however, overdosing may pose greater risk of adverse 

reactions. Young patients may not benefit from therapeutic advances 

because physicians choose to prescribe existing, less effective medications 

in the face of insufficient pediatric information about a new medication. 

The failure to produce drugs in dosage forms that can be used by young 

children such as liquids or chewable tablets can also deny them access to 

important medications. 

Pediatric Drug Development

423112398171145231269201921

0

50

100

1998 1999 2000 2001 2002

Calendar year

Number

Pediatric exclusivity determinations Pediatric exclusivity labeling changes

Written requests issued

Pediatric Rule 

thrown out; clearer 

authority sought 

In October 2002, the 

U.S. District Court for 

the District of 

Columbia ruled that we 

lacked legislative 

authority to issue our 

Pediatric Rule and has 

barred us from 

enforcing it. 

The government 

decided not to pursue 

an appeal and will 

work with Congress to 

pursue legislation 

requiring drug 

manufacturers to 

conduct appropriate 

pediatric clinical trials. 

Internet resources 

Our Web site for up-todate pediatric labeling 

changes is at http://

www.fda.gov/cder/

pediatric/index.htm. 

2002 pediatric drug 

statistics 

 20 exclusivity 

determinations made 

 19 exclusivity 

labeling changes 

 21 written requests 

issued 
18 

CDER 2002 Report to the Nation 

Electronic Submissions 

The number of new drug applications submitted electronically continues to 

grow. Last year’s electronic submissions were double the number 

submitted in the previous year. Overall, we had more electronic 

submissions last year than in the previous four years combined. 

The number of participating companies and the number of applications 

with electronic components continues to grow. About 70 percent of newly 

filed new drug applications have an electronic component, and two-thirds 

are completely electronic. About 17 percent of new or expanded use 

applications have an electronic component with 85 percent being 

completely electronic. 

Last year, we began receiving generic drug applications in electronic 

format. We continue to receive electronic drug advertising material in 

electronic format. 

Reviewers continue to find that electronic submissions provided as 

described in our guidance documents allow them to be more efficient. Our 

training programs include hands on classroom training as well as on-site 

training to teams receiving electronic applications. This training improves 

the ability to use the submissions effectively. 

We have been working with other regulatory agencies and pharmaceutical 

groups in the International Conference on Harmonization (page 38) to 

complete the electronic common technical document. In 2003, we expect to 

begin receiving investigational new drug applications, annual reports and 

Drug Master Files in e-CTD format. 

In addition to receiving electronic applications, we have received over 

22,000 electronic individual case safety reports from manufacturers. These 

reports are transmitted electronically and automatically entered into the 

Adverse Event Report System (page 27). This allows the reviewers to 

evaluate the reports sooner and reduces our resources for entering 

information into the system. 

Pregnancy labeling 

We have reviewed the 

current system of 

labeling drugs for use 

by pregnant women 

and are developing an 

improved, more 

comprehensive and 

clinically meaningful 

approach. 

We are consulting with 

multiple government 

agencies, medical 

experts, consumer 

groups and the 

pharmaceutical 

industry to develop this 

new labeling format. 

Last year, we began 

seeking public 

comment on a draft 

guidance that will 

provide sponsors with 

advice on how to 

establish pregnancy 

exposure registries. 

Registries that 

prospectively monitor 

the outcomes of 

pregnancies in women 

exposed to a specific 

drug can provide 

clinically relevant 

human data for 

treating or counseling 

patients who are 

pregnant or 

anticipating pregnancy. 

Antimicrobial resistance 

The emergence of drug-resistant bacteria is considered to be a major threat 

to the public health. We developed a regulation outlining new labeling 

designed to help reduce the development of drug-resistant bacterial strains. 

This rule became final in February 2003 and aims at reducing the 

inappropriate prescription of antibiotics to children and adults for common 

ailments such as ear infections and chronic coughs. 

Details of our other efforts and resources are at http://www.fda.gov/cder/

drug/antimicrobial/default.htm. 

Public meeting on 

antimicrobial drug 

development 

We along with industry 

and academia 

cosponsored a two-day 

public meeting to 

explore the scientific 

and regulatory issues in 

developing drugs to 

treat highly resistant 

pathogens. 

Internet resources 

More information on 

our electronic 

submissions program is 

at http://www.fda.gov/

cder/regulatory/ersr/.
19 

Improving Public Health Through Human Drugs 

Over-the-Counter Drug Review 

We approved 13 new drugs or Rx-to-OTC switches, 11 of which can be 

used by children. Among the approvals are: 

 Guiafenesin extended release 600 mg tablets (Mucinex) helps loosen 

phlegm and thin bronchial secretions to rid the bronchial passageways 

of bothersome mucus and make coughs more productive for adults and 

children 12 years old and older. 

 Ibuprofen (Ibuprofen 200 mg Liquigel Tabs) provides temporary relief 

of minor aches and pains due to headache, muscular aches, minor pain 

of arthritis, toothache, backache, the common cold, and menstrual 

cramps, and to temporarily reduce fever, for adults and children 12 

years of age and older. 

 Ibuprofen/pseudoephedrine (Advil Cold & Sinus Liquigels) provides 

temporary relief of symptoms associated with the common cold, 

sinusitis, or flu, including nasal decongestion, headache, fever, body 

aches and pains, in adults and children 12 years of age and older. 

 Ibuprofen/pseudoephedrine (Children’s Advil Cold Suspension)

provides temporary relief of symptoms associated with the common 

cold, sinusitis, or flu, including nasal decongestion, headache, fever, 

body aches and pains, in children 2 to 11 years of age. 

 Ibuprofen/pseudoephedrine/chlorpheniramine (Advil Allergy Sinus 

Caplet) provides temporary relief of symptoms associated with hay 

fever or other upper respiratory allergies, and the common cold in 

adults and children 12 years of age and older. 

 Nicotine polacrilex (Commit Lozenge 2 mg and 4 mg) reduces 

withdrawal symptoms, including nicotine craving, associated with 

quitting smoking, for use in adults 18 years of age and older.

 A nicotine transdermal system (Nicotrol TD) is approved to reduce 

withdrawal symptoms, including nicotine craving, associated with 

quitting smoking, for use in adults 18 years old and older.

Over-the-counter 

drug statistics 

 13 new drugs or 

Rx-to-OTC switch 

approvals 

First nonsedating 

antihistamine 

approved for OTC 

use 

Loratadine provides 

temporary relief of 

symptoms of hay fever 

or other upper 

respiratory allergies, 

runny nose, sneezing, 

itchy, watery eyes and 

itching of the nose or 

throat. 

We approved six 

formulations. The first 

three are for people age 

6 and older, the syrup 

is for those as young as 

2, while combinations 

with a decongestant are 

for those 12 and older. 

 Loratadine 

(Alavert) 

 Loratadine 

(Claritin) 

 Loratadine 

(Claritin Reditabs) 

 Loratadine 

(Claritin Syrup) 

 Loratadine and 

pseudoephedrine 

(Claritin-D 12) 

 Loratadine and 

pseudoephedrine 

(Claritin-D 24 Hour) 

How we regulate 

OTC drugs 

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. 

Drugs can also be 

approved for OTC sale 

through the new drug 

review process. 

Improved labels 

for OTC medicines 

American consumers 

are benefiting from 

easy-to-understand 

labels on drugs they 

buy without a 

prescription. 

A mandatory 

changeover to the new 

labels, titled “Drug 

Facts,” began in 2002. 

OTC New Approvals & New Uses

201918753836113

0

12

24

1996 1997 1998 1999 2000 2001 2002

Calendar year

Number

New approvals or Rx-to-OTC switches New uses
20 

CDER 2002 Report to the Nation 

Generic Drug Review 

We approved 321 generic drug products in 2002, including 80 products that 

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

product. The median approval time for generic drugs was 18.3 months. 

The median statistic for total approval time has hovered at about 18 to 19 

months for five years. We are making changes to decrease the overall time 

to approval of applications. We are improving the efficiency of our generic 

drug review process and increasing the number of chemistry reviewers by 

one-third. 

Notable 2002 generic drug approvals 

Examples of first-time approvals for the brand-name equivalent drug are: 

 Loratadine (Claritin) used as an antihistamine. 

 Isotretinoin (Accutane) used to treat severe acne. 

 Potassium Iodide Tablets for use in protecting the thyroid gland in the 

event of a radiation emergency. 

 Metformin (Glucophage) used to treat diabetes. 

 Cefuroxime Axetil (Ceftin) used to treat infections. 

Our approval of generic versions of these drugs last year could save 

American consumers and the federal government hundreds of millions of 

dollars each year. 

We also issued 63 tentative approvals and 20 approvables last year: 

 Tentative approvals. The only difference between a full approval and a 

tentative approval is that the final approval of these applications is 

delayed due to existing patent or exclusivity on the innovator drug 

product. These and other legal issues continue to be a challenge to the 

generic drug review program. While tentative approvals represent a full 

workload for us, they are only displayed in the chart on the next page 

once they are converted to full approvals. For example, some of the 321 

approvals in 2002 represent conversions of tentative approvals granted 

in 2002 or previous years. 

 Approvables. Approvable applications are reviewed and ready for full 

approval except for a pending labeling issue, generally related to legal 

matters such as exclusivity. These also represent full workload but are 

only displayed once they are converted to full approval. 

Electronic 

submissions 

Through public 

presentations, we are 

encouraging the 

generic drug industry 

to submit their 

applications 

electronically. More 

information electronic 

submissions is on 

page 18.

How we approve 

generic drugs 

Generics are not 

required to repeat the 

extensive clinical trials 

used in the 

development of the 

original, brand-name 

drug. Instead, they 

must show 

bioequivalence to the 

brand-name reference 

listed drug. 

Scientists measure the 

amount of the generic 

drug that reaches the 

bloodstream and how 

long it takes to get 

there. This rate and 

extent of absorption is 

called bioavailability. 

The bioavailability of 

the generic drug is then 

compared to that of the 

brand-name reference 

listed drug. 

The generic version 

must deliver the same 

amount of active 

ingredients into a 

patient’s bloodstream 

and in the same time as 

the brand-name 

reference listed drug. 

Brand-name drugs are 

subject to the same 

bioequivalency tests as 

generics when their 

manufacturers 

reformulate them. 

Generic drug Web 

site 

You can find more 

information about our 

generic drug program 

at http://www.fda.gov/

cder/ogd/.
21 

Improving Public Health Through Human Drugs 

Generic drug 

statistics 

 321 generic drug 

approvals 

 Median approval 

time: 18.3 months 

 392 receipts 

 63 tentative 

approvals 

 20 approvables 

Generic drugs a top priority 

“Encouraging rapid and fair access to generic medications after the 

expiration of appropriate patent protection” is one of the major priorities 

for new FDA Commissioner Mark McClellan, M.D., Ph.D. He noted that 

the generic drugs play an essential role in promoting the health of 

Americans. 

He assured the generic industry that we would work to reduce the time to 

approval for generic products and that generics must be safe and effective. 

We will work to identify steps such as improving guidance and 

communication to help improve the overall quality of applications thus 

gaining faster approvals. 

A copy of his remarks is available at http://www.fda.gov/oc/speeches/2002/

gpha.html. 

Tentative 

approvals 

 1995: 15 

 1996: 25 

 1997: 40 

 1998: 40 

 1999: 56 

 2000: 61 

 2001: 73 

 2002: 63 

Generic Drug Approvals

Median times, approvals

27.023.019.318.018.618.218.118.3

207

212 273

225

186

244 234

321

0

18

36

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Months

0

200

400

Number

Median approval times Number of generic approvals

Generic Drug Applications Received

283307330345296365320392

0

200

400

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Number

Applications received (workload in future years)
22 

CDER 2002 Report to the Nation 

Internet availability 

Our generic drug 

public service 

announcements are at 

http://www.fda.gov/

cder/consumerinfo/

generic_info/default.

htm.

Building consumer confidence in generic drugs 

We launched our program to promote consumer confidence in the safety 

and effectiveness of generic drugs. We are informing health care 

practitioners and consumers about the rigorous review and approval 

process that generic drugs undergo before we approve them for sale in this 

country. Partnerships and networking with other groups are helping us to 

bring the message to more people. The consumer education program 

includes: 

 Newspaper articles. For example, 420 articles have appeared in local 

newspapers in 30 states. 

 Posters, brochures and give-away items. 

 Public service announcements, which have appeared in magazines such 

as JAMA, Forbes, Chain Drug Review and Geriatric Times.

 Advertisements on buses in Chicago, Los Angeles and New York. 

 We are developing a Web-based course on generic drug safety and 

effectiveness for pharmacists and other health professionals. 
23 

Improving Public Health Through Human Drugs 

Assessing Data Quality, Research Risks 

To protect the rights and welfare of volunteers and verify the quality and 

integrity of data submitted for our review, we perform on-site inspections 

of clinical trial study sites, institutional review boards, sponsors, study 

monitors and contract research organizations. Our programs to protect 

volunteers are challenged by increases in the number of clinical trials; 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. 

When obtaining data about the safety and effectiveness of drugs, sponsors 

rely on 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, including manufacturers, institutional review 

boards, study sponsors, clinical investigators and their staffs, monitors, 

contract research organizations, hospitals and other institutions. 

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 vulnerable populations, such as 

children, the mentally impaired or prisoners. 

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. 

Top 5 deficiency 

categories for 

clinical 

investigator 

inspections 

 Failure to follow the 

protocol 

 Failure to keep 

adequate and accurate 

records 

 Problems with the 

informed consent form 

 Failure to report 

adverse events 

 Failure to account 

for the disposition of 

study drugs 

Inspections of 

clinical research in 

2002 

We conducted a total of 

487 inspections of 

clinical research: 

 276 U.S. clinical 

investigators 

 30 foreign clinical 

investigators 

 166 institutional 

review boards 

 15 sponsors, 

monitors or contract 

research organizations International 

inspections of 

clinical research 

We have conducted 490 

inspections of clinical 

research in 51 

countries from 1980 to 

2002. 

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. 

These efforts include 

our work with the 

International 

Conference on 

Harmonization 

(page 38) and the 

Declaration of Helsinki. 

Inspections of Clinical Research

3934015872974214312466418442936119110296491552825838139282763016615

0

200

400

1996 1997 1998 1999 2000 2001 2002

Calendar year

Number

U.S. clinical investigators Foreign clinical investigators

Institutional review boards Sponsors, monitors, CROs
24 

CDER 2002 Report to the Nation 

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 third five-year extension last year, 

known as PDUFA III. This reauthorization will ensure that we have the 

expert staff and resources to review applications promptly and get safe, 

effective new drugs into the hands of the people who need them. 

PDUFA III maintains the high review performance goals of PDUFA II, 

which included reduced drug review times and increased and accelerated 

our consultations with drug sponsors. In addition, PDUFA III remedies 

resource shortages that affected the program in recent years. 

Under PDUFA II, we collected significantly less in user fees than estimated 

due to a reduced number of new drug applications and an increased 

proportion of submissions whose fees were waived. The reauthorization 

puts the user fee program on a sound financial basis. 

We are also concerned about the safety of new medicines following 

approval. In recent years, 50 percent of all new drugs worldwide have been 

launched in the United States, and American patients have had access to 78 

percent of the world’s new drugs within the first year of their introduction. 

PDUFA III allows us to spend some user fees to increase surveillance of 

the safety of medicines during their first two years on the market or three 

years for potentially dangerous medications. It is during this initial period, 

when new medicines enter into wide use, that we are best able to identify 

and counter adverse side effects that did not appear during the clinical 

trials. 

Full information on PDUFA III, including the latest performance and 

procedure goals, is on the Web at http://www.fda.gov/oc/pdufa/PDUFA3.

html. 

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 

12 of the 14 

performance goals for 

the fiscal year 2001 

receipt cohort, the 

latest year for which we 

have full statistics. 

 In addition to 

surpassing all goals for 

original new drug 

applications in fiscal 

year 2001, we exceeded 

all three of the goals for 

new molecular entities. 

 We are on track for 

meeting or exceeding 

all of the user fee 

performance goals for 

fiscal year 2002. 

Internet resources 

for user fees 

Our user fee Web site 

has links to more 

documents and 

information including 

our user fee 

performance report to 

Congress. 

The page is at http://

www.fda.gov/cder/

pdufa/default.htm.
25 

Improving Public Health Through Human Drugs 

2 

DRUG SAFETY

AND QUALITY

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

everything about the safety of a drug before we approve it. Therefore, 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. 

We monitor the quality of marketed drugs and their promotional materials 

through product testing and surveillance. As Americans are increasingly 

receiving the benefits of important new drugs before they are available to 

citizens of other countries, we must be especially vigilant in our 

surveillance. In addition, we develop policies, guidance and standards for 

drug labeling, current good manufacturing practices, clinical and good 

laboratory practices and industry practices to demonstrate the safety and 

effectiveness of drugs. 

Highlights of drug safety and quality activities in 2002 include: 

 Processing and evaluating 320,860 reports of adverse drug events, 

including 20,455 submitted directly from individuals. 

 Reviewing about 3,000 reports of medication errors, half of which are 

due to error-prone labeling. 

 Mandating that five drug products be dispensed with specific consumer 

information to help make sure that they are used safely and effectively. 

 Issuing 688 letters to help ensure that the promotion of drug products 

presents a fair balance of risks and benefits and isn’t false or 

misleading. 

 Issuing warnings for misbranded or fraudulent products and products 

marketed as “street drug alternatives.” 

 Issuing 4,733 export certificates for U.S. drug products. 

 Developing technology for the rapid identification of counterfeit drug 

products. 

 Conducting shelf-life extensions for stockpiled drugs. 

Mission 

Protect the public 

health by ensuring that 

human drugs are safe 

and effective. 
26 

CDER 2002 Report to the Nation 

Known side effects 

Unavoidable Avoidable 

Medication 

errors 

Product quality 

defects 

Preventable 

adverse 

events 

Injury 

or death 

Remaining 

uncertainties 

 Unexpected side effects 

 Unstudied uses 

 Unstudied populations 

Sources of Risk from Drug Products 

Types of Risks from Medicines 

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. For example, the drug is administered incorrectly or the 

wrong drug or dose is administered. 

Remaining uncertainties. These include unexpected side effects, long-term 

effects and unstudied uses and populations. For example, a rare event 

occurring in fewer than 1 in 10,000 persons won’t be identified in normal 

premarket testing. 

Drug Safety 

We evaluate the ongoing safety profiles of drugs available to American 

consumers using a variety of tools and disciplines. We maintain a system of 

postmarketing 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 reactions, drug-drug 

interactions and medication errors. 

Medication error 

prevention 

We work hard to 

ensure the safe use of 

drugs we approve by 

weeding out brand 

names that look or 

sound like the names of 

existing products. We 

identify and avoid 

brand names, labels 

and packaging that 

might contribute to 

problems or confusion 

in prescribing, 

dispensing or 

administering. 

We review about 250 

reports of medication 

errors each month. 

About half are due to 

error-prone labeling 

such as look-alike 

labels, poor package 

design and confusing 

names. 

Our comprehensive 

Web site on medication 

errors is at http://www.

fda.gov/cder/drug/

MedErrors/default.

htm.
27 

Improving Public Health Through Human Drugs 

We have access to commercial databases that contain non-patientidentifiable information on the actual use of marketed prescription drugs in 

adults and children. This dramatically augments our ability to determine the 

public health significance of adverse event reports we receive. 

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. 

Adverse Event Reporting System 

A powerful drug safety tool is the Adverse Event Reporting System. This 

computerized system combines the voluntary adverse drug reaction reports 

from MedWatch and the required reports from manufacturers. These 

reports often form the basis of “signals” that there may be a potential for 

serious, unrecognized, drug-associated events. When a signal is detected, 

further testing of the hypothesis is undertaken using various 

epidemiological and analytic databases, studies and other instruments and 

resources. AERS offers paper and electronic submission options, 

international compatibility and pharmacovigilance screening. 

Electronic submissions 

AERS was designed and implemented so that the majority of the reports 

would be entered electronically. We are in the process of migrating the 

reporting format from paper to electronic. In a pilot program, we are 

accepting electronic individual case safety reports from five major drug 

firms. Electronic submissions into AERS represent 15 percent of the total 

expedited reports we received. We estimate the cost of receiving a report is 

cut from $31 per report to $3 to $19 per report for those submitted 

electronically. 

Adverse event 

reporting 

In 2002, we received 

320,860 reports of 

suspected drug-related 

adverse events: 

 20,455 MedWatch 

reports directly from 

individuals 

 128,869 

manufacturer 15-day 

(expedited) reports 

 171,546 

manufacturer periodic 

reports (35,095 serious 

and 136,451 

nonserious)

Report types 

 Direct reports from 

MedWatch. An 

individual, usually a 

health care 

practitioner, notifies us 

directly of a suspected 

serious adverse event. 

 15-day (expedited) 

reports. Manufacturers 

report these serious 

and unexpected 

adverse events to us as 

soon as possible within 

15 days of discovering 

the problem. 

 Manufacturer 

periodic reports. These 

report all other adverse 

events, such as those 

less than serious or 

described in the 

labeling. These are 

submitted quarterly for 

the first three years of 

marketing and 

annually after that. 

Nonserious reports are 

displayed separately 

starting with 1998. 

AERS on Internet 

You can learn more 

about the Adverse 

Event Reporting 

System at http://www.

fda.gov/cder/aers/

default.htm.

Post-Marketing Adverse Event Reports

320,860

278,143 266,991 286,738

247,604

212,843 191,865

156,477

0

200,000

400,000

1995 1996 1997 1998 1999 2000 2001 2002

Calendar year

Number

Direct (MedWatch) 15-day Periodic Nonserious periodic
28 

CDER 2002 Report to the Nation 

MedWatch drug 

safety Internet 

resources 

The latest medical 

product safety 

information can be 

found at http://www.

fda.gov/medwatch/.

You can sign up for 

immediate e-mail 

notification of 

MedWatch safety 

information at http://

www.fda.gov/

medwatch/new.htm.

MedWatch Outreach and Reporting 

We administer the MedWatch program that helps promote the safe use of 

drugs by: 

 Rapidly disseminating new safety information on the Internet and by 

providing e-mail notification to health professionals, institutions, the 

public and our MedWatch partners 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 and problems with all FDAregulated medical products. Reports can be filed by mail, fax, telephone 

or the Internet. 

 Educating health professionals and consumers about the importance of 

recognizing and reporting serious adverse events and product problems, 

including medication errors. Our education program includes Internet 

outreach, speeches, articles and exhibits. 

Last year, subscribers to our e-mail notification service increased to about 

30,000. 

We issued 36 safety alerts for drugs. Notifications were posted on the 

Internet and e-mailed to individuals and our 190 MedWatch partner 

organizations. 

Each month, our subscribers and partners received 25 to 45 safety-related 

labeling changes for drugs. 

Adverse event reporting enforcement 

We enforce regulations on postmarketing adverse event reporting to ensure 

that reports are accurate, timely and complete. We develop regulatory 

strategies and initiate inspections to determine industry compliance with 

the regulations. We use a risk-based approach to identify firms for 

inspection. We focus on firms with: 

 Reporting deficiencies. 

 Drug products that pose a significant health risk. 

 Other priority issues that impact the public health. 

 We evaluate the inspection findings and determine if enforcement 

action is appropriate. 
29 

Improving Public Health Through Human Drugs 

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. 

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. 

Drug shortages 

on the Internet 

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 http://

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.

Medication Guides 

We may require specific written patient information for selected 

prescription drugs that pose a serious and significant public health concern. 

This information is called a Medication Guide. Medication Guides must be 

distributed to patients with each prescription dispensed. We require 

Medication Guides when the information is necessary for patients to use 

the product safely and effectively or to decide whether to use or to continue 

to use the product. Last year, we approved Medication Guides for four 

innovator products and one generic product: 

 Alosetron (Lotronex). 

 Isotretinoin (Amnesteem), generic product; Medication Guide 

previously approved for Accutane. 

 Ribavirin (Copegus). 

 Sodium oxybate (Xyrem). 

 Teriparatide, rDNA origin (Forteo). 

Patient information for prescription drugs 

We continued our research and evaluation activities in support of the 

private sector providing patients with useful information about their 

prescription drugs. The target goal for 2006 is for 95 percent of patients to 

receive useful information with new prescriptions. This past year we 

worked on evaluating the written patient medication information materials 

they received. 

Additionally, we carried out a telephone survey of U.S. consumers about 

where they get their information about prescription drugs. 

Drugs with special 

safety restrictions 

Controls on 10 

prescription drugs 

include limiting 

distribution to specific 

facilities; limiting 

prescription to 

physicians with special 

training or expertise; 

or requiring certain 

medical tests with their 

use. 

Consumers should not 

buy these drugs over 

the Internet. 

As of April 30, 2003, 

these drugs are: 

 Alosetron 

 Bosentan 

 Clozapine 

 Dofetilide 

 Fentanyl citrate 

 Isotretinoin 

 Mifepristone 

 Sodium oxybate 

 Thalidomide 

 Trovafloxacin 

mesylate or 

alatrofloxacin mesylate 

injection 

More information is at 

http://www.fda.gov/oc/

buyonline/

consumeralert120902.

html. 
30 

CDER 2002 Report to the Nation 

Top 10 reasons for 

drug recalls in 

fiscal year 2002: 

 Penicillin cross 

contamination 

 Lack of assurance of 

sterility 

 Labeling: wrong or 

incorrect expiration 

date 

 Subpotency 

 Dissolution failure 

 Stability data do not 

support expiration date 

 Labeling: incorrect 

product or mispacking/

miscarton 

 Particulate matter 

 cGMP deviations: 

failure to perform or 

document performance 

of requirement 

 Foreign substance 

Drug Recalls and Withdrawals 

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. The most common 

reasons for drug recalls include those listed in the column at the right. In 

other cases, a drug is determined to be unsafe for continued marketing and 

must be withdrawn completely. 

Recalls 

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. 

No safety-based withdrawals in 2002 

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. There 

were no drugs withdrawn from the U.S. market last year for safety reasons.

Record of safety-based market withdrawals 

When drug withdrawals are compared based on year of approval, the recent 

period when we applied user-fee review goals is similar to the previous 

period. 

How we coordinate 

drug recalls 

We coordinate drug 

recall information, 

assist manufacturers or 

distributors in 

developing recall plans 

and prepare health 

hazard evaluations to 

determine the risk 

posed to the public by 

products being 

recalled. 

We classify recall 

actions in accordance 

to 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 

notification about the 

recall. 

Drug Recalls

19160226532483417688352723161562487235483

0

200

400

1995 1996 1997 1998 1999 2000 2001 2002

Fiscal year

Number

Prescription Over-the-counter

Drug recalls in 

fiscal year 2002 

 354 prescription 

drugs 

 83 over-the-counter 

drugs 
31 

Improving Public Health Through Human Drugs 

Pre-PDUFA period. Between Jan. 1, 1971, and Dec. 31, 1993, we 

approved 477 new molecular entities, and 13 (2.7 percent) were eventually 

withdrawn. Nearly all the drugs we approved in this period were received 

before we implemented PDUFA review goals. 

PDUFA period. Between Jan. 1, 1994, and Dec. 31, 2002, we approved 

275 NMEs, and 7 (2.5 percent) have been withdrawn. Nearly all drugs we 

approved in this period were reviewed under PDUFA goals. 

Recent safetybased drug 

withdrawals 

Drug name 

(year approved/ 

year withdrawn)

 Phenylpro- 

 panolamine 

 (—/2000) 

 (never approved 

 by FDA) 

 Fenfluramine

 (1973/1997) 

 Azaribine 

 (1975/1976) 

 Ticrynafen 

 (1979/1980) 

 Zomepirac 

 (1980/1983) 

 Benoxaprofen 

 (1982/1982) 

 Nomifensine 

 (1984/1986) 

 Suprofen 

 (1985/1987) 

 Terfenadine 

 (1985/1998) 

 Encainide 

 (1986/1991) 

 Astemizole 

 (1988/1999) 

 Flosequinan 

 (1992/1993) 

 Temafloxacin 

 (1992/1992) 

 Cisapride 

 (1993/2000) 

 Dexfenfluramine 

 (1996/1997) 

 (not an NME)

 Bromfenac 

 (1997/1998) 

 Cerivastatin 

 (1997/2001) 

 Grepafloxin 

 (1997/1999) 

 Mibefradil 

 (1997/1998) 

 Troglitazone 

 (1997/2000) 

 Rapacuronium 

 (1999/2001) 

 Alosetron* 

 (2000/2000) 

*Returned to market in 

2002 with restricted 

distribution.

Recent safetybased drug 

withdrawals 

(cont.)

Safety-Based NME Withdrawals

Based on year of approval

2.7% 2.5%

0.0%

1.5%

3.0%

Pre-PDUFA

(13)

PDUFA

(7)

Approval periods (number withdrawn as of April 30, 2003)

Percentage

Percentage withdrawn

Risk management plan for alosetron 

Immediately after the announcement of the safety-related withdrawal of 

alosetron in 2000, distraught patients, stunned that this therapy had been 

taken away from them, began to contact us demanding access to a drug 

they characterized as “giving them their lives back.” 

Alosetron, a treatment for diarrhea-predominant irritable bowel syndrome 

in women, had been withdrawn because outcomes from ischemic colitis, a 

known side effect, were more serious than predicted by the results of 

clinical trials and because of serious complications of constipation. 

We worked with the manufacturer to compile a formal risk management 

program for alosetron, which we approved last year. This program 

includes: 

 A prescribing program encompassing physician qualifications, 

physician agreements and a prescription sticker procedure. 

 An education program for physicians, pharmacists and patients. 

 Commitments by the manufacturer to report adverse events. 

 An evaluation of program effectiveness. 

The indicated patient population was narrowed, and a lower starting dose 

was specified in the label. 

We have approved a number of programs designed to limit the risks of 

specific drugs. In the case of certain drugs such as thalidomide and 

clozapine, these programs are of proven benefit. 
32 

CDER 2002 Report to the Nation 

Drug Promotion Review 

The information about a drug available to physicians and consumers is just 

as important to its safe use as drug quality. We promote and protect the 

health of Americans by ensuring that drug advertisements and other 

promotional materials are truthful and balanced. We operate a 

comprehensive program of education, surveillance and enforcement about 

drug advertising and promotion. 

Launches and advisories 

When requested, we review advertisements and other promotional 

materials before drug companies launch marketing campaigns that 

introduce new drugs or campaigns that introduce new indications or 

dosages for approved drugs. In fiscal year 2002, we issued 186 advisory 

letters to companies regarding their promotional materials for launch 

campaigns. 

We issued 304 other advisory letters to the industry regarding proposed 

promotional pieces, both professional and consumer directed. In addition, 

we issued 161 other types of correspondence to the pharmaceutical 

industry, such as letters of inquiry, closure letters or acknowledgement 

letters. 

Regulatory actions 

We issued 37 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 a product or indication before approval. 

These were either “untitled” letters for violations or “warning” letters for 

more serious or repeat violations. Examples of specific types of violative 

promotions include promotional exhibit hall displays, oral representations, 

Internet sites, plus traditional materials such as journal advertisements and 

sales brochures. We are also making sure that our warning and untitled 

letters will stand up in court, to provide more effective deterrence to 

recurrent patterns of misleading advertising. 

Direct-to-consumer promotion 

Included in our letters were 188 regarding direct-to-consumer promotion. 

This compares with 190 letters in 2001. Of last year’s letters, 36 were for 

launch campaigns, 142 for non-launch advisories, and 10 were regulatory 

letters. 

We are working on improving our oversight of DTC advertising. Evidence 

from our studies as well as those conducted by consumer groups and other 

entities consistently shows that DTC ads lead to more patients seeking care 

for undertreated conditions. This often results in a different treatment that is 

more appropriate for the patient than the advertised drug. But physicians 

and others are concerned that consumers may not always get a balanced 

Proposed rule to 

revise prescription 

drug labeling 

We continued to work 

on a final rule, based 

on comments from the 

public to our proposal 

in 2001. 

The main purpose of 

labeling is to 

communicate essential 

information about 

prescription drugs to 

health care providers.
33 

Improving Public Health Through Human Drugs 

Drug promotion 

review statistics 

We issued a total of 688 

drug promotion letters 

last year. 

 37 regulatory action 

letters 

 186 launch 

campaigns 

 465 advisory 

acknowledgement or 

closure letters view of the benefits and risks of a product. Consequently, we are working 

on the issue of how manufacturers could provide clearer and more concise 

information for consumers derived from the drug’s approved labeling. 

DTC advertising surveys 

We completed two national telephone surveys and conducted preliminary 

analyses. One survey of 943 consumers is a follow-up to the 1999 survey 

of patients’ attitudes and behaviors associated with direct-to-consumer 

advertisements. The other is a new survey of 500 physicians’ attitudes and 

behaviors associated with direct-to-consumer advertisements. 

Preliminary findings of the two surveys include: 

 About 40 percent of patients and about 45 percent of physicians feel 

DTC advertising encourages information seeking about potentially 

serious medical conditions. 

 About 80 percent of patients and 70 percent of physicians feel DTC 

advertising creates awareness of new treatments. 

 About 40 percent of patients and 75 percent of physicians feel DTC 

advertising make it seem that the drug will work for everyone or make 

the patients think the drug works better than it does. 

 About 40 percent of physicians believe that patients understand the 

possible risk and negative effects of drugs, compared to 80 percent 

who believe patients understand the benefits and positive effects. 

 Over half of physicians report feeling at least a little pressure to 

prescribe when asked for a prescription. 

More is available at http://www.fda.gov/cder/ddmac/globalsummit2003/

index.htm.

Drug Promotion Review

12941722055824553923739917135077311727651510517859737186465

0

400

800

1995 1996 1997 1998 1999 2000 2001 2002

Fiscal year

Number

Regulatory actions Launch campaigns Other letters
34 

CDER 2002 Report to the Nation 

Drug Product Quality 

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 two 

basic strategies to meet this goal: 

 Evaluating the findings of inspections that examine the conditions and 

practices in plants where drugs are manufactured, packed, tested and 

stored. 

 Monitoring the quality of finished drug products in distribution, through 

sampling and analysis. 

We identify, evaluate and analyze inspection findings for trends in 

deficiencies. We develop guidances to assist drug manufacturers in gaining 

a better understanding of our regulations. We communicate the 

expectations of compliance through outreach programs. We review all 

international pharmaceutical inspection reports. We determine which 

foreign manufacturers are acceptable to supply active pharmaceutical 

ingredients or finished drug products to the U.S. market. 

Reporting systems for drug quality problems 

Two important post-marketing tools help us rapidly identify significant 

health hazards associated with the manufacturing and packaging of drugs: 

 Drug Quality Reporting System. Through MedWatch (page 28), we 

receive reports of observed or suspected drug quality defects associated 

with marketed drugs. We evaluate and prioritize the reports to 

determine potential health hazards and industry trends. These reports 

significantly assist us in developing special programs and surveys. We 

identify significant health hazards associated with drug manufacturing, 

packaging and labeling and initiate field inspection assignments. We 

review inspection reports and recommend appropriate corrective action. 

We maintain a central reporting system to detect problem areas and 

trends. 

 Field Alert Reports. Firms are required to notify FDA promptly of 

possible problems that may represent safety hazards for their marketed 

drug products. FDA’s district offices evaluate these reports and conduct 

follow-up inspections. We review and evaluate the inspection findings 

to determine if firms are complying with reporting requirements. We 

review and approve enforcement recommendations for failure to meet 

these requirements. 

Prescription drugs 

sold without 

approved 

applications 

We identify drugs that 

are marketed without 

an approved new or 

generic drug 

application. We assess 

unapproved drugs to 

maximize protection of 

the public health and 

make best use of FDA’s 

limited resources. We 

prioritize drugs that 

may be subject to 

compliance actions into 

risk-based categories 

according to safety 

considerations, effects 

on public health or 

subversion of the new 

drug approval process. 

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 riskbased 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. 

Sampling criteria 

 Microbial/endotoxin 

concerns 

 Stability concerns 

 Sterility issues 

 Dissolution issues 

 Impurities/

contaminants 

 Product quality 

history 

 Counterfeit drugs 

 History of violations 
35 

Improving Public Health Through Human Drugs 

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 an 

inspection to make sure a firm can consistently manufacture the product. 

Finally, routine inspections evaluate the firm’s entire operations. 

Misbranded drugs, unsubstantiated claims 

Mislabeled, fraudulent, hazardous products. We often encounter 

mislabeled and fraudulent products that make unsubstantiated claims. 

Consumers may use these products inappropriately or incorrectly. They 

may use a fraudulent product for treating a serious disease condition in 

place of an effective treatment or delay the use of effective treatment. For 

these reasons, products that are mislabeled, fraudulent or make unproven 

claims may pose a significant health risk. 

Occasionally, fraudulent products may also contain toxic compounds that 

are likely to cause serious illness or injury. In addition, the marketing of 

products that are either mislabeled or fraudulent threatens to undermine the 

U.S. drug development and approval process as well as the ongoing overthe-counter drug review process. 

Protecting 

consumers from 

misbranded or 

fraudulent drugs 

We protect consumers 

from mislabeled, 

fraudulent or 

hazardous products by 

identifying and taking 

steps to remove 

products that pose 

public health risk from 

the market. We issue 

enforcement letters and 

pursue enforcement 

actions such as seizures 

of violative products 

and injunctions against 

firms or individuals. 

Last year, more than 

30 such letters were 

issued based on 

misbrandings or 

fraudulent claims 

found in labeling and 

on Internet sites. These 

addressed various 

illegally marketed 

products, many 

masquerading as 

dietary supplements, 

including several 

containing 

androstendione, 

ephedra-related 

compounds or human 

growth hormone. 

We also sent letters 

concerning “street drug 

alternatives,” products 

intended for 

recreational use as 

alternatives to illicit 

controlled substances. 

FDA Inspections of Manufacturing Plants 773 1,775 1,844 1,144 1,085 1,436 822 1,268 1,497 890 1,276

1,519

0

1,000

2,000

1999 2000 2001 2002

Fiscal year

Number

New drug preapproval Generic preapproval Current good manufacturing practice

Preapproval 

inspections 

During fiscal year 2002, 

FDA evaluated: 

 890 plants in 

support of new drug 

applications 

 1,276 domestic firms 

in support of generic 

drug applications 

Good 

manufacturing 

practice 

inspections 

There were 1,519 good 

manufacturing practice 

inspections (1,109 nongas) in fiscal year 2002. 

 We reviewed 28 

field recommendations 

for regulatory action 

and approved 12. These 

included six 

injunctions, two 

seizures and four 

warning letters. 

 We reviewed 210 

foreign establishment 

inspection reports, 

resulting in one 

warning letter. 
36 

CDER 2002 Report to the Nation 

Drug Product Quality Science 

Laboratory support 

Last year our efforts included: 

 Rapid identification of counterfeit products using near-infrared 

spectroscopy and chemical imaging to discriminate drug products and 

raw materials. 

 Shelf-life extensions for drug products on the joint FDA and 

Department of Defense Shelf-Life Extension Program. We assess 

stability profiles of stockpiled drugs for risk management. 

Process analytical technologies initiative 

Our goal for this initiative is to facilitate the introduction of new and 

emerging technologies that will improve the capability and efficiency of the 

pharmaceutical manufacturing process while maintaining or improving 

product quality. Known as process analytical technologies, these are 

systems for continuous analysis and control of manufacturing processes 

based on real-time or rapid measurements during processing. These 

systems involve in-line, on-line or at-line monitoring, measuring and 

controlling in manufacture of drug substance and drug products. 

We are using a collaborative process to develop this initiative. We are 

bringing together experts in the areas of analytical chemistry, physical 

chemistry, pharmaceutical technology, regulatory compliance, chemical 

engineering and international pharmaceutical manufacturing. These include 

experts from industry and academia along with our own and those from 

other FDA components. 

We are encouraging the adoption of this technology in drug manufacturing 

because it can enhance process understanding, improve overall product 

quality and lead to increased efficiencies. This also addresses many of the 

objectives of the Pharmaceutical cGMPs for the 21st Century Initiative 

(page 4).

A steering committee comprised of senior FDA managers is involved in the 

development of a general guidance on the use of these new technologies. 

We have formed a special review team to evaluate process analytical 

technologies when used by the industry. On the team, our own chemistry 

reviewers and compliance officers will join FDA’s field investigators on 

inspections. 

By organizing public meetings and workshops, we have gathered 

information related to development and use of process analytical 

technologies and shared our own research data. 

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 

(page 38).

We heave a new 

program to advance 

rapid microbiology test 

methods. 
37 

Improving Public Health Through Human Drugs 

Export Certificates 

We promote goodwill and cooperation between the United States and 

foreign governments through the Export Certificate Program. These 

certificates enable American manufacturers to export their products to 

foreign customers and foreign governments. The demand for certificates by 

foreign governments remains high due to expanding world trade, ongoing 

international harmonization initiatives and international development 

agreements. 

The certificates attest that the drug products are subject to inspection by the 

FDA and are manufactured in compliance with current good manufacturing 

practices. Export certificates verify that 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. 

Export certificates 

issued in fiscal 

year 2002: 

 4,733 

Export Certificates Issued

1,7474,4994,3784,3823,9734,1974,5424,733

0

2,500

5,000

1995 1996 1997 1998 1999 2000 2001 2002

Fiscal year

Number

Export certificates issued
38 

CDER 2002 Report to the Nation 

3 

INTERNATIONAL

ACTIVITIES

Highlights from 2002 include: 

 Completing the electronic Common Technical Document. 

 Publishing seven ICH documents. 

International Conference on 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 has worked to bring 

together government regulators and drug industry experts from innovator 

trade associations in the European Union, Japan and the United States. 

We are leading the FDA’s collaboration with the ICH. This work will help 

make 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. 

Harmonization initiative in the Americas 

We are working with the Pan American Health Organization to promote 

regulatory harmonization within the Americas. PAHO is part of the United 

Nations system, serving as the World Health Organization’s regional office 

for the Americas. The initiative, called the Pan American Network for Drug 

Regulatory Harmonization or PANDRH, will search for common ground 

on various topics in a prioritized work plan. 

We are the lead for two topics of high priority—good manufacturing 

practices and bioequivalence. We are working with the countries of Latin 

America to provide training on these two important issues. Training to the 

same standards should help lead to harmonization. Other urgent issues are 

good clinical practices and counterfeit drugs. 

Mission 

We participate through 

appropriate processes 

with representatives of 

other countries to 

reduce the burden of 

regulation, harmonize 

regulatory 

requirements and 

achieve appropriate 

reciprocal 

arrangements. 

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. 

Last year, we 

completed work on 

making the document 

suitable for electronic 

submission. 

ICH guidance 

documents 

Last year we published 

seven ICH guidance 

documents. 

As of April 30, 2003, we 

had published 45 final 

documents and eight 

drafts. 
39 

Improving Public Health Through Human Drugs 

U.S.-European Union Mutual Recognition Agreement 

This agreement would provide for reciprocal reliance on inspection 

systems in the United States and each of the 15 member nations of the 

European Union. The globalization of the pharmaceutical industry is 

outpacing our resources to inspect pharmaceutical manufacturing plants 

worldwide. Once fully implemented, the agreement would allow us to base 

our regulatory decisions on inspection data from “equivalent authorities” in 

the European Union. Equivalent authorities are those with regulatory 

systems for good manufacturing practices that we have assessed and 

determined will achieve a comparable level of public health protection. 

While the agreement would allow us to use an inspection report from one 

of our European counterparts as though it were our own, the actual 

regulatory decision would be up to us. Our experts in good manufacturing 

practices are leading the FDA team that is working with a team from the 

European Union to implement this agreement. 

A planned three-year transition to full implementation has ended, and two 

important issues remain to be resolved: 

 The European Union says it will not proceed until we provide a 

complete schedule for assessment of all of the member state authorities. 

 We want assurance of being able to exchange information with 

regulators as they are found equivalent, rather than waiting for all of 

them to be done as the European Union has wanted. 

Internet sources 

 More information 

about our international 

activities, including 

Spanish language 

materials, is at http://

www.fda.gov/cder/

audiences/iact/iachome.

htm.

 We have published 

ICH documents as 

guidances to industry. 

These are on our Web 

site at http://www.fda.

gov/cder/guidance/

index.htm.

 PAHO information 

is at http://www.paho.

org. Information on 

PANDRH is at http://

www.paho.org/english/

gov/cd/cd42_13-e.pdf.

 The Mutual 

Recognition Agreement 

is at http://www.mac.

doc.gov/mra/mra.htm.

MRA update 

 This past year we 

proposed a joint 

procedure providing 

for the exchange of 

inspection reports and 

provided an assessment 

of the progress made in 

exchanging certain 

product quality 

information. These 

issues were provided 

for review to the 

European Union. 

 Our audit team 

prepared to visit the 

second member state 

after substantially 

completing the first, 

but the assessment was 

put on hold by the 

European Union. 

 The European 

Union has not resumed 

their assessment of our 

system. 

Module 1 

Administrative 

and prescribing 

information 

(not harmonized) 

Module 2 

Nonclinical 

overview 

Nonclinical 

summary 

Clinical 

overview 

Modular Structure of Common Technical Document 

Clinical 

summary 

Module 4 

Nonclinical 

study reports 

Module 3 

Quality 

data 

Module 5 

Clinical 

study reports 

Quality 

overall 

summary 
40 

CDER 2002 Report to the Nation 

4 

COMMUNICATIONS

Highlights from 2002 include: 

 Meeting almost weekly with outside experts on difficult scientific and 

public health issues. 

 Responding to more than 73,000 individual requests for information. 

 Receiving nearly 9 million visits and more than 163 million hits on our 

Internet information site, which has 50,000 pages and documents, five 

databases and 250,000 hyperlinks. 

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. 

Risk management public hearing. We received valuable input about our 

ongoing efforts to improve our risk communication and to develop new and 

effective risk management tools. The purposes of the hearing were to: 

 Obtain public input into improving risk management for prescription 

drugs. 

 Identify stakeholders for future collaboration on risk management. 

 Improve our understanding of existing risk management tools. 

 Guide improvements in and creation of new tools 

 Explore assessment strategies. 

Workshops 

 New approach to plant inspections: Systems inspections. To provide the 

widest possible industry access, this workshop was held in three 

locations.

 Pediatric oncology drug development. We obtained public input on 

various aspects of developing drugs to treat cancer in children, 

including prioritization of new and emerging agents, clinical trial design 

and access to new therapies. 

 Scientific workshops. We held technical workshops to help identify 

scientific and regulatory issues in such fields as antimicrobial 

resistance, pharmacogenomics and pharmacogenetics, and drug 

substance and product specification. 

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 

Mission 

Carry out our 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. 

Internet updates 

We have 44,000 

subscribers to our 

service that provides 

daily and weekly e-mail 

updates of new content 

on our Web site. 

To subscribe, visit 

http://www.fda.gov/

cder/cdernew/listserv.

html.
41 

Improving Public Health Through Human Drugs 

Consumer and industry outreach 

 Regulations. We published seven final regulations, and we sought 

public comment on another three proposed regulations. 

 Guidances. We published 11 guidances for industry that explain our 

position on best practices in scientific and technical areas. We 

published another 19 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 23 documents last year. 

 Trade press. We responded to about 2,400 telephone and e-mail 

requests from the specialized press covering the pharmaceutical 

industry. 

 Exhibits. We exhibited at 19 conferences, reaching an estimated 

audience of more than 111,000 consumers, educators and health care 

professionals. 

 Videoconferencing. We held about 100 domestic and foreign 

videoconferences for academia, industry and associations. 

 CDER Live! We produced two satellite television broadcasts and Web 

transmissions for a largely pharmaceutical audience estimated at over 

5,000 viewers. The first program dealt with managing the risks of 

medicines, and the second highlighted new provisions in PDUFA III. 

Both programs featured our own and industry experts. 

 Drug reviews on Internet. Our Internet site now contains our reviews of 

more than 200 approved new drugs or new uses for approved drugs. 

 Freedom of Information requests. We responded to nearly 5,000 

requests under the Freedom of Information Act. 

 General information requests. We answered more than 32,000 

telephone inquiries, 23,000 e-mails and 5,000 letters from consumers, 

health professionals and industry. We responded to 5,800 requests for 

documents and guidance publications. 

Ombudsman’s 

activity 

In its seventh year, our 

ombudsman provided 

informal dispute 

resolution for both 

regulated industry and 

our own employees. 

He provided 

information and 

guidance to industry, 

health professionals 

and consumers. 

He helped management 

identify better ways of 

conducting business. 

Lastly, he represented 

us in product 

jurisdiction issues 

submitted to FDA’s 

Ombudsman’s Office. 

This has been a 

particularly active area 

with the development 

of novel medical 

products. 

Public education 

programs 

 Benefits vs. risks of 

medication use 

 Buying drugs from 

outside the United 

States 

 Buying prescription 

drugs online 

 Drug interactions 

 Generic drug 

quality 

 Medical gas safety 

 Misuse of 

prescription pain 

relievers 

 Over-the-counter 

medicine labels 

 Pregnancy and drug 

use 

 Proper drug dosing 

for children 

Many of these are 

available on the 

Internet at http://www.

fda.gov/cder/

consumerinfo/

DPAdefaultht.htm.

Average Monthly Use of CDER Internet Site

156 226 406 549 750 32 72

13.5

9.3

6.7

2.5 3.1

1.3 0.5

0

500

1,000

1996 1997 1998 1999 2000 2001 2002

Calendar year

Visitors (thousands)

0

8

16

Hits (millions)

Visitors (thousands) Hits (millions)
42 

CDER 2002 Report to the Nation 

Where to Find More Information 

We support multiple ways to obtain information about drug products and 

the laws, regulations and guidances concerning them. 

Selected Internet sites 

 FDA Internet home page: http://www.fda.gov/

 CDER Internet home page: http://www.fda.gov/cder/

 CDER’s consumer drug information sheets for new medicines approved 

since January 1998: 

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

 From Test Tube to Patient: New Drug Development in the United 

States: http://www.fda.gov/fdac/special/newdrug/ndd_toc.html

 CDER organizational charts: http://www.fda.gov/cder/cderorg.htm

 CDER key officials: http://www.fda.gov/cder/directories/keyoffic.pdf

Telephone 

We respond to specific questions about prescription, over-the-counter and 

generic drugs for human use. You can telephone us toll free at 

1-888-INFO FDA or directly at 301-827-4573. 

E-mail 

We can be contacted at druginfo@cder.fda.gov.

Regular mail 

U.S. Food and Drug Administration 

Center for Drug Evaluation and Research 

Drug Information Division 

HFD-240, Room 12B-05 

5600 Fishers Lane 

Rockville, MD 20857 
43 

Improving Public Health Through Human Drugs 

Organizational Structure of the Center for Drug Evaluation and Research 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Center Director 

 Director 

 Deputy Director 

 Controlled Substances Staff 

 Associate Director for Policy 

 EEO/Recruitment Staff 

Office of Executive Programs 

 Executive Operations Staff 

 Review Standards Staff 

 Advisors & Consultants Staff 

 International Program 

 Information Management Program 

 Ombudsman 

Office of Medical Policy 

 Div. of Scientific Investigations 

 Div. of Drug Marketing Advertising 

& Communications 

Office of New Drugs

 Pharmacology/Toxicology Staff 

 Program Management Team 

 Study Endpoints & Labeling Team 

 Pregnancy Labeling Team 

 Guidance Policy Team 

 Regulatory Affairs Team 

Office of Pharmacoepidemiology 

& Statistical Science 

Office of Pharmaceutical Science 

 Informatic Computation Safety Analysis 

Staff 

 Quality Implementation Staff 

 Operation Staff 

 Microbiology Team 

Office of Counter-Terrorism & 

Pediatric Drug Development 

 Div. of Pediatric Drug Dev. 

 Div. of Counter-Terrorism 

Office of Drug Evaluation I 

 Div. of Neuropharmacological 

Drug Products 

 Div. of Oncology Drug Products 

 Div. of Cardio-Renal Drug 

Products 

Office of Drug Evaluation II 

 Div. of Pulmonary Drug Products 

 Div. of Metabolic & Endocrine 

Drug Products 

 Div. of Anesthetic, Critical Care 

& Addiction Drug Products 

Office of Drug Evaluation III 

 Div. of GastroIntestinal 

& Coagulation Drug Products 

 Div. of Reproductive & Urologic 

Drug Products 

 Div. of Medical Imaging 

& Radiopharmaceutical Drug 

Products 

Office of Drug Evaluation IV 

 Div. of Anti-Infective Drug 

Products 

 Div. of Anti-Viral Drug Products 

 Div. of Special Pathogen & 

Immunologic Drug Products 

Office of Drug Evaluation V 

 Botanical Review Team 

 Div. of Anti-Inflammatory, 

Analgesic, & Ophthalmologic 

Drug Products 

 Div. of Dermatologic & Dental 

Drug Products 

 Div. of Over-the-Counter Drug 

Products 

Office of Drug Safety 

 Div. of Surveillance, Research 

& Comm. Support 

 Div. of Medication Errors 

& Tech. Support 

 Div. of Drug Risk Evaluation 

Office of Biostatistics 

 Quantitative Methods 

& Research Staff 

 Div. of Biometrics I 

 Div. of Biometrics II 

 Div. of Biometrics III 

Office of Information 

Technology 

 Quality Assurance Staff 

 Technology Support Services 

Staff 

 Div. of Data Management & 

Services 

 Div. of Infrastructure Management 

& Services 

 Div. of Applications Development 

Services 

Office of Regulatory Policy 

 Div. of Regulatory Policy I 

 Div. of Regulatory Policy II 

 Div. of Information Disclosure 

Policy 

Office of Management 

 Div. of Management & Budget 

 Div. of Management Services 

Office of Training 

& Communications 

 Div. of Training & Development 

 Div. of Drug Information 

 Div. of Public Affairs 

 Div. of Library & Info. Services 

Office of Compliance 

 Div. of New Drugs & Labeling 

Compliance 

 Div. of Manufacturing & Product 

Quality 

 Div. of Compliance Risk Mgmt. 

& Surveillance 

Office of Testing & Research 

 Laboratory of Clinical Pharmacology 

 Div. of Applied Pharmacology 

Research 

 Div. of Pharmaceutical Analysis 

 Div. of Product Quality Research 

Office of New Drug Chemistry 

 Div. of New Drug Chemistry I 

 Div. of New Drug Chemistry II 

 Div. of New Drug Chemistry III 

Office of Clinical Pharm. 

& Biopharmaceutics 

 Div. of Pharmaceutical Evaluation I 

 Div. of Pharmaceutical Evaluation II 

 Div. of Pharmaceutical Evaluation III 

Office of Generic Drugs 

 Div. of Chemistry I 

 Div. of Chemistry II 

 Div. of Bioequivalence 

 Div. of Labeling & Program Support 

1-888-INFO FDA 

5/5/03 

American Consumers 
44 

CDER 2002 Report to the Nation 

U.S. Department of Health and Human Services

Food and Drug Administration 

Center for Drug Evaluation and Research