45 

Improving Public Health Through Human Drugs 

Center for Drug Evaluation and Research 2001

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 2001 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/2001/rtn2001.pdf

 HTML: http://www.fda.gov/cder/reports/rtn/2001/rtn2001.htm

 Slides: http://www.fda.gov/cder/reports/rtn/2001/rtn2001.ppt

Suggested citation: Food and Drug Administration. CDER 2001 Report to 

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

Maryland, 2002. 
47 

Improving Public Health Through Human Drugs 

CONTENTS

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

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

2000 HIGHLIGHTS ....................................................................... 3 

 Counterterrorism ................................................................. 4 

 Scientific Research ............................................................. 6 

1 DRUG REVIEW ........................................................................ 7 

 New Drug Review .............................................................. 8 

 New or Expanded Use Review ......................................... 14 

 Pediatric Exclusivity ......................................................... 15 

 Over-the-Counter Drug Review ........................................ 17 

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

 User Fee Program ............................................................. 20 

 Manufacturing Supplement Review ................................. 21 

 Electronic Submissions ..................................................... 22 

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

 Drug Review Team ........................................................... 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 Promotion Review ................................................... 30 

 Drug Recalls and Withdrawals ......................................... 32 

 Drug Product Quality ........................................................ 33 

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

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

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

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

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

i 
48 

CDER 2001 Report to the Nation 

Graphs and Charts 

Standard New Drugs .................................................................... 8 

Priority New Drugs ...................................................................... 9 

Standard New Molecular Entities .............................................. 10 

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

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

Over-the-Counter Drugs ............................................................ 17 

Generic Drugs ............................................................................ 19 

Manufacturing Supplements ...................................................... 21 

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

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

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

Drug Promotion Review ............................................................ 31 

Drug Recalls .............................................................................. 32 

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

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: 

 Provide rapid access to new therapies while maintaining rigorous safety and 

effectiveness standards. 

 Listen to the voices of consumers, patients and health care professionals as 

well as those of regulated industry. 

 Match the effort in premarket evaluation with a vigorous postmarket 

monitoring program. 

 Make sure we support the people in CDER as well as serving the outside 

world. 

However, routine operations were not the hallmark of a year that witnessed the 

terrorist attacks on and after Sept. 11. The brutal assaults challenged us to rise to 

the defense of the American consumers. In close cooperation with other 

authorities, we responded with our traditional vigor, initiative and scientific 

expertise. 

We developed strategies to strengthen the protection of drug products against 

willful contamination and to improve the availability of drugs for the prevention 

or treatment of injuries caused by biological, chemical or nuclear agents. 

For example, we took the initiative to publish a notice that the antibiotics 

doxycycline and penicillin G procaine are safe and effective for the postexposure prevention of inhalational anthrax. This notice included explicit dosing 

based on our review of scientific literature and data from the same rhesus 

monkey study that had been used to support our August 2000 approval of 

ciprofloxacin for post-exposure prevention of inhalational anthrax. The assurance 

that the three drugs are safe and effective for this use eased public concerns about 

a potential shortage of medication for the victims of the mailed anthrax powder. 

We also stepped up our work on measures to encourage the development of new 

drugs to counter the toxic effects of chemical, biological, radiological and 

nuclear weapons. 

In addition to doing our part in protecting Americans against terrorism, we 

evaluated many new drugs that advanced the frontier of modern medicine. For 

example, we approved a new drug to treat a rare form of life-threatening cancer 

in two and one-half months. We are continuing to develop science-based data on 

safety and dosing regimens for drugs to treat children. 

Once again, we met all of the demanding application review goals of the 

Prescription Drug User Fee Act, but we have encountered challenges. Our efforts 

to meet goals for drug development may have had an unintended impact on 

approval times for standard applications. These approval times have begun to 

increase because more applications require multiple review cycles to reach 

approval. We are watching trends closely. 
50 

CDER 2001 Report to the Nation 

iv 

Our generic drug program is providing a steady supply of more affordable drugs 

that meet our uniform and stringent standards for safety, effectiveness and 

quality. We are developing an education program to bolster consumer confidence 

in generic drugs. 

We continued to enhance our drug safety program. In recent years fully 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. More rigorous safety monitoring of newly 

approved drugs in the first few years on the market is key to detecting 

unanticipated problems earlier. We have entered into several agreements that will 

give us access to data about the actual use of prescription drugs by children and 

adults. This will augment our ability to determine the significance of adverse 

events we receive. We will have the benefit of advice about general and productspecific safety issues from a new panel of experts in areas related to risk 

perception and management, pharmacology and other related disciplines. 

We launched an important initiative to build the scientific data needed to 

modernize American drug manufacturing. While Americans have the highest 

quality of drugs in the world, the process used to produce them can be expensive 

and wasteful. We have observed an increasing trend toward manufacturingrelated problems, such as recalls, disruptions of manufacturing operations and the 

loss of availability of essential drugs. Modern technology holds the promise of 

manufacturing to the same or higher quality standards while reducing the 

workload for industry and for us and ensuring the highest quality drug products 

for American consumers. 

We are making strenuous efforts to come to grips with the reality of globalization 

in the marketplace. Cornerstones of our efforts are the International Conference 

on Harmonization, the Mutual Recognition Agreement with the European Union, 

and building relationships with the international regulatory community. We have 

begun work to promote harmonization within the Americas. 

An urgent priority for us is improving our communications. Information is a key 

element in the safe and effective use of drugs. We are collaborating and 

leveraging with a broad spectrum of groups to improve information for 

prescribers and consumers. 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. 

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 for safe and effective use. 

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 doesn’t stop. 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 

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 2001 Report to the Nation 

about suspected problems from manufacturers, health care professionals 

and consumers. Sometimes, manufacturers run into production problems 

that might endanger the health 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 

2001 HIGHLIGHTS

We are pleased to present our sixth 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. 

In the wake of the terrorist attacks, our nation was prepared with an 

antibiotic approved to treat inhalational anthrax. We had worked on this 

program for several years and reported on the approval in last year’s 

report. We were rapidly able to provide health professionals with 

additional guidance on using other safe and effective medicines. 

Drug review 

People with cancer, heart disease, HIV, AIDS, and other serious conditions 

have benefited from our approvals in 2001. We met our obligations to 

Congress for prompt and thorough review of drug applications supported 

by user fees. Our reviews of generic drugs have been prompt and 

predictable. 

We approved 66 new drugs, including 24 new molecular entities. New 

molecular entities contain an active substance never before approved for 

marketing in any form in the United States. We also approved 91 new or 

expanded uses of already approved drugs. We increased choices for selfcare by approving six medicines for over-the-counter marketing and one 

new or expanded use for an existing over-the-counter drug. We approved 

234 generic equivalents for prescription or over-the-counter drugs. 

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 more rapidly 

and take corrective action more quickly. We augmented our riskassessment ability by gaining access to actual use data. We will be able to 

consult with a new expert panel of advisors. 

Last year, we processed and evaluated more than 280,000 adverse drug 

events. We issued nearly 900 letters to help ensure that the promotion of 

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

misleading. We mandated that three drug products be dispensed with 

specific consumer information that will help ensure the products are used 

safely and effectively. Our review of the safety profile of one approved 

drug resulted in its voluntary withdrawal, and the manufacturer of another 

drug withdrew it after reviewing safety reports. 

Communications 

We met almost weekly 

with outside experts on 

difficult scientific and 

public health issues. 

We held two week-long 

introductory 

workshops for our 

stakeholders. 

We responded to more 

than 52,000 individual 

requests for 

information. 

Each month, our 

Internet information 

site averaged nearly 

550,000 visitors and 10 

million hits. 

We developed public 

education campaigns 

in areas such as risk 

management and 

buying prescription 

drugs over the 

Internet. 

Realignment 

We began the new year 

with a revised 

structure aimed at 

aligning similar 

functions and creating 

smaller, more 

manageable work 

units. 

Our organizational 

charts are at http://

www.fda.gov/cder/

cderorg.htm.
4 

CDER 2001 Report to the Nation 

Counterterrorism 

The terrorist attacks of Sept. 11, 2001, and the subsequent anthrax 

contamination of the mail underscored our role in: 

 Protecting the nation’s drug supply from attack or deliberate 

contamination. 

 Assuring the availability of medicines to treat victims of terrorist and 

bioterrorist attacks. 

 Preparing ourselves to continue operations during a crisis. 

The first therapy for those exposed to a terrorist attack or a biological 

warfare agent is often a drug. We have been taking an aggressive and 

proactive approach to getting antibioterrorism treatment information into 

the labeling of already approved drugs. We approved the first such drug, 

ciprofloxacin, in 2000 for treating inhalational anthrax. 

The Sept. 11 terrorist attacks and the subsequent anthrax attacks have 

vaulted this work and other actions to protect public health and safety to 

our top priority. 

On Sept. 11, we continued to communicate with the Centers for Disease 

Control and Prevention. By that night, the CDC had submitted to us a 

“streamlined” investigational new drug application that would allow 

government physicians to prescribe the antibiotic gentamicin for the 

treatment of pneumonic plague in the event of a bioterrorist attack. 

In November, in response to concerns about a potential nuclear event, we 

finalized our guidance on potassium iodide, or KI, as an agent to protect 

the thyroid gland in radiation exposure emergencies. 

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 began accepting the first new drug applications in 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. 

We are collaborating on prioritizing issues for our harmonization efforts 

among the countries of North and South America. We are leading the U.S. 

consultations with the European Union to allow for reciprocal reliance on 

manufacturing plant inspections. Last year we began exchanging recall 

information and alerts concerning significant emerging product quality 

problems with the European Union. 

The animal 

efficacy rule 

We are preparing a 

final regulation to 

implement our 1998 

proposal, commonly 

called “the animal 

efficacy rule.” The rule 

would permit us to rely 

on animal evidence 

when a bioterrorism 

agent’s mechanism of 

toxicity is well 

understood in humans; 

the efficacy endpoints 

in the animal trials are 

clearly related to 

benefit in humans; the 

drug’s effect is 

demonstrated in a 

species expected to 

react similarly to 

humans; and data 

allow selection of an 

effective human dose. 

Such approvals could 

include possible 

postmarketing studies 

when feasible and 

ethical, possible 

restrictions on 

distribution and a 

requirement that 

information about the 

basis of approval be 

provided to patients. 
5 

Improving Public Health Through Human Drugs 

Ciprofloxacin 

for anthrax 

We recognized several 

years ago that no drugs 

were specifically 

labeled for the 

treatment or postexposure prevention of 

inhalational anthrax. 

We worked on 

ciprofloxacin first, 

based on expert 

assessment that 

anthrax was the most 

likely biological agent. 

We also feared that 

anthrax might be 

modified to be 

resistant to older 

antibiotics with an 

anthrax indication. 

Ciprofloxacin has an 

enormous safety 

database. It has been 

used for more than 14 

years with more than 

100 million 

prescriptions in the 

United States and 250 

million worldwide—

more than 4 million of 

those for children. 

We knew we could get 

similar drug levels in 

humans to the blood 

levels in the monkeys 

that the U.S. Army had 

exposed to anthrax. 

We initiated the 

identification and 

collection of the data. 

The sponsor then 

submitted a 

supplemental 

application, which we 

approved. 

Immediate response to the anthrax crisis 

 Published new labeling information for doxycycline and procaine 

penicillin in post-exposure management to prevent the development of 

inhalational anthrax. 

 Issued a public health advisory on the use of doxycycline for anthrax 

exposure. 

 Coordinated with other agencies to halt the importation of unapproved 

ciprofloxacin. 

 Posted information on antibiotic use for anthrax on the Internet. 

Ongoing and long-term counterterrorism work 

 Coordinating with the Department of Defense to develop an 

appropriate animal model to study whether available antibiotics, which 

aren’t labeled for pneumonic plague, are effective in the treatment of 

this highly contagious lung disease. 

 Cooperating with the National Institutes of Health, CDC, DOD and 

sponsors from industry to facilitate development of both investigational 

new drug applications and new uses for already approved drugs that 

could be used as medical countermeasures to a terrorist attack with 

agents such as smallpox and plague. 

 Assisting the CDC to obtain follow-up drug safety and outcome 

information for patients treated with antibiotics during the anthrax postexposure prophylaxis campaign. 

 Expediting work on a final regulation that would allow us to rely on 

animal studies and supporting data to approve drugs for bioterrorism 

agents when clinical studies in humans would be unethical. 

 Assisting the CDC in managing the National Pharmaceutical Stockpile. 

 Coordinating with FDA’s field inspectors and manufacturers to help 

evaluate and resolve any manufacturing concerns that might arise 

during emergency production. 

 Expediting reviews and inspections for manufacturing supplements that 

may be required for expanded drug production. 

 Working with CDC, DOD and the Department of Veterans Affairs to 

implement a shelf-life extension program for stockpiled drugs for 

civilian and military use. 

 Gathering and maintaining information on drugs that might be effective 

in an attack, including data on manufacturers, bulk suppliers, 

inventories and lead times for production. 

Internet resources 

To help prepare our 

nation for possible 

bioterrorism attacks, 

we are working with 

other federal agencies 

to make sure adequate 

supplies of medicines 

are available to the 

American public. 

Our Internet site provides links to the most 

current information on 

drug therapy, including information on special populations such 

as children and pregnant women, plus advice on purchasing and 

taking medication. You 

can find it at http://

www.fda.gov/cder/

drugprepare/default.

htm.
6 

CDER 2001 Report to the Nation 

Leveraging 

scientific 

resources 

The Product Quality 

Research Institute is a 

unique and innovative 

collaboration among 

our scientists and 

those from academia 

and industry. PQRI 

conducts research to 

establish better 

testing methods, 

standards and 

controls for assessing 

product quality and 

manufacturing and 

management 

processes (PQRI 

update, page 36).

The institute’s 

research will help us 

develop consistent 

and reasonable 

requirements for 

product quality 

information in 

regulatory 

submissions. 

Leveraging scientific 

expertise in this way 

contributes to 

streamlining the drug 

development and 

approval processes 

for industry and 

ourselves while 

ensuring the highest 

level of product 

quality for American 

consumers. 

Scientific Research 

We advance the scientific basis of regulatory practice by developing and 

evaluating new scientific methods and 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 

linkage between nonclinical and clinical studies, enhancing the 

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 

 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, blood vessels, kidney, immune system and liver. 

 Identifying cellular and tissue biomarkers predictive of safety and 

efficacy, through DNA microarrays and noninvasive imaging. The use 

of these novel technologies enables evaluations of their strengths and 

limitations for practical applications that could improve the interface 

between drug development and regulatory practice. 

 Elucidating the molecular mechanisms operating in transgenic mice to 

ensure the appropriate use of more rapid and reliable tests that will 

detect the cancer-causing potential of drugs. 

 Developing experimental models for detecting early signals of damage 

in liver cells. This will facilitate understanding why certain types of 

drugs cause liver damage. 

Clinical Pharmacology 

 Results from St. John’s Wort interaction studies demonstrated that this 

herb could reduce the effectiveness of some prescription drugs. The 

results also provided the scientific basis for our recommendation to 

FDA’s Center for Food Safety and Applied Nutrition and the Federal 

Trade Commission on the labeling of St. John’s Wort products. 

 Results from studies on the metabolism of hormone replacement 

therapy provided critical information for labeling these products and 

drugs that will be co-administered with them. 

 We evaluated the stability and palatability of ground and dissolved 

antibiotic tablets for use in children in a bioterrorism emergency. 

 Noninvasive imaging is an emerging technology increasingly used drug 

development. We are using this tool to extend our long-standing 

interest in the application of dose-concentration-response principles for 

regulatory decision-making by viewing drugs and their actions directly 

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

concentrations and/or downstream indicators of target modulation. 

Studies of drugs 

that affect 

metabolic 

enzymes 

We carefully monitor 

the inhibition of drug 

metabolism in both our 

research and review 

programs. 

Clarithromycin is an 

example of drugs that 

have mechanism-based 

effects on metabolic 

enzymes. 

These often cause 

longer-lasting drug 

interactions and have 

resulted in serious 

adverse events when 

additional drugs are 

prescribed. 

Data on and an 

understanding of the 

effect and the timecourse of mechanismbased inhibitors is 

critical for providing 

accurate dosing 

information when new 

drugs are coadministered with 

these agents. 
7 

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 their generic 

equivalents. 

We met or exceeded all the performance goals we agreed to under 

legislation authorizing us to collect user fees for drug reviews. 

We approved 24 new medicines that have never been marketed before in 

this country and 234 generic versions of existing drugs. We authorized 

seven medicines to be sold over the counter without a prescription. 

We conducted 463 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: 

 Two new drugs to treat cancer. 

 Four drugs to treat heart disease and circulatory disorders. 

 The first in a new class of drugs approved to treat HIV infection. 

 One new drug for Alzheimer’s disease. 

 One new drug for schizophrenia. 

 Two new prescription drugs for migraine headaches. 

 One new COX-2 selective anti-inflammatory drug for arthritis and 

menstrual cramping. 

 The first in a new class of antifungals. 

 A synthetic drug to prevent blood clots that is the first in a new class. 

 Two new drugs to treat glaucoma, a leading cause of blindness. 

 Three new or expanded uses to treat breast cancer. 

 New shorter dosing regimens of an over-the-counter treatment for 

vaginal yeast infections. 

 A new over-the-counter use for aspirin to treat migraine. 

 Three new drugs and three new or expanded uses of existing drugs for 

“orphan” patient populations of 200,000 or fewer. 

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 2001 

 66 new drugs 

 24 new 

molecular entities 

 3 orphan new drugs 

 91 new or expanded 

uses for already 

approved drugs 

 3 orphan new or 

expanded uses 

 6 over-the-counter 

drugs or Rx-to OTC 

switches 

 1 new or expanded 

use for an over-thecounter drug 

 234 generic 

equivalents 

for prescription 

and over-the counter 

drugs 
8 

CDER 2001 Report to the Nation 

Standard NDA Approvals

Median times, approvals

16.218.715.117.814.715.012.012.012.013.812.012.012.014.0

67

102 101

65

55

78

56

0

12

24

1995 1996 1997 1998 1999 2000 2001

Calendar year

Months

0

60

120

Approvals

Median FDA review time Median total approval time Number approved

New Drug Review 

Standard new drugs. We took 143 actions on standard new drug 

applications, of which 56 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. 

Priority new drugs. We took 27 actions on priority new drug applications, 

of which 10 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. 

New molecular entities. Twenty-four 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. 

Orphan drugs 

We approved three 

“orphan” products to 

treat disorders with 

patient populations of 

200,000 or fewer: 

 Bosentan (Tracleer) 

treats pulmonary 

arterial hypertension. 

 Imatinib mesylate 

(Gleevec) treats 

chronic myeloid 

leukemia. 

 Zoledronic acid 

(Zometa) treats excess 

calcium in the blood 

caused by tumors. 

Standard NDAs

Actions, filings*, approval percentages

185922259020092153871471011978714391

51%

36% 45% 42% 37% 40% 39%

0

150

300

1995 1996 1997 1998 1999 2000 2001

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 new 

drugs 

 56 approvals 

 Median review 

time: 12.0 months 

 Median approval 

time: 14.0 months 

 143 actions 

 91 filings 
9 

Improving Public Health Through Human Drugs 

Priority new drugs 

(N=NME)

Bimatoprost 

(Lumigan) (N) 

Budesonide (Entocort 

EC) 

Caspofungin acetate 

(Cancidas) (N) 

Fondaparinux sodium 

(Arixtra) (N) 

Imatinib mesylate 

(Gleevec) (N) 

Mesalamine (Canasa) 

Tenofovir disoproxil 

fumarate (Viread) (N) 

Travoprost (Travatan) 

(N) 

Valganciclovir 

hydrochloride 

(Valcyte) 

Zoledronic acid 

(Zometa) (N) 

Priority NDA Approvals

Median times, approvals

6.06.07.87.86.26.46.26.46.16.16.06.06.06.0

29 20 28

10

20

15 25

0

12

24

1995 1996 1997 1998 1999 2000 2001

Calendar Year

Months

0

15

30

Approvals

Median FDA review time Median total approval time Number approved

Priority NDAs

Actions, filings*, approval percentages

312444263532462743314121276

57%

37%

49% 65% 54%

66% 48%

0

25

50

1995 1996 1997 1998 1999 2000 2001

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

Orphan drugs. Three 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. 

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. 

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. 

Priority new drugs 

 10 approvals 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 27 actions 

 6 filings 
10 

CDER 2001 Report to the Nation 

Notable 2001 new drug approvals 

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

disease and other disorders. 

People with cancer 

One of our most important approvals last year was for imatinib mesylate 

(Gleevec), a new oral treatment for patients with chronic myeloid leukemia, 

a rare life-threatening form of cancer. We reviewed the application for the 

drug in two and one-half months and approved it under a special procedure 

that permits the marketing of important therapies on the basis of their effect 

on surrogate markers. The sponsor is committed to carry out additional 

studies demonstrating the drug’s long-term safety and effectiveness. The 

drug was developed for use in a U.S. patient population of fewer than 

200,000 and was, therefore, designated an orphan drug. 

Zoledronic acid (Zometa) is an intravenous bisphonsphonate for the 

treatment of hypercalcemia of malignancy, the most common lifethreatening metabolic complication associated with cancer. This 

complication, which is characterized by elevated serum calcium levels, 

Standard NME Approvals

Median times, approvals

15.917.814.615.114.415.012.313.414.016.315.419.915.719.0

18 17 30

19

35

14

16

0.0

12.0

24.0

1995 1996 1997 1998 1999 2000 2001

Calendar Year

Months

0

20

40

Number

Median FDA review time Median total approval time Number approved

Standard NMEs

Filings*

34292428221526

0

20

40

1995 1996 1997 1998 1999 2000 2001

Calendar year

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

Number

Filings

New molecular 

entities 

Almotriptan malate 

(Axert) 

Bimatoprost 

(Lumigan) 

Bosentan (Tracleer) 

Caspofungin acetate 

(Cancidas) 

Cefditoren pivoxil 

(Spectracef) 

Desloratadine 

(Clarinex) 

Drospirenone/ethinyl 

estradiol (Yasmin) 

Dutasteride 

(Dutasteride) 

Ertapenem sodium 

(Invanz) 

Etonogestrel/ethinyl 

estradiol (NuvaRing) 

Fondaparinux sodium 

(Arixtra) 

Formoterol fumarate 

(Foradil Aerolizer) 

Standard NME 

statistics 

 17 approvals 

 Median review 

time: 15.7 months 

 Median approval 

time: 19.0 months 

 26 filings 
11 

Improving Public Health Through Human Drugs 

affects more than 10 percent of all cancer patients and generally occurs late 

in the course of the disease. 

People with heart and circulatory disease 

One new approval last year for cardiac patients is nesiritide (Natrecor) for 

the treatment of acute decompensated congestive heart failure. The drug, 

which was developed with the use of recombinant DNA technology, is a 

synthetic version of a human hormone that dilates veins and arteries. 

Perflutren lipid microsphere (Definity) is an ultrasound contrast agent for 

use with suboptimal echocardiograms. It increases the power of heart 

ultrasounds and may provide earlier and more definitive diagnoses for 

millions of difficult-to-image patients at risk for heart disease. The drug is 

the first and only ultrasound contrast agent in the United States that is nonblood derived, eliminating the risks and concerns associated with the use of 

blood-based products. 

Priority NME Approvals

Median times, approvals

6.06.07.79.66.46.76.26.26.36.96.06.06.06.0

7

9 9 9

18 16

19

0.0

12.0

24.0

1995 1996 1997 1998 1999 2000 2001

Calendar year

Months

0

10

20

Approvals

Median FDA review time Median total approval time Number approved

Priority NMEs

Filings*

1616181516154

0

12

24

1995 1996 1997 1998 1999 2000 2001

Calendar year

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

Number

Filings

Frovatriptan succinate 

(Frova) 

Galantamine 

hydrobromide 

(Reminyl) 

Imatinib mesylate 

(Gleevec) 

Nesiritide (Natrecor) 

Norelgestromin/ethinyl 

estradiol (Ortho Evra) 

Perflutren lipid 

microsphere (Definity) 

Pimecrolimus (Elidel) 

Tenofovir disoproxil 

fumarate (Viread) 

Travoprost (Travatan) 

Valdecoxib (Bextra) 

Ziprasidone 

hydrochloride 

(Geodon) 

Zoledronic acid 

(Zometa) 

New molecular 

entities (continued) 

Priority NME 

statistics 

 7 approvals 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 4 filings 
12 

CDER 2001 Report to the Nation 

Men 

Dutasteride 

(Dutasteride) treats 

benign prostatic hyperplasia, a non-cancerous 

enlargement of the 

prostate gland, which 

can lead to the manifestation of lower urinary tract symptoms. 

The pathological 

changes of this disorder are found in about 

50 percent of men in 

their 50s and up to 90 

percent of men in 

their 90s. 

Fondaparinux sodium (Arixtra) is for the prophylaxis of deep-vein 

thrombosis, which may lead to pulmonary embolism after orthopedic 

surgery for hip fracture, hip replacement and knee replacement. The drug 

is a synthetic compound and the first in a new class of antithrombotic 

agents that selectively inhibit Factor Xa. 

Bosentan (Tracleer) is to improve exercise ability and decrease the rate of 

clinical worsening in patients with pulmonary arterial hypertension with 

significant limitation of physical activity. The drug is the first to be 

approved in a new class of drugs called endothelin receptor antagonists. 

The disease is a chronic, life-threatening disorder that can severely 

compromise the function of the lungs and heart. 

People with HIV and AIDS 

The first in a new class of drugs to combat HIV was approved, a oncedaily medication that blocks an enzyme involved in the replication of the 

disease. Tenofovir disoproxil fumarate (Viread) is for the treatment of HIV 

infection when taken in combination with other antiretroviral agents. The 

drug is the first nucleotide analogue reverse transcriptase inhibitor 

approved for the treatment of HIV. The drug works by blocking reverse 

transcriptase, an enzyme involved in the replication of HIV. As a 

nucleotide, the drug remains in cells longer than many other antiretroviral 

drugs, allowing for once-daily dosing. 

Valganciclovir hydrochloride (Valcyte) treats the eye infection 

cytomegalovirus retinitis in patients with AIDS. 

People with arthritis 

Valdecoxib (Bextra), a COX-2 specific inhibitor, is for treating the signs 

and symptoms of osteoarthritis, adult rheumatoid arthritis and the pain 

associated with menstrual cramping. 

People with glaucoma 

We approved two ophthalmic solutions for reducing elevated intraocular 

pressure in patients with open-angle glaucoma or ocular hypertension. 

Bimatoprost (Lumigan) and travoprost (Travatan) treat patients who are 

intolerant of, insufficiently responsive or inadequately controlled using 

other intraocular pressure-lowering medications. Glaucoma is a leading 

cause of preventable blindness. 

People with mental and neurological disorders 

Ziprasidone hydrochloride (Geodon) is for the treatment of schizophrenia, 

a life-long illness that strikes men and women in their late adolescence or 

early 20s, often with multiple relapses and impaired daily functioning. 

Galantamine hydrobromide (Reminyl) is for the treatment of mild to 

moderate Alzheimer’s disease. 

Notable 2001 new drug approvals (continued)
13 

Improving Public Health Through Human Drugs 

New drug 

statistics on 

Internet 

Other statistics are 

available on our Web 

site at http://www.fda.

gov/cder/rdmt/default.

htm.

We approved two drugs for the acute treatment of migraine with or without 

aura in adults: almotriptan malate (Axert) and frovatriptan succinate 

(Frova).

Infectious diseases 

Caspofungin acetate (Cancidas) is for the treatment of invasive 

aspergillosis in patients who are refractory to or intolerant of other 

therapies. The drug is the first in a new class of antifungals and works by 

attacking the fungal cell wall. Aspergillosis is a life-threatening fungal 

infection in high-risk patients, especially cancer patients, organ and bonemarrow transplant recipients, and patients with HIV/AIDS. 

Cefditoren pivoxil (Spectracef) is a cephalosporin antibiotic for the 

treatment of acute exacerbations of chronic bronchitis, pharyngitis/

tonsillitis and uncomplicated skin and skin structure infections in adults 

and children 12 years and older. 

Ertapenem sodium (Invanz) is a long-acting injectable antibiotic for 

treatment of adults with moderate to severe bacterial infections, including 

complicated intra-abdominal infections, complicated skin and skin 

structure infections, community-acquired pneumonia, complicated urinary 

tract infections and acute pelvic infections. 

People with respiratory diseases and allergies 

Formoterol fumarate (Foradil) is a fast-acting, long-lasting bronchodilator 

for the maintenance treatment of asthma and the prevention of 

bronchospasm in reversible obstructive airways disease. The drug provides 

both long-lasting symptom control and rapid bronchodilation from a single 

product. 

Desloratadine (Clarinex) treats nasal and non-nasal symptoms of seasonal 

allergic rhinitis in adults and children 12 years of age and older. The drug 

is a once-daily, nonsedating antihistamine. 

People with skin disease 

Pimecrolimus (Elidel) is the first non-steroid cream for mild to moderate 

atopic dermatitis in patients 2 years and older. Commonly known as 

eczema, atopic dermatitis is an itchy skin condition that primarily affects 

children and may last until the late teen-age years or even for life. 

People with gastrointestinal disorders 

Mesalamine (Canasa) is a suppository for the treatment of active ulcerative 

proctitis, an inflammation of the rectum. 

Budesonide (Entocort EC) treats mild to moderate active Crohn’s disease, 

an inflammatory disease, involving the ileum and/or ascending colon. 

Women 

We approved three 

contraceptives, 

including two that 

deliver continuous 

doses of the hormones 

progestin and estrogen 

in new ways to prevent 

pregnancy: 

 Etonogestrel/ethinyl 

estradiol (NuvaRing),

the first monthly 

vaginal ring for birth 

control, delivers the 

hormones through a 

flexible, transparent 

polymer ring inserted 

in the vagina. 

 Norelgestromin/

ethinyl estradiol (Ortho 

Evra), the first skin 

patch approved for 

birth control, releases 

the hormones through 

the skin into the blood 

stream and has to be 

changed each week. 

Both the ring and the 

patch have to be 

removed one week 

each month when the 

woman menstruates. 

We also approved a 

new low-dose oral 

contraceptive, 

drospirenone/ethinyl 

estradiol (Yasmin).

Notable 2001 new drug approvals (continued)
14 

CDER 2001 Report to the Nation 

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. When studying approved drugs in children 

(page 15), 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. 

Last year we took action on 213 applications for new or expanded uses of 

already approved drugs. We approved 91, including six that were given 

priority reviews of six months or less. Three of the approvals were for 

orphan uses in patient populations of 200,000 or fewer. 

Notable 2001 new or expanded use approvals 

We approved capecitabine (Xeloda) when used with docetaxel for the 

treatment of locally advanced or metastatic breast cancer after failure to 

respond to anthracycline-containing cancer therapy. The drug was also 

approved for first-line treatment of metastatic colorectal carcinoma when 

treatment with fluoropyrimidine therapy alone is preferred. 

Letrozole (Femara) is for first-line treatment of postmenopausal women 

with hormone receptor positive or hormone receptor unknown locally 

advanced or metastatic breast cancer. 

Verteporfin (Visudyne) is for the treatment of patients with eye disease 

affecting the central, clearest portion of vision, specifically for those with 

predominantly classic subfoveal choroidal neovascularization due to 

macular degeneration, presumed ocular histoplasmosis or pathologic 

myopia. 

Pantoprazole sodium (Protonix I.V.) is an injection for the treatment of the 

pathological hypersecretion of stomach acid associated with ZollingerEllison Syndrome. 

Orphan new or 

expanded uses 

Somatropin [rDNA] 

(Genotropin) is for 

long-term treatment 

of growth failure in 

children born small 

for their gestational 

age and who fail to 

manifest catch-up 

growth by the time 

they are 2 years old. 

Topiramate 

(Topamax) treats 

Lennox-Gastaut 

syndrome, a severe 

seizure disorder that 

occurs in children 

(two approvals). 

Priority new or 

expanded uses 

Capecitabine 

Letrozole 

Pantoprazole sodium 

Sodium ferric 

gluconate 

Somatropin [rDNA 

origin] for injection 

Verteporfin 
15 

Improving Public Health Through Human Drugs 

New or expanded 

uses (efficacy 

supplements) 

 91 approvals 

 Median review 

time: 10.1 months 

 Median approval 

time: 11.3 months 

 6 priority reviews 

 3 orphan uses 

 213 actions 

New or Expanded Uses

Actions, approval percentages

185196189173184205213

37% 43%

57%

53% 65%

72%

60%

0

125

250

1995 1996 1997 1998 1999 2000 2001

Calendar year

Actions

0%

50%

100%

Percent

Actions Percentage of actions that are approvals

New or Expanded Use Approvals

Median times, approvals

14.216.012.313.911.911.911.711.810.210.410.010.010.111.3

91

97 134

118

124

108 69

0

12

24

1995 1996 1997 1998 1999 2000 2001

Calendar year

Months

0

70

140

Approvals

Median FDA review time Median total approval time Number approved

Pediatric Exclusivity 

The 2002 Best Pharmaceuticals for Children Act 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 

allows us to collect user fees for reviewing these pediatric supplements and 

requires they be reviewed as priority supplements. The law also authorizes 

the federal government to contract for pediatric studies for drugs that lack 

patent protection or other marketing exclusivity. 

Pediatric exclusivity has helped us uncover important new dosing and 

safety information that will help pediatricians and other prescribers use 

drugs to treat children more confidently. As of March 2002, we had 

received 300 proposed pediatric study requests from manufacturers and 

had issued 241 written requests. These studies could potentially involve 

more than 32,000 children. Pediatric studies have already been conducted 

on more than 65 drugs. Reports from these studies have been submitted, 

exclusivity granted to 56 drugs, and new pediatric labeling in 31 as of 

March 2002. 

Pediatric 

exclusivity 

cumulative 

statistics 

 300 proposed 

pediatric study 

requests received 

 241 written requests 

issued 

 31 labeling changes 

Internet resource 

Our pediatric medicine 

page is at http://www.

fda.gov/cder/pediatric/

index.htm. 
16 

CDER 2001 Report to the Nation 

Approved information to treat children’s illnesses 

Of the 31 drugs with newly approved pediatric information in their labels, 

nine had significant changes for dosing, safety or use, and one drug 

available in several different products was not recommended for pediatric 

use. The nine with significant changes were: 

 Gabapentin (Neurontin), a seizure drug, requires higher doses in 

children younger than 5 years in order to control seizures, and new 

adverse events such as hostility and aggression were identified in 

children younger than 12. 

 Propofol (Diprivan), an anesthesia drug, showed higher death rates 

when used for sedation in pediatric intensive care units compared with 

standard sedative agents (9 percent vs. 4 percent); serious slowing of 

the heart rate can occur when the drug is coadministered with fentanyl, 

a pain drug. 

 Sevoflurane (Ultane), used for anesthesia, had rare cases of seizures 

reported in children without a previous seizure history. 

 Ribavirin/Intron A (Rebetron), a treatment for chronic hepatitis C, 

showed increased suicidal ideation or attempts among pediatric 

patients compared with adults (2.4 percent vs. 1 percent) and 

decreased the rate of linear growth and weight gain during therapy, 

with general reversal in the post-treatment period. 

 Pimecrolimus (Elidel) is for short-term and intermittent long-term 

therapy in mild to moderate eczema in non-immunocompromised 

patients older than 2 years, but it is not recommended in patients 

younger than 2 for safety concerns including infections, fever and 

diarrhea. 

 Midazolam (Versed), used for sedation and to reduce anxiety, showed 

higher risk of serious life-threatening situations in children with 

congenital heart disease and pulmonary hypertension. Studies 

identified the need to begin therapy at the lower end of the dosing 

range in these patients to prevent respiratory compromise. 

 Etodolac (Lodine), when used in the management of the signs and 

symptoms of juvenile rheumatoid arthritis for children 6 to 16 years 

old, requires higher weight-adjusted doses in younger children that is 

about twice the lower dose recommended in adults for effective 

treatment. 

 Fluvoxamine (Luvox), when used to treat obsessive compulsive 

disorder, requires higher doses in adolescents than previously 

recommended; however, girls ages 8 to 11 may require lower doses. 

 Studies of buspirone (Buspar) failed to establish safety and 

effectiveness in patients 6 to 17 years old for treatment of general 

anxiety disorder at doses recommended for adults.

Pediatric 

conditions with 

approved labeling 

Drugs with newly 

developed approved 

pediatric use 

information in their 

labeling are used to 

treat conditions such 

as: 

 Abnormal heart 

rhythms 

 Allergies 

 Anesthesia and 

sedation 

 Diabetes mellitus 

 Heartburn 

 High blood pressure 

 High cholesterol 

 High eye pressure 

 HIV infection 

 Inflammation 

 Juvenile 

rheumatoid arthritis 

 Low levels of 

calcium associated 

with severe kidney 

disease 

 Obsessive 

compulsive disorder 

 Pain 

 Seizures 

 Skin disorders 

Approved 

information 

recommends 

against pediatric 

use 

Newly approved 

labeling shows that 

several products with a 

specific topical steroid 

are not recommended 

for pediatric use. They 

are: 

Betamethasone 

(Diprolene AF, 

Diprosone Cream, 

Ointment, Lotion), used 

to treat corticosteroidresponsive skin 

disorders, is not 

recommended in 

patients younger than 

12 because it 

suppressed adrenal 

axis activity and 

caused local adverse 

reactions, including 

signs of skin atrophy. 

Betamethasone/

clotrimazole 

(Lotrisone), a 

treatment for 

ringworm infections, is 

not recommended in 

patients younger than 

17 because it 

suppressed adrenal 

axis activity. 
17 

Improving Public Health Through Human Drugs 

Over-the-Counter Drug Review 

In 2000, we approved six new drugs and one new use for over-the-counter 

marketing. 

New OTC medicines and new uses 

Miconazole nitrate (Monistat 3) is to treat vaginal yeast infections and 

external itching associated with a vaginal yeast infection. This is not the 

first OTC approval for this compound. 

Miconazole nitrate (Monistat 1). This is a one-day treatment regimen vs. a 

three-day treatment regimen under Monistat 3 (above) and a seven-day 

treatment regimen under Monistat 7. 

The combination clemastine fumarate, pseudoephedrine hydrochloride and 

acetaminophen (Tavist A/S/H) treats symptoms of hay fever and other 

seasonal allergies. This is the first approval for this combination but not the 

first time for any of these compounds on the OTC market. 

Chlorhexidine gluconate and ethyl alcohol (Avagard-CHG) is for use as a 

surgical hand scrub or hand wash for healthcare personnel. This is not the 

only chlorhexidine product available OTC. 

Aspirin, 500 mg, (Bayer Extra Strength Aspirin for Migraine Pain) is for 

the treatment of migraine headaches. This represents a new OTC use for 

aspirin. 

A cream with 1 percent butenafine hydrochloride (Lotrimin Ultra) is an 

Rx-to-OTC switch for the use of this drug product to treat jock itch, 

athlete’s foot and ringworm. 

A nasal spray containing cromolyn sodium (Nasalcrom) is now approved 

for OTC use down to 2 years of age.

Over-the-counter 

drug statistics 

 6 new drugs or 

Rx-to-OTC switch 

approvals 

 1 new or expanded 

use approval for an 

OTC drug 

Public meeting 

airs OTC 

antihistamine 

issues 

A citizen’s petition 

submitted in 1997 

asked us to consider 

switching the 

antihistamines 

loratadine, 

fexofenadine and 

cetirizine to OTC 

marketing status. 

Last year, our advisory 

panel of outside 

experts concluded that 

these drugs would be a 

reasonably safe 

alternative for 

consumers to treat 

nasal symptoms of 

seasonal and 

nonseasonal allergies. 

We and the 

manufacturers are 

considering their 

recommendation. 

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. 

Titled “Drug Facts,” 

the new labels become 

mandatory in May 

2002. 

These new labels 

improve a consumer’s 

ability to use an OTC 

drug safely and 

properly and to find 

and understand its 

benefits and risks. 

OTC New Approvals & New Uses

2019187538361

0

12

24

1996 1997 1998 1999 2000 2001

Calendar Year

Number

New approvals or Rx-to-OTC sw itches New uses
18 

CDER 2001 Report to the Nation 

Generic Drug Review 

We received 320 submissions and approved 234 generic drug products in 

2001, including 40 separate molecules in 55 products that represent the 

first time a generic drug was available for the brand-name product. The 

median approval time for generic drugs was 18.1 months. 

We are making changes to decrease the overall time to approval of 

applications. The median statistic for total approval time has hovered at 

about 18 to 19 months for five years. Planned changes include several 

efficiencies in the review process and hiring of additional chemistry 

reviewers. 

Notable 2001 generic drug approvals

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

 Fluoxetine (Prozac) used to treat depression. 

 Buspirone (BuSpar) used to treat anxiety disorders. 

 Famotidine (Pepcid) used to treat ulcers. 

 Lovastatin (Mevacor) used to control lipid profiles. 

 Omeprazole (Prilosec) used to treat ulcers. 

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 73 tentative approvals and 13 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 234 approvals in 2001 represent conversions of tentative approvals 

granted in 2001 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. 

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://internet-dev.

fda.gov/cder/ogd/index.

htm.
19 

Improving Public Health Through Human Drugs 

Generic drug 

statistics 

 234 generic drug 

approvals 

 Median approval 

time: 18.1 months 

 320 submissions 

 73 tentative 

approvals 

 13 approvables 

Building consumer confidence in generic drugs 

To promote consumer confidence in the safety and effectiveness of generic 

drugs, we are developing a multimedia education program. The goal will 

be to educate health care practitioners and consumers about the rigorous 

review and approval process that generic products undergo before we 

approve them for sale in this country. We are creating partnerships and a 

network with other government agencies. The efforts will include: 

 Focus groups to determine what information is needed. 

 Print media public service announcements. 

 Radio public service announcements. 

 Presentations at organizational meetings for health-care professionals. 

Electronic submissions 

The electronic submissions initiative is a continuing priority. We 

developed and issued a draft guidance on a standardized format for 

application submission that will be compatible for both new drug and 

generic applications. This should promote industry participation in the 

program. 

Generic Drugs

Submissions*

283307330345296365320

0

200

400

1995 1996 1997 1998 1999 2000 2001

Calendar year

*Submissions = w orkload in subsequent years

Number

Submissions

Generic Drug Approvals

Median times, approvals

27.023.019.318.018.618.218.1

207 212 273 225

186

244 234

0

12

24

36

1995 1996 1997 1998 1999 2000 2001

Calendar year (tentative approvals)

Months

0

100

200

300

Number

Median approval times Number of generic approvals

Tentative 

approvals 

 1995: 15 

 1996: 25 

 1997: 40 

 1998: 40 

 1999: 56 

 2000: 61 

 2001: 73 
20 

CDER 2001 Report to the Nation 

User Fee Program 

We met all of the demanding review goals of the Prescription Drug User 

Fee Act for applications submitted in fiscal year 2000, the latest year for 

which there are meaningful review statistics. We are on track for meeting 

them in fiscal year 2001. 

The law, first enacted in 1992, was renewed for an additional five years in 

1997. Under the law, the drug industry pays user fees for new drug 

applications, efficacy supplements and some other activities. User fees 

helped us hire additional scientists to perform reviews. As a result, we are 

able to respond more rapidly to new drug applications without 

compromising review quality. That means more quality drug products are 

reaching American practitioners and consumers more quickly. 

We agreed in 1992 to specific performance goals for the prompt review of 

four categories of submissions: original new drug applications, 

resubmissions of original NDAs, efficacy supplements to already approved 

marketing applications and manufacturing supplements to already 

approved new drug marketing applications. 

With the 1997 reauthorization, known as PDUFA II, we committed to 

additional goals intended to improve our responsiveness to and 

communication with industry sponsors during the early years of drug 

development. These goals specify timeframes for activities such as 

scheduling meetings and responding to various sponsor requests. While the 

intent of the 1992 law was to speed up the review process, the intent of 

PDUFA II is to speed up the entire drug development process. 

We have encountered challenges in trying to meet the PDUFA II goals. 

The fees we collected have been significantly less than expected due to a 

reduced number of new drug applications and an increased proportion of 

submissions whose fees were exempted or waived. At the same time, the 

number of goal-driven tasks for which we collect no fees increased 

substantially under PDUFA II. So far we have been able to meet most of 

our performance goals. 

Our efforts to meet the PDUFA II goals may have had an unintended 

impact on approval times of standard new drug applications. These 

approval times have begun to increase because more applications require 

multiple review cycles to reach approval. This may be due to the fact that 

reviewers have been pressed to meet the additional PDUFA II goals for 

drug development, such as meeting management, special protocol 

assessments and responses to clinical holds. Reviewers have had less time 

for resolving last-minute problems with these standard applications before 

the action goal date. Such applications must undergo an additional review 

cycle with its attendant timeframes and goals. Statistics on this trend are 

preliminary, and we are watching it closely. 

User fee review 

goals 

Under PDUFA II, our 

review goals 

continued to shorten. 

By fiscal year 2002, 

the goals called for us 

to review and act on 

90 percent of: 

 Priority new drug 

applications and 

efficacy supplements 

(those for products 

providing significant 

therapeutic gains) 

within six months. 

 Standard new 

drug applications and 

efficacy supplements 

within 10 months. 

 Manufacturing 

supplements not 

requiring prior 

approval within six 

months, and those 

requiring prior 

approval within four 

months. 

 Class 1 

resubmissions of 

original applications 

(those involving 

minor changes) within 

two months, and 

Class 2 resubmissions 

of original 

applications (those 

involving changes not 

specifically identified 

in the user fee goals 

document) within 6 

months. 

User fee report 

Our full report to 

Congress on our user 

fee performance is at 

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

pdufa/report2001/

pdufareport.html.
21 

Improving Public Health Through Human Drugs 

Manufacturing 

Supplement Review 

We review many types of changes in the 

manufacturing of drugs and their 

packaging, including location, machinery, 

processes and suppliers of raw materials. 

We do this so that American consumers 

can trust the high quality of FDAapproved medicines. Manufacturers 

notify us in advance of certain 

manufacturing changes. These are known 

as “manufacturing supplements” to new 

drug or generic drug applications. In 

many cases, they represent the industry’s 

efforts to modernize plants and equipment 

or to make manufacturing more efficient. 

New drug 

manufacturing 

supplements 

 1,394 approvals 

 Median FDA review 

time: 4.4 months 

 Median total 

approval time: 

4.5 months 

Generic drug 

manufacturing 

supplements 

 2,333 approvals 

 2,453 receipts 

Generic Drug Manufacturing Supplements

Approvals, receipts 

1,9032,2841,9692,3142,333

2,453 2,522

3,036

2,370

2,118

0

2,000

4,000

1997 1998 1999 2000 2001

Calendar year

Number

Number of supplements approved Number of supplements received

NDA Manufacturing Supplements

Actions, approval percentages

1,6741,7821,6301,6591,7471,6051,720

81%

61%

80% 72% 83% 81% 84%

0

1,000

2,000

1995 1996 1997 1998 1999 2000 2001

Calendar year

Number

0%

50%

100%

Number

Actions Percent of actions that are approvals

NDA Manufacturing Supplement Approvals

Median times, approvals

5.95.45.15.24.04.04.5

1,024

1,422

1,178 1,375

1,419

1,345 1,394

0

6

12

1995 1996 1997 1998 1999 2000 2001

Calendar year

Months

0

800

1,600

Approvals

Median total approval time Number approved
22 

CDER 2001 Report to the Nation 

Electronic Submissions 

Currently, the entire archival copy of the new drug application, 

postmarketing safety reports and advertising and promotional material can 

be submitted in electronic format without paper. We find submissions 

provided electronically as described in our guidance documents both 

easier to process and more efficient to review. 

While the number of electronic submissions continues to increase each 

year, only 15 percent of supplements and amendments are submitted in 

electronic format. Over the next year, we look to industry to increase the 

number of electronic-only submissions. 

Over the past year, we have worked on and begun evaluating electronic 

submission projects that will: 

 Provide a Web-based tool for companies to register establishments 

and list products. 

 Make use of standardized study data submissions to improve the 

review process. 

 Improve the way we process and review labeling changes. 

We also are working on the ability to accept the following documents in 

electronic format: 

 Abbreviated new drug applications for generic drugs. 

 Annual reports for marketing applications. 

 Investigational new drug applications for premarket clinical studies. 

 Individual case safety reports for marketed drugs (page 27).

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. 

Antimicrobial resistance 

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

threat to the public health. We play an active role in the federal 

government’s efforts to address this growing problem and its effects on 

drug development and regulation. 

We are developing approaches to provide education and information on 

the appropriate use of antibiotics to health care professionals and 

consumers. 

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

drug/antimicrobial/default.htm.
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 2001 

We conducted a total 

of 463 inspections of 

clinical research: 

 258 U.S. clinical 

investigators 

 38 foreign clinical 

investigators 

 139 institutional 

review boards 

 28 sponsors, 

monitors or contract 

research 

organizations 

Inspections of Clinical Research

312281704393401587297421431246641844293611911029649155282583813928

0

200

400

1995 1996 1997 1998 1999 2000 2001

Calendar year

Number

U.S. clinical investigators Foreign clinical investigators

Institutional review boards Sponsors, monitors, CROs

International 

inspections of 

clinical research 

We have conducted 

457 inspections of 

clinical research in 47 

countries from 1980 to 

2001. 

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. 
24 

CDER 2001 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 review team’s 

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. 

 Biopharmaceutists 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 check for interactions with other 

drugs. 

 Clinical pharmacologists evaluate factors that influence the 

relationship between the body’s response and the drug dose. They 

assist physician members of the team in assessing the clinical 

significance of changes in the body’s response to drugs through the use 

of exposure-response relationships. 

Scientific training 

for reviewers 

Our systematic, 

internal training 

program in science, 

policy and job-related 

skills for reviewers is 

based on core 

competencies, 

learning pathways 

and individual 

development plans. 

 The program grew 

from seven courses 

offered in 1997 to 

more than 20 

currently offered. 

Existing courses were 

also revised. 

 Reviewer 

participants increased 

six-fold, from about 

250 in 1997 to 1,500 

currently. 

 Last year, we 

brought in 44 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. 
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 include: 

 Processing and evaluating 286,755 reports of adverse drug events, 

including 19,324 submitted directly from individuals. 

 Accepting 15 percent of expedited adverse event reports electronically. 

 Issuing “cyber letters” and warnings to 11 Internet sites selling 

unapproved foreign ciprofloxacin in the wake of the anthraxcontaminated mail. 

 Issuing 880 letters to help ensure that the promotion of drug products 

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

misleading. 

 Mandating that three drug products be dispensed with specific 

consumer information to help make sure that they are used safely and 

effectively. 

 Evaluating results of 822 preapproval inspections of new drugs, 1,268 

preapproval inspections of generic drugs and 1,497 postapproval 

inspections. 

 Issuing 4,542 export certificates for U.S. drug products. 

 Launching a major initiative to assist industry in improving the 

capability and efficiency of drug manufacturing while maintaining or 

improving quality for consumers. 

 Evaluating the first scientific recommendations from the Product 

Quality Research Institute. 

Mission 

Protect the public 

health by ensuring that 

human drugs are safe 

and effective. 

New expert panel 

We will be able to 

consult with a new 

Drug Safety and Risk 

Management 

Subcommittee to the 

Advisory Committee 

for Pharmaceutical 

Science. 

The new panel is 

composed of nationally 

recognized experts in 

the areas of risk 

perception, risk 

management, 

pharmacoepidemiology, clinical 

pharmacology, clinical 

research and 

medication errors who 

will advise us on 

general and productspecific safety issues. 

Actual use data 

now available 

We awarded three contracts that give us access to commercial databases that contain 

non-patientidentifiable information on the actual use 

of marketed prescription drugs in adults 

and children. 

This information will 

significantly augment 

our ability to determine the public health 

significance of reports 

we receive through 

AERs and other 

sources. 
26 

CDER 2001 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, longterm 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 poisonings. We use this information to update drug 

labeling and, on rare occasions, reevaluate the approval or marketing 

decision. 

Medication errors 

We help ensure the 

safe use of drugs we 

approve by 

identifying and 

avoiding brand names 

that contribute to 

problems in 

prescribing, 

dispensing or 

administration of the 

product. 

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 

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 include new labeling, “Dear Health Care Practitioner” letters, 

restricted distribution programs or product marketing termination. 

Information technology 

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. In 2001, electronic submissions into AERS represented 15 percent 

of the total expedited reports we received. We estimate the cost of 

receiving a report is cut from $18 per report to $5 per report for those 

submitted electronically. 

Adverse event 

reporting 

In 2001, we received 

286,755 reports of 

suspected drugrelated adverse 

events: 

 19,324 MedWatch 

reports directly from 

individuals. 

 115,012 

manufacturer 15-day 

(expedited) reports. 

 152,419 

manufacturer 

periodic reports 

(70,306 serious and 

82,113 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 286,755

278,143 266,991

247,604

212,843 191,865

156,477

0

150,000

300,000

1995 1996 1997 1998 1999 2000 2001

Calendar year

Number

Direct (MedWatch) 15-day Nonserious periodic Periodic
28 

CDER 2001 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 more than doubled 

to about 20,000. 

We issued about 40 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. 

Risk management 

case study 

We have learned in 

recent years that our 

traditional methods for 

informing prescribers 

of changes in a drug’s 

risks and benefits have 

little effect once 

prescribing patterns 

have been well 

established. 

One example is the 

new risk management 

program for 

isotretinoin. 

The drug is very 

effective in treating the 

most serious form of 

acne, but its use carries 

significant potential 

risks, including birth 

defects and even fetal 

death. 

In recent years, as 

more women receive 

prescriptions for 

isotretinoin, the risk 

that pregnant women 

may be inappropriately using the drug 

has increased. 

On advice from our 

expert panel and in 

consultation with us, 

the manufacturer 

made significant 

changes to 

isotretinoin’s risk 

management program 

for pregnancy 

prevention. 

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. Cyber Letters for Foreign Ciprofloxacin 

In the wake of the public health crisis surrounding anthrax-contaminated 

mail, we issued “cyber letters” to 11 Web sites selling unapproved foreign 

ciprofloxacin (page 5). We issued warnings to Internet vendors abroad who 

were offering ciprofloxacin to American consumers. We informed 

consumers that they should be aware of these risks associated with 

obtaining a prescription drug over the Internet: 

 The product could be contaminated and harmful. 

 The product could be a counterfeit and not contain the drug’s active 

ingredient. 

 The product could contain the wrong dose of the drug. 

 Without adequate screening by a health care professional, the product 

may not be safe and appropriate for the user. 

 The consumer may not have access to a health care professional if a 

serious side effect occurs after taking the product. 

 The consumer may receive no product at all after sending payment. 

Buying medicines online 

Many consumers find it saves time and money to buy their medicines 

online. We have information to help consumers determine whether a Web 

site is a licensed pharmacy in good standing. You can find out more about 

buying medicines online at http://www.fda.gov/oc/buyonline/default.htm. 

Drug-induced liver 

injury 

Drug-induced liver 

injury is the most 

common cause for 

removing approved 

drugs from the market, 

limiting a drug to 

second-line use or 

requiring special 

monitoring or 

restricted use. 

We cosponsored a twoday conference and 

workshop to help 

foster consensus on 

principles and areas 

for research and 

further work. 

Conference materials 

are available at http://

www.fda.gov/cder/

livertox/default.htm.

We have been working 

with manufacturers to 

address how to carry 

out studies in patients 

with impaired liver 

function to provide 

information on dose 

adjustment in such 

patients. 
30 

CDER 2001 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 2001, we issued 178 advisory 

letters to companies regarding their promotional materials for launch 

campaigns. 

We issued 313 other advisory letters to the industry regarding proposed 

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

we issued 284 other types of correspondence to the pharmaceutical 

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

letters. 

Regulatory actions 

We issued 105 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 (20 letters), oral 

representations (11 letters), Internet Web sites (10 letters), plus traditional 

materials such as journal advertisements and sales brochures. 

Direct-to-consumer promotion 

Included in our letters were 190 regarding direct-to-consumer promotion. 

This compares with 215 letters in 2000. Of last year’s letters, 50 were for 

launch campaigns, 123 for non-launch advisories, and 16 were regulatory 

letters. Of the regulatory letters, seven were for advertisements broadcast 

on television or radio, five for print advertisements, three for a 

combination of broadcast and print advertisements, and one for a Web site. 

We initiated two national telephone surveys. One is a follow-up to our 

1999 survey of patients’ attitudes and behaviors associated with direct-toconsumer advertisements. The other is a new survey of physicians’ 

attitudes and behaviors associated with direct-to-consumer advertisements. 
31 

Improving Public Health Through Human Drugs 

Drug promotion 

review statistics 

We issued a total of 

880 drug promotion 

letters last year. 

 105 regulatory 

action letters 

 178 launch 

campaigns 

 597 advisory 

acknowledgement or 

closure letters Patient information for prescription drugs 

We continued our research activities in support of the private plan to 

provide patients with useful information about their prescription drugs. 

The target goal is for 75 percent of patients to receive useful information 

with new prescriptions. This past year we worked on evaluating the 

written patient medication information materials received. 

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

where they get their information about prescription drugs. 

Medication Guides 

We may require specific written patient information for selected 

prescription drugs that pose a serious and significant public health 

concern. These are called Medication Guides. They must be distributed to 

patients with each prescription dispensed. We determine if a drug requires 

a Medication Guide because information is necessary for patients to use 

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

product. Last year we issued Medication Guides for three products.

Proposed rule to revise prescription drug labeling 

We received more than 100 comments on our December 2000 proposal to 

revise the content and format of prescription drug labeling. Companies, 

associations, academicians and individuals commented, and we will 

respond when we publish the final regulation. 

The main purpose of labeling is to communicate essential information 

about prescription drugs to health care providers. The proposal would add 

a highlights section of critical prescribing information and an index. It 

would reorganize and reorder labeling to make the information easier for 

practitioners to find, read and use. We expect the proposed changes to 

contribute to our risk communication efforts by improving the 

accessibility of labeling information and consequently enhancing the safe 

and effective use of prescription drugs. 

Medication 

Guides issued 

in 2001: 

 Bosentan 

(Tracleer) 

 Ribavirin 

(Rebetol) 

 Ribavirin and 

interferon alfa-2b 

(Rebetron), a 

combination drug and 

biologic product 

Drug Promotion Review

129417220558245539237399171350773117276515105178597

0

400

800

1995 1996 1997 1998 1999 2000 2001

Fiscal year

Number

Regulatory actions Launch campaigns Other letters
32 

CDER 2001 Report to the Nation 

Top 10 reasons for 

drug recalls in 

fiscal year 2001: 

 Deviations from 

current good 

manufacturing 

practices 

 Subpotency 

 Stability data fail to 

support expiration 

date 

 Failure of drug to 

dissolve properly 

 Correctly labeled 

product in the wrong 

carton or package 

 Strength of product 

incorrectly labeled 

 Microbial 

contamination of 

nonsterile products 

 Drug product 

marketed without an 

approved new or 

generic application 

 Lack of assurance 

of sterility in 

production or testing 

of sterile drug 

products 

 Discoloration 

 Counterfeit dosage 

form 

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. 

Safety-based withdrawals in 2001 

In some cases, there is an intrinsic property of the drug that makes it 

necessary to withdraw the drug from the market for safety reasons. For 

example, these drugs were withdrawn from the U.S. market last year for 

safety reasons: 

 Cerivastatin (Baycol), a cholesterol lowering drug, was voluntarily 

withdrawn because of reports of sometimes fatal rhabdomyolysis, a 

severe muscle adverse reaction. 

 Rapacuronium (Raplon), an injectable anesthesia drug, was 

voluntarily withdrawn from the market after its manufacturer received 

reports indicating that the drug might have been associated with 

bronchospasm, a mild to severe inability to breathe normally that can 

lead to permanent injury or death.

Drug Recalls

191602265324834177883527231615624872

0

200

400

1995 1996 1997 1998 1999 2000 2001

Fiscal year

Number

Prescription Over-the-counter

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. 
33 

Improving Public Health Through Human Drugs 

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. 

 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, 2001, we approved 

258 NMEs, and 7 (2.7 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) 

Recent safetybased drug 

withdrawals 

(cont.)

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. 

Safety-Based NME Withdrawals

Based on year of approval

2.7% 2.7%

0.0%

1.5%

3.0%

Pre-PDUFA

(13)

PDUFA

(7)

Approval periods (number withdrawn as of April 30, 2002)

Percentage

Percentage withdrawn
34 

CDER 2001 Report to the Nation 

Reporting systems for drug quality problems 

Two important 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 defects and quality problems 

associated with marketed drugs. We evaluate and prioritize the reports 

to determine potential health hazards and industry trends and to 

develop special programs and surveys. We identify significant health 

hazards associated with drug manufacturing, packaging and labeling 

and initiate field inspections 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 any 

significant 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. 

Risk-based surveillance sampling of drugs 

We monitor the quality of the nation’s drug supply through surveillance 

and sampling of foreign and domestic finished dosage forms and bulk 

shipments of active ingredients. The drug products surveyed are selected 

according to a risk-based strategy that targets products with the greatest 

potential to harm the public health. FDA district offices conduct followup inspections to determine the cause of sample failures and to assure 

corrective action by the firms. 

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. These begin with those posing the most saftey considerations 

and effect on public heatlh. 

Sampling criteria 

Criteria for our riskbased surveillance 

sampling of drugs 

include: 

 High-volume/highrisk products 

 Therapeutic 

importance 

 Emerging problems 

 Dissolution issues 

 New molecular 

entities 

 Method validation 

issues 

 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. 

 Preapproval inspections. During fiscal year 2001, FDA evaluated 822 

plants in support of new drug applications. Also, FDA evaluated 1,268 

domestic firms in support of generic drug applications. 

 Good manufacturing practice inspections. There were 1,497 good 

manufacturing practice inspections in fiscal year 2001. We reviewed 48 

field recommendations for regulatory action and approved 18. These 

included two injunctions, eight seizures and four warning letters. We 

reviewed 249 foreign establishment inspection reports. These reviews 

resulted in 10 warning letters. 

Unsubstantiated claims; fraudulent, hazardous products 

We often encounter products marketed to U.S. consumers that make illegal 

and unsubstantiated medical claims. These may include claims to treat 

serious diseases that have proven effective treatments. Products making 

unproven claims may, therefore, pose a significant health risk. Consumers 

may use a fraudulent product in place of an effective treatment or may 

delay the use of effective treatment. On occasion, fraudulent products are 

found to contain toxic components that are likely to cause serious illness or 

injury. 

In addition, the marketing of products making unsubstantiated claims 

threatens to undermine the U.S. drug development and approval process by 

interfering with the incentive for new drug development. 

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

0

1,000

2,000

1999 2000 2001

Fiscal year

Number

New drug preapproval Generic preapproval Current good manufacturing practice

Protecting 

consumers from 

fraudulent drugs 

We protect U.S. 

consumers from 

fraudulent or 

hazardous drug 

products by: 

 Issuing enforcement 

letters to firms or 

individuals marketing 

fraudulent products. 

Last year, more than 

50 such letters were 

issued based on 

unsubstantiated claims 

found in product 

labeling and on 

Internet sites. 

 Pursuing 

enforcement actions. 

These include seizures 

of violative products 

and injunctions against 

firms or individuals 

who continue to 

market violative 

products. 
36 

CDER 2001 Report to the Nation 

Drug Product Quality Science 

Research 

We conduct scientific research on drug product quality issues. Last year 

our efforts included: 

 Developing and validating methods for testing the quality of drug 

products and rapid identification of counterfeit products. This included 

work on near-infrared spectroscopy and near-infrared imaging. 

 Approving 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 

We launched an initiative to assist manufacturers in improving the 

capability and efficiency of the pharmaceutical 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. 

To assist in this effort, 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. 

Product quality scientific workshops 

We cosponsored two scientific workshops to bring together our scientists 

with those from academia and industry to discuss our approaches and 

industry’s experiences and perspective. 

The workshops were: 

 Assuring Quality and Performance of Sustained and Controlled 

Release Parenterals. This workshop covered dispersed systems 

(microspheres, liposomes, gels and suspensions) as well as implants of 

small molecule and peptide therapeutics for human and animal use. 

 Streamlining the Chemistry, Manufacturing and Controls Regulatory 

Process for New and Generic Drugs. This workshop discussed 

scientific criteria for establishing a class of drugs considered to be low 

risk with respect to product quality. 

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 initiated a new 

program to advance 

rapid microbiology test 

methods. This included 

advisory committee 

meetings and a 

proposed subcommittee to resolve 

administrative and 

technical hurdles. 

PQRI update 

We are evaluating the 

first scientific 

recommendations from 

the Product Quality 

Research Institute 

(page 6). These are 

aimed at ensuring 

thorough mixing of a 

drug within the blend 

and dosage unit.

PQRI has a number of 

working groups 

addressing the issues 

such as: 

 Methods for 

determining physical 

attributes of drug 

substances starting 

with particle size 

 Impurities and how 

best to detect, identify 

and quantify them 

 Reliance on product 

specifications 

 Qualifying changes 

to container/closure 

systems - solid oral 

dosage forms 

 Leachables and 

extractables in orally 

inhaled and nasal drug 

products 

 Particles size 

distribution 

comparisons 
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 2001: 

 4,542 

Export Certificates Issued

1,7474,4994,3784,3823,9734,1974,542

0

2,500

5,000

1995 1996 1997 1998 1999 2000 2001

Fiscal year

Number

Export certificates issued
38 

CDER 2001 Report to the Nation 

3 

INTERNATIONAL

ACTIVITIES

Highlights from 2001 include: 

 Accepting the first new drug applications in 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. 

 Nearing completion of the electronic CTD. 

 Prioritizing issues for our harmonization efforts among the countries of 

North and South America. 

 Leadership of the U.S. consultations with the European Union to allow 

for reciprocal reliance on manufacturing plant inspections. 

 Exchanging recall information and alerts concerning significant 

emerging product quality problems with the European Union. 

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. 

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. 

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.
39 

Improving Public Health Through Human Drugs 

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. 

U.S.-European Union Mutual Recognition Agreement 

This agreement provides 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 will 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 will allow us to use an inspection report from one of 

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

decision will 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. 

Common 

Technical 

Document 

update 

The ICH Common 

Technical Document 

allows data in the 

same format to be 

submitted to drug 

review authorities in 

all three ICH regions. 

 We have received 

five new drug 

submissions in CTD 

format, several for 

new dosage forms. 

Some submissions use 

paper for some 

sections and 

electronic media for 

others. 

 Work on making 

the document suitable 

for electronic 

submission is nearing 

completion. 

MRA update 

A planned three-year 

transition to full 

implementation has 

not proceeded as 

smoothly as 

anticipated, but both 

parties remain 

optimistic 

 Last year, we 

began exchanging 

recall information 

and alerts concerning 

significant emerging 

product quality 

problems. 

 We proposed 

exchanging inspection 

reports on a pilot 

basis and audited the 

first E.U. member 

state. 

 A team of E.U. 

officials audited our 

regulatory system for 

good manufacturing 

practices with a 

positive outcome. 

Modular Structure of Common Technical Document 

Nonclinical

written and tabulated 

summaries 

Module 1 

Administrative 

and prescribing 

information 

(not harmonized) 

Module 2 

General introduction and overall 

summaries of quality, nonclinical 

and clinical information 

Clinical

written and tabulated 

summaries 

Module 4 

Nonclinical 

study reports 

Module 3 

Quality 

data 

Module 5 

Clinical 

study reports 
40 

CDER 2001 Report to the Nation 

4 

COMMUNICATIONS

Highlights from 2001 include: 

 Meeting almost weekly with outside experts on difficult scientific and 

public health issues. 

 Responding to more than 52,000 individual requests for information. 

 Launching twice-yearly, week-long introductory workshops for our 

stakeholders. 

 Receiving nearly 6.6 million visitors and about 111 million hits on our 

Internet information site, which has 40,000 pages and documents, five 

databases and 175,000 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 analyzed public 

comments on proposed new rules, and we sought and received comments 

on our guidances to industry. 

In special public meetings, we received valuable input from outside 

scientists, consumer and patient groups, professional and scientific 

societies, industry and trade associations about: 

 Converting certain prescription antihistamines to over the counter sales 

(page 17).

 The effects of medication on vehicle operators. This was our first joint 

meeting with the National Transportation Safety Board. It was held in 

response to the board’s request for warning labels on medicines that 

may impair a person’s ability to drive, fly, sail or operate vehicles. 

Workshops 

 CDER 101. We inaugurated a workshop for external stakeholders 

including foreign regulators. Our cosponsors were two non-profit 

organizations and an academic institution. The workshop features many 

of our experts in a week-long introduction to our mission, organization 

and regulatory processes. We held two workshops in 2001 and will 

continue to offer them twice a year. 

 Scientific workshops. We cosponsored one workshop addressing druginduced liver damage (page 30) and two addressing product quality 

issues in manufacturing (page 36).

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 40,000 

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 regulations, and we sought public 

comment on another five proposed regulations.

 Guidances. We published 15 guidances for industry that explain our 

position on best practices in scientific and technical areas. We 

published another 16 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 20 documents last year.

 Trade press. We responded to more than 2,340 telephone and e-mail 

requests from the specialized press covering the pharmaceutical 

industry. 

 Exhibits. We exhibited at 23 conferences, reaching an estimated 

audience of over 100,000 consumers, educators and health care 

professionals. 

 Videoconferencing. We held about 100 domestic and foreign 

videoconferences for academia, industry and associations. 

 CDER Live! We conducted a satellite television broadcast and webcast 

for more than 5,000 industry employees in which we discussed our 

proposal to improve the format and content of the prescription drug 

label. 

 Drug reviews on Internet. We posted on our Internet site our reviews of 

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

 Information requests. We responded to 6,000 requests under the 

Freedom of Information Act and more than 16,500 e-mail requests 

from industry, consumers, patients and health care professionals. 

 Other communications. We answered more than 34,000 telephone 

inquiries, 1,100 faxes and 8,800 written requests. We responded to 

nearly 6,000 requests for documents and guidance publications. 

Ombudsman’s 

activity 

In its sixth year of 

operation, our 

ombudsman helped 

settle issues between us 

and industry, health 

professionals and 

consumers. 

 The ombudsman 

handled about 100 

disputes. 

 He answered more 

than 1,300 e-mails, 

approximately 1,000 

telephone calls and 20 

letters. 

 In addition, the 

ombudsman held 

about 20 meetings with 

external parties. 

Public education 

campaigns 

In response to 

expressed need for 

information from the 

public and health care 

professionals, we 

developed campaigns 

about: 

 Benefits vs. risks of 

medication use 

 Buying prescription 

medical products over 

the Internet 

 Aspirin therapy to 

reduce the risk of heart 

attacks and strokes 

 The new over-thecounter medicine 

labels 

 Misuse of 

prescription pain 

relievers

 Drug interactions

Average Monthly Use of CDER Internet Site

156 226 406 549 32 72

9.3

6.7

2.5 3.1

1.3

0.5

0

500

1,000

1996 1997 1998 1999 2000 2001

Calendar year

Visitors (thousands)

0

5

10

Hits (millions)

Visitors (thousands) Hits (millions)

Partnering to 

reduce medical 

gas mix-ups 

We developed an 

outreach plan to 

eliminate deaths and 

injuries occurring 

when incorrect medical 

gas tanks are 

connected to oxygen 

lines in hospitals and 

nursing homes. This 

involved more than 

two dozen health care 

organizations and 

several accreditation 

organizations. 
42 

CDER 2001 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

 FDA Modernization Act of 1997 CDER-related documents: 

http://www.fda.gov/cder/fdama/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 Handbook: http:// www.fda.gov/cder/handbook/index.htm

 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 Staff 

 Ombudsman 

Office of Executive Programs 

 Executive Operations Staff 

 Review Standards Staff 

 Advisors and Consultants Staff 

 International Program 

 Information Management Program 

Office of Medical Policy 

 Div. of Drug Marketing Advertising & 

Communications 

 Div. of Scientific Investigations 

Office of New Drugs

 Pharmacology/Toxicology Staff 

 Program Management Team 

 Reports & Data Management Team 

Office of Pharmacoepidemiology 

& Statistical Sciences 

Office of Pharmaceutical Science 

 Informatic Computation Safety Analysis 

Staff 

 Quality Implementation Staff 

 Operation Staff 

Office of Pediatric Drug 

Development & Program 

Initiatives 

 Pediatric Therapeutics Staff 

 Program Initiatives Staff 

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-Viral Drug Products 

 Div. of Anti-Infective Drug 

Products 

 Div. of Special Pathogen & 

Immunologic Drug Products 

Office of Drug Evaluation V 

 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 Infrastructure 

Management and Services 

 Div. of Applications 

Development Services 

 Div. of Data Management & 

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 and Budget 

 Div. of Management Services 

Office of Training & 

Communications 

 Project Management Program 

Staff 

 Div. of Training & Development 

 Div. of Drug Information 

 Div. of Public Affairs 

 Div. of Library and Info. Services 

Office of Compliance 

 Div. of Labeling and 

Nonprescription Drug 

Compliance 

 Div. of Prescription Drug 

Compliance and Surveillance 

 Div. of Manufacturing & Product 

Quality 

Office of Testing and Research 

 Laboratory of Clinical Pharmacology 

 Div. of Applied Pharmacology 

Research 

 Div. of Pharmaceutical Analysis 

 Div. of Product Quality Research 

Office of New Drug Chemistry 

 Microbiology Team 

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