Center for Drug Evaluation and Research 2003

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 
CDER 2003 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/2003/rtn2003.pdf

HTML: http://www.fda.gov/cder/reports/rtn/2003/rtn2003.htm

Slides: http://www.fda.gov/cder/reports/rtn/2003/rtn2003.ppt

Suggested citation: Food and Drug Administration. CDER 2003 Report to 

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

Maryland, 20857. 
Improving Public Health Through Human Drugs 

i 

CONTENTS

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

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

2003 HIGHLIGHTS .......................................................................3 

 Critical Path Initiative..........................................................4 

 Pharmaceutical GMPs Initiative..........................................6 

 Counterterrorism..................................................................7 

 Scientific Research ..............................................................9 

1 DRUG REVIEW.......................................................................11 

 New Drug Review .............................................................12 

 New or Expanded Use Review..........................................19 

 Pediatric Drug Development .............................................23 

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

 Over-the-Counter Drug Review ........................................25 

 Generic Drug Review ........................................................26 

 Electronic Submissions .....................................................29 

 Preganancy Labeling .........................................................30 

 Assessing Data Quality, Research Risks ...........................31 

 Drug Review Team............................................................32 

2 DRUG SAFETY AND QUALITY...............................................33 

 Types of Risks from Medicines.........................................34 

 Drug Safety........................................................................34 

 MedWatch Outreach and Reporting..................................36 

 Medication Error Prevention .............................................37 

 Drug Shortages ..................................................................37 

 Drug Recalls ......................................................................38 

 Safety-Based Drug Withdrawals .......................................39 

 Drug Promotion Review....................................................40 

 Drug Product Quality ........................................................42 

 Drug Product Quality Science ...........................................44 

3 INTERNATIONAL ACTIVITIES ...............................................45 

 Export Certificates.............................................................47 

4 COMMUNICATIONS................................................................48 

 Where to Find More Information ......................................50 
CDER 2003 Report to the Nation 

ii 

Graphs and Charts 

Critical Path..................................................................................5 

Priority New Drugs ....................................................................12 

Priority New Molecular Entities ................................................13 

Standard New Drugs ..................................................................14 

Standard New Molecular Entities ..............................................15 

Priority New or Expanded Uses .................................................20 

Standard New or Expanded Uses ...............................................21 

Pediatric Drug Development......................................................23 

Over-the-Counter Drugs.............................................................25 

Generic Drug Approvals ............................................................27 

Generic Drug Tentative Approvals ............................................27 

Generic Drug Applications Received.........................................28 

Inspections of Clinical Research ................................................31 

Sources of Risk from Drug Products..........................................34 

Post-Marketing Adverse Event Reports.....................................35 

Drug Recalls...............................................................................38 

Safety-Based NME Withdrawal Percentages.............................39 

Drug Promotion Review.............................................................41 

FDA Inspections of Manufacturing Plants.................................43 

Export Certificates Issued ..........................................................47 

Average Monthly Use of CDER Internet Site............................49 

Organizational Chart ..........................................Inside back cover 
Improving Public Health Through Human Drugs 

iii 

Director’s Message 

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

challenge of promoting and protecting the public health. We were pleased to welcome our 

new colleagues involved in the review of therapeutic biologics. The dedication, creativity 

and expertise of all our professional staff have enabled us to meet our everyday deadlines 

and embark on new initiatives under the framework of FDA’s strategic plan. The strategic 

plan is very familiar to us because it builds on what we have been doing. The plan outlines a 

very ambitious effort to achieve five broad priority goals. 

Efficient, science-based risk management 

We have long led the world in applying the principles of risk management—assessing public 

health risks, analyzing methods for reducing them and taking appropriate action. With the 

expanding complexity of our medical challenges and the need to reduce the health risks 

facing the public at the lowest cost to society, efficient risk management is more important 

than ever. 

Our approach to efficient risk management requires the use of the most current biomedical, 

statistical, managerial and economic science. We aim to achieve quicker access to safe and 

effective new products and reduce public health risks without unnecessary costs by: 

 Identifying scientific research gaps along the critical path to drug approval. 

 Employing principles and technologies that can reduce avoidable delays and costs in 

product approvals. 

 Overhauling and updating the way medical products are manufactured. 

 Implementing an enforcement strategy that combines clear communications to industry 

backed up by effective civil and criminal enforcement. 

Patient and consumer safety 

Too many Americans suffer from preventable adverse events related to pharmaceutical 

products resulting in human suffering and avoidable medical costs. Consequently, we are 

enhancing our post-market monitoring, communication and regulatory activities. 

In addition, one of the most promising new ways we can improve the system for reporting 

safety problems is to have direct and secure access to relevant modern electronic health 

information. By supplementing the current passive reporting systems and partnering with 

healthcare providers and other government agencies, we will develop more innovative and 

effective information on the risks associated with regulated products. 

We will help speed the implementation of safer systems for medical care through steps such 

as: 

 Bar coding medications in hospitals. 

 Implementing 21st-century methods for communicating with health professionals to 

reduce adverse events. 

 Improving our current system for colleting and acting on adverse events related to the 

products we regulate. 
CDER 2003 Report to the Nation 

iv 

Better informed consumers 

Informed consumers represent our nation’s greatest public health asset, because the choices 

Americans make every day can have a great impact on their own health and the health of the 

nation. 

We are undertaking major new efforts to ensure consumers have the most up-to-date, truthful 

information on the benefits and risks of regulated products. In this arena, we meet two 

complementary objectives: 

 Ensure the information that sponsors provide about prescription drug products is accurate 

and allows for their safe use. 

 Communicate directly with the public concerning benefits and risks of the products we 

regulate. 

Our goal is a well-informed public, empowered to make better choices to improve their 

health. 

Counterterrorism 

We are working harder and more creatively than ever to speed the availability of the next 

generation of safer, more effective countermeasures to protect Americans from biological, 

chemical, nuclear and radiological agents of terrorism. We have two complementary—but 

necessarily separate—roles in this effort: 

 We will help get products developed. 

 We will then review marketing approval data on the same products. 

A strong FDA 

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

rests squarely on our most important resource: a talented and dedicated staff. More than ever, 

we rely on a solid cadre of experienced physicians, toxicologists, chemists, statisticians, 

mathematicians, project managers and other highly qualified and dedicated professionals. 

The expertise of our professional staff is essential for making our regulatory decisions 

balanced and fair. A committee of our scientists oversees an extensive program of training, 

seminars, case study rounds and guest lectures that helps keep our scientists up-to-date on the 

latest developments in their disciplines and current industry practices. 

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

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

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

information to health professionals, patients and consumers. 

Janet Woodcock, M.D. 

Director, January-September 2003 

Center for Drug Evaluation and Research 

Acting Deputy Commissioner for Operations 

Food and Drug Administration 

Steven Galson, M.D., MPH 

Acting Director 

Center for Drug Evaluation and Research 
Improving Public Health Through Human Drugs 

1 

INTRODUCTION

Who we are 

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

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

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

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

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

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

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

computer science, legal affairs and regulatory matters. 

What we do 

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

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

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

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

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

market, we monitor them for problems.

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

in the United States must first test it. We monitor clinical research to ensure 

that people who volunteer for studies are protected and that the quality and 

integrity of scientific data are maintained. The company then sends us the 

evidence from these tests to prove the drug is safe and effective for its 

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

pharmacologists and other scientists to review the company’s data and 

proposed use for the drug. If the drug is effective and we are convinced its 

health benefits outweigh its risks, we approve it for sale. We don’t actually 

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

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

researchers bring new drugs to American consumers more rapidly. We also 

review drugs that you can buy over the counter without a prescription and 

generic versions of over-the-counter and prescription drugs.

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

States, our consumer protection mission continues. We monitor the use of 

marketed drugs for unexpected health risks. If new, unanticipated risks are 

detected after approval, we take steps to inform the public and change how 

a drug is used or even remove a drug from the market. We also monitor 

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

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

from manufacturers, health care professionals and consumers. Sometimes, 

manufacturers run into production problems that might endanger the health 

What is a drug? 

We regulate drugs used 

to treat, prevent or 

diagnose illnesses. 

However, drugs include 

more than just 

medicines. 

For example, fluoride 

toothpaste, 

antiperspirants, 

dandruff shampoos and 

sunscreens are all 

considered “drugs.” 

You can buy some 

drugs in a store without 

a prescription, while 

others require a 

doctor’s prescription. 

Some are available in 

less-expensive generic 

versions. 

Prescription drugs 

Prescription medicines 

must be administered 

under a doctor’s 

supervision or require 

a doctor’s 

authorization for 

purchase. There are 

several reasons for 

requiring a medicine be 

sold by prescription: 

 The disease or 

condition may be 

serious and require a 

doctor’s management. 

 The medicine itself 

may cause side effects 

that a doctor needs to 

monitor. 

 The same symptoms 

may be caused by 

different diseases that 

only a doctor can 

diagnose. 

 The different causes 

may require different 

medicines. 

 Some medicines can 

be dangerous when 

used to treat the wrong 

disease. 
CDER 2003 Report to the Nation 

2 

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 it is 

primarily the Federal Trade Commission that regulates advertising of overthe-counter drugs, we regulate unapproved products that may be marketed 

OTC, including their associated promotional materials, to ensure that they 

meet applicable approval requirements and are not fraudulent. 

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. We also protect drug quality with rigorous manufacturing 

inspections to ensure compliance with current Good Manufacturing 

Practice requirements. 

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 with the American public when making difficult decisions about the 

drugs that they use. We hold public meetings about once a week to get 

expert, patient and consumer input into our decisions. We also announce 

most of our policy and technical proposals in advance. This gives members 

of the public, academic experts, industry, trade associations, consumer 

groups and professional societies the opportunity to comment before we 

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

meetings with consumer and patient groups, professional societies and 

pharmaceutical trade associations. These help us obtain enhanced public 

input into our planning and priority-setting practices. 

Over-the-counter 

drugs 

You can buy OTC 

drugs without a 

doctor’s prescription. 

You can successfully 

diagnose many 

common ailments and 

treat them yourself 

with readily available 

OTC products. 

These range from acne 

products to cold 

medications. 

As with prescription 

drugs, we closely 

regulate OTC drugs to 

ensure that they are 

safe, effective and 

properly labeled. 

Generic drugs 

A generic drug is a 

chemical copy of a 

brand-name drug. 

There are generic 

versions of both 

prescription and overthe-counter drugs. 

Generic drugs 

approved by the FDA 

have the same 

therapeutic effects as 

their brand-name 

counterparts. 

Scientific research 

We conduct and 

collaborate on focused 

laboratory research 

and testing. This 

maintains and 

strengthens the 

scientific base of our 

regulatory policymaking and decisionmaking. We focus on: 

 Drug quality, safety 

and performance 

 Improved 

technologies 

 New approaches to 

drug development and 

review 

 Regulatory 

standards and 

consistency 
Improving Public Health Through Human Drugs 

3 

2003 HIGHLIGHTS

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

year offered many Americans new or improved choices for protecting and 

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

Drug review 

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

have benefited from our approvals in 2003. We saw improved results from 

the previous year on overall approvals and decreases in the time it took us 

to review and approve most applications. 

A highlight was the approval of 21 new molecular entities with active 

ingredients never before marketed in the United States. This number 

increased from the 2002 total of 17. Priority approvals for products of 

special medical importance increased from 2002 as well. There were 14 

priority NDAs and nine priority NMEs, compared to 11 and seven in 2002, 

respectively.. 

We met all of our obligations to Congress for prompt and thorough review 

of drug applications supported by user fees. 

We increased choices for self-care by approving three medicines for overthe-counter marketing. This included the first switch of a previously 

prescription-only treatment for frequent heartburn. 

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

approved 263 generic equivalents for prescription or over-the-counter 

drugs. These included first-time generic approvals of treatments for 

depression, seizures and high blood pressure. 

Drug safety and quality 

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

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

corrective action quickly. 

We processed and evaluated more than 370,000 adverse drug events and 

3,000 reports of medication errors. We proposed a regulation that called for 

over-the-counter medicines commonly used in hospitals and all prescription 

medicines to have a bar code. The rule became final in 2004. 

We continued to focus on managing risks of marketed medicines, including 

having a public workshop to gather consumer and scientific input on our 

proposals for risk management strategies during drug development and 

after a drug is marketed. 

We held several public meetings to discuss our effort to promote 

modernization of pharmaceutical manufacturing. 

Communications 

We met almost weekly 

with outside experts on 

difficult scientific and 

public health issues. 

Each month, our 

Internet information 

site averaged 750,000 

visitors and 13.5 

million hits. 

We developed public 

education campaigns in 

areas such as antibiotic 

resistance and buying 

drugs from outside the 

United States. Our 

education program on 

generic drug quality, 

specially funded by 

Congress, has been 

enormously successful, 

with many 

organizations 

reproducing our 

materials at no cost to 

the government. 

International 

activities 

We continued our close 

work with our 

colleagues in Japan and 

the European Union on 

finding ways to make 

the drug development 

process more efficient 

and uniform. 

We entered new 

information-sharing 

agreements with 

Canada, Switzerland 

and the European 

Union. 

Quality systems 

We are starting down a 

long road toward 

making major 

improvements to our 

quality systems to 

improve the way we do 

our work. We already 

have some quality 

systems and subsystems 

in place, so we will 

build on those and add 

new ones. 

The basic concepts 

underlying quality 

systems are quite 

simple: 

 Say what you do. 

 Do what you say. 

 Prove it. 

 Improve it. 
CDER 2003 Report to the Nation 

4 

Critical Path Initiative 

FDA’s March 2004 report, Innovation or Stagnation?—Challenge and 

Opportunity on the Critical Path to New Medical Products, provides our 

analysis of the “pipeline problem.” 

There is a slowdown—instead of an expected acceleration—in innovative 

medical therapies reaching patients. The medical product development path 

is becoming increasingly challenging, inefficient and costly. 

As a consequence, our mission to ensure the availability of safe and 

effective medical treatments for Americans that take advantage of the latest 

science is becoming compromised. 

In our view, the applied sciences for product development have failed to 

keep pace with the tremendous advances in the basic sciences. New 

science is not being used to guide the development process in the same 

way that it is accelerating the discovery process. 

To focus the attention of the public, academic researchers, funding 

agencies and industry, our report identifies: 

 The critical path for product development from design and discovery to 

commercial marketing. 

 The scientific and technical dimensions of the critical path. 

 The three types of research that support the critical path. 

Critical path dimensions 

From the earliest phases of preclinical work to commercialization, 

developers must manage successfully in these three dimensions: 

 Assessing safety—showing that a product is adequately safe for each 

stage of development. 

 Demonstrating medical utility—showing a new product will actually 

benefit people. 

 Industrialization—turning a laboratory concept into a consistent and 

well-characterized medical product that can be mass produced. 

The traditional tools used to assess product safety—animal toxicology and 

outcomes from human studies—have changed little over many decades and 

have largely not benefited from recent gains in scientific knowledge. 

Better tools are needed to identify products that will prove clinically useful 

and eliminate impending failures more efficiently and earlier in the 

development process. 

Critical path 

An idealized “critical 

path” encompasses the 

medical product 

development process. 

The critical path begins 

after basic research 

provides candidate 

products for 

development. These 

products then face 

successively more 

rigorous evaluation 

steps along the path, 

including: 

 Drug discovery 

 Preclinical 

development 

 Clinical 

development 

 Scale-up for mass 

production 

 FDA filing/approval 

and launch preparation 

A striking feature of 

this path is the 

difficulty, at any point, 

of predicting ultimate 

success with a novel 

candidate. Recent 

biomedical research 

breakthroughs have 

not improved our 

ability to identify 

successful candidates. 

Critical path 

research 

These different types of 

research support 

medical product 

development: 

 Basic research is 

directed toward a 

fundamental 

understanding of 

biology and disease 

processes. It provides 

the foundation for 

product development. 

 Translational 

research is concerned 

with moving basic 

discoveries from 

concept into clinical 

evaluation and is often 

product or disease 

specific. 

 Critical path 

research is directed 

toward improving the 

medical product 

development process 

itself by establishing 

new evaluation tools. 
Improving Public Health Through Human Drugs 

5 

Critical Path 

Basic 

Research 

Drug 

Discovery 

Preclinical 

Development Clinical Development 

FDA Filing/ 

Approval & 

Launch 

Preparation 

Safety 

Drug 

Structure 

Activity 

Relationship 

In Vitro 

and Animal 

Testing 

Human 

and Animal 

Testing 

Safety 

Follow 

Up 

Medical 

Utility 

Industrialization 

In Vitro and 

Computer 

Model 

Evaluation 

In Vitro 

and Animal 

Models 

Human 

Efficacy 

Evaluation 

Drug 

Structure 

Activity 

Relationship 

Characterization 

Small-Scale 

Production 

Manufacturing 

Scale-up 

Refined 

Specifications 

Mass 

Production 

Translational Research 

Critical Path Research 

Dimensions 

The current drug discovery process, based on in-vitro screening techniques 

and animal models of often poorly understood clinical relevance, is 

fundamentally unable to identify candidates with a high probability of 

effectiveness. Reaching a more systemic and dynamic understanding of 

human disease will require major additional scientific efforts as well as 

significant advances in bioinformatics. 

The challenges involved in successful industrialization are complex, 

though highly underrated in the scientific community. Problems in physical 

design, characterization, manufacturing scale-up and quality control 

routinely derail or delay development programs and keep needed 

treatments from patients. 

The way forward 

This initiative is not a fundamental departure for us, but rather builds on 

our proven best practices for developing industry guidance and expediting 

the availability of promising medical technologies. 

The next steps in this initiative include a series of workshops and meetings, 

to start development of a National Critical Path Opportunities list and to 

identify the key priorities. 

The full report is available at http://www.fda.gov/oc/initiatives/criticalpath/

whitepaper.html.

Research needed 

to improve 

development tools 

While the biomedical 

research community 

has widened its efforts 

to include translational 

research, in our report, 

we call for a new focus 

on critical path 

research. 

Together with 

academia, patient 

groups, industry and 

other government 

agencies, we need to 

embark on an 

aggressive, 

collaborative research 

effort to create a new 

generation of 

performance standards 

and predictive tools 

that will provide better 

answers about the 

safety and effectiveness 

of investigational 

products, faster and 

with more certainty. 

We at FDA are 

uniquely suited to take 

a major role in this 

effort because of our 

experience overseeing 

medical product 

development, 

assessment and 

manufacturing/

marketing; our vast 

clinical and animal 

databases; and our 

close interactions with 

all the major players in 

the critical path 

process. 
CDER 2003 Report to the Nation 

6 

Pharmaceutical cGMP Initiative 

Our regulatory and quality control systems for pharmaceutical products, 

known as current good manufacturing practices, have become a gold 

standard for the world; however, the last comprehensive revisions to these 

regulations took place nearly a quarter of a century ago.

Pharmaceutical cGMPs for the 21st Century is a multi-year Agency effort 

begun in 2002 to enhance the regulation of pharmaceutical manufacturing 

and product quality. 

We evaluated our internal operations under this initiative last year: 

 We are developing a quantitative, risk-based site-selection model for 

use in choosing sites for inspection. This will encourage 

implementation of risk-based approaches that focus on critical areas. It 

will ensure a risk-management approach is applied to allocating FDA 

inspection resources. 

 We revised our Preapproval Inspection Compliance Program to give 

field inspectors more opportunity to use a risk-based approach, allowing 

greater flexibility in determining whether a preapproval inspection is 

warranted. The number of categories of drug products that require 

mandatory inspection have been reduced. 

Guidances to encourage manufacturing improvements 

We issued one final and four draft guidances to encourage rapid adoption 

by industry of modern manufacturing practices. These were: 

 A final guidance on the use of electronic records and signatures. which 

explains the goals of this initiative and removes barriers to scientific 

and technological advances and encourages the use of risk-based 

approaches. The guidance clarifies the scope and application of Part 11 

of the Code of Federal Regulations and provides for our enforcement 

discretion in certain areas while we undertake rulemaking to revise 

Part 11. 

 A draft guidance on the aseptic processes used in the manufacture of 

sterile drugs, emphasizing current science and risk-based approaches. 

This provides recommendations on how to build quality into products 

using science-based facilities, equipment and systems design. Sterile 

drug products are generally of high therapeutic significance, and our 

proactive efforts to enhance cGMP understanding in this area are 

intended to promote compliance and ensure a steady supply of these 

medically necessary products to U.S. consumers. 

 A draft guidance on a process for resolving disputes arising over 

scientific and technical issues related to pharmaceutical current good 

manufacturing practices. 

cGMP initiative 

goals 

 Public health 

protection is 

strengthened by 

implementing riskbased approaches that 

focus both industry and 

our attention on critical 

areas for improving 

product safety and 

quality 

 The regulatory 

review program and 

the inspection program 

operate in a 

coordinated and 

synergistic manner 

 Regulation and 

manufacturing 

standards are applied 

consistently using stateof-the-art 

pharmaceutical science 

 Innovation in the 

pharmaceutical 

manufacturing sector is 

encouraged 

 Our resources are 

used most effectively 

and efficiently to 

address the most 

significant health risks. 

More information is at 

http://www.fda.gov/

cder/gmp/index.htm. 

cGMP 

collaborations 

 A collaboration with 

two universities to 

identify the factors that 

predict manufacturing 

performance to further 

refine our 

pharmaceutical 

manufacturing riskbased assessment. 

 A collaboration with 

the National Science 

Foundation’s Center 

for Pharmaceutical 

Processing Research 

allowing us to expand 

our scientific 

foundation in the area 

of innovative 

pharmaceutical 

manufacturing 

technology. 

 A cooperative 

research and 

development 

agreement with a 

major pharmaceutical 

manufacturer to 

research chemical 

imaging applications in 

pharmaceutical 

manufacturing and 

quality assurance. 

 A memorandum of 

understanding between 

us and FDA’s field 

force to set up the 

Pharmaceutical 

Inspectorate who will 

devote most of their 

time to conducting 

human drug 

manufacturing quality 

inspections. 
Improving Public Health Through Human Drugs 

7 

Counterterrorism 

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

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

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

 Assuring the availability of medicines to treat victims of terrorism 

attacks. 

 Leveraging resources with other federal agencies to answer scientific 

questions concerning therapies to treat conditions against terrorism 

agents. 

 Protecting the nation’s drug supply from attack or deliberate 

contamination. 

 Preparing ourselves to continue operations during a crisis. 

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

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

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

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

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

bulk suppliers, inventories and lead times for production. We participate in 

preparedness and response activities to test and establish appropriate 

communications procedures for emergency situations. We are collaborating 

with the Centers for Disease Control and Prevention on plans for obtaining 

post-event outcome data on the use of medical countermeasures. 

Shelf-life extension 

for drug stockpiles 

Our laboratories 

perform shelf-life 

extension testing for 

drug products 

stockpiled by the U.S. 

military and the 

Strategic National 

Stockpile. 

We published the 

Guidance for Federal 

Agencies and State and 

Local Governments: 

Potassium Iodide 

Tablets Shelf Life 

Extension as a draft, 

and it became final in 

March 2004. 

Counterterrorism 

Internet resources 

We provides links to 

the most current 

information on: 

 Drugs to prevent or 

treat disease caused by 

terrorism agents 

including drugs for use 

against anthrax, 

plague, radiation 

emergencies and 

chemical agents. 

 Drug development 

of counterterrorism 

products. 

 Vaccines. 

 Pediatric 

counterterrorism 

measures. 

 Prescribing and 

buying 

countermeasures. 

You can find these 

links at http://

www.fda.gov/cder/

drugprepare/

default.htm. 

 A draft guidance on preparation and use of a comparability protocol for 

assessing chemistry, manufacturing and control changes to protein drug 

products and biological products. 

 A draft guidance for process analytical technology, a framework for 

allowing regulatory processes to adopt more readily state-of-the-art 

technological advances in drug development, production and quality 

assurance (page 44). 

Collaborative 

research on 

pneumonic plague 

We are collaborating 

with the National 

Institute of Allergy and 

Infectious Diseases and 

the U.S. Army Medical 

Research Institute of 

Infectious Diseases to 

investigate the use of 

the antibiotic 

gentamicin and other 

antimicrobials for the 

treatment of 

pneumonic plague. 

Natural history, 

pharmacokinetic and 

toxicology studies were 

performed to support 

planned efficacy studies 

using a non-human 

primate model of 

pneumonic plague. 
CDER 2003 Report to the Nation 

8 

Counterterrorism notable 2003 achievements 

 Approved pyridostigmine bromide tablets (page 16) as a pretreatment to 

increase survival after exposure to Soman “nerve gas” poisoning. The 

product is approved for combat use by U.S. armed forces. This is the 

first drug approved under the animal efficacy rule.

 Approved lower doses of the atropine autoinjector (AtroPen) (page 19)

for use in children and adolescents exposed to certain nerve agents and 

insecticides. The atropine autoinjector was approved for adult use in 

1973. 

 Approved insoluble Prussian blue (Radiogardase) capsules (page 16) to 

treat people exposed to radiation contamination from harmful levels of 

cesium-137 or thallium poisoning. The application for this drug was 

sent in response to the publication of our findings that Prussian blue 

would be safe and effective for this indication when produced under 

conditions specified in approved marketing applications. More 

information is at http://www.fda.gov/cder/drug/infopage/prussian_blue/.

 Published our findings on intravenous chelators for treating exposure to 

radioisotopes. We determined that pentetate calcium trisodium 

(Ca-DTPA) and pentetate zinc trisodium (Zn-DTPA) are safe and 

effective, when produced under conditions specified in approved 

marketing applications, for treatment of contamination with radioactive 

isotopes of the elements plutonium, americium and curium. We are 

encouraging manufacturers to use these findings to submit new drug 

applications. 

 Published information on the World Wide Web on how to dissolve and 

mix doxycycline tablets with food or drinks. Following an exposure to 

inhalational anthrax, parents may receive stockpiled tablets for their 

children if suspensions are not available. We published these 

instructions for making palatable doses of the antibiotic to give small 

children who may not be able to swallow tablets. 

 Participated in emergency response activities, including the 

international Global Mercury smallpox exercise and the U.S. 

government’s Scarlet Cloud anthrax exercise. We also began testing 

components of our continuity of operations plan to assure that we can 

maintain vital operations and service. 

 Began discussions with CDC on mechanisms to collect and assess 

outcome information following the use of medical countermeasures in a 

terrorist event. 

 Drafted a guidance for industry that we published in March 2004, 

Vaccinia Virus: Developing Drugs to Mitigate Complications from 

Smallpox Vaccination.

Animal efficacy 

rule 

Certain human drugs 

and biologics intended 

to reduce or prevent 

serious or lifethreatening conditions 

may be approved based 

on animal evidence of 

effectiveness when 

human efficacy studies 

are not ethical or 

feasible. The 

regulation, also known 

as Subpart I for drugs 

(21 CFR Part 314) or 

Subpart H for biologics 

(21 CFR Part 601) 

applies when: 

 The 

pathophysiology of the 

disease and the 

mechanisms of action 

of the drug are 

reasonably wellunderstood. 

 The efficacy 

endpoints in the animal 

trials are clearly 

related to human 

benefit. 

 The drug effect is 

demonstrated in more 

than one wellcharacterized animal 

species expected to 

react with a response 

predictive for humans; 

and 

 Data allow selection 

of an effective human 

dose. 

Counterterrorism 

scientific research 

Some medical 

countermeasures are 

stockpiled in tablet 

form that may be 

difficult to swallow for 

infants, small children 

and others. Two 

examples are 

doxycycline, for postexposure prophylaxis 

for anthrax, and 

potassium iodide, for 

use in emergencies 

involving radioactive 

iodine. 

We used the “electronic 

tongue” instrument to 

extend our studies of 

the stability and 

palatability of these 

drugs when crushed 

and mixed with 

different foods or 

drinks. We compared 

the results to those of 

human taste panels. 

We developed an 

exposure-response 

model for 

pyridostigmine, an 

anti-nerve gas agent, to 

extrapolate animal 

efficacy data to a 

human dose regimen. 
Improving Public Health Through Human Drugs 

9 

Scientific Research 

We advance the scientific basis of regulatory practice by developing, 

evaluating or applying the best, most appropriate and contemporary 

scientific methods to regulatory testing paradigms. We provide scientific 

support for reviewer training, regulatory decision making and the 

development of regulatory policy. 

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

clinical studies, enhancing methodology for assuring product quality, 

building databases for improved drug development and review and 

providing regulatory support through laboratory testing. 

Linking nonclinical and clinical studies 

 We are identifying, evaluating and establishing relvant protein 

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

help detect the very earliest damage that can be caused by certain drugs 

to the heart, kidney, immune system and liver. 

 To enhance safety within broad segments of patient populations and 

enable safe development of new drug classes, we are working on the 

identification and elucidation of associated serum biomarkers and 

mechanisms responsible for the development of vascular inflammation 

in specific organ systems. 

 We conduct targeted research on microarrays, a new technology that 

can identify thousands of genes or proteins rapidly and at the same 

time. We are evaluating how this technology could improve the 

interface between drug development and regulatory practice. 

 We established scientific research capabilities in the analyses of 

medicinal plant and herbal products. 

 We continue to explore noninvasive imaging technology to extend our 

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

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

 We are developing a standardized approach for using exposureresponse information to help evaluate the risks and benefits of drug 

therapies and recommending dose adjustments in special populations. 

 We are developing a pediatric population pharmacokinetics study 

design template to facilitate implementation of sparse sample strategies 

in pediatric drug development. 

Clinical 

pharmacology 

 We are exploring 

the utility and value of 

quantitative drugdisease state models 

and clinical trial 

simulation in drug 

development and 

regulatory review. 

 We issued the final 

guidance on ExposureResponse Relationships: 

Study Design, Data 

Analysis, and 

Regulatory 

Applications.

 We cosponsored an 

open workshop 

pharmacogenomics in 

drug development and 

regulatory Decisionmaking. 

 We published a 

draft guidance for 

industry, 

Pharmacogenomic Data 

Submissions, to provide 

a better understanding 

on the current use of 

pharmacogenomics in 

drug development and 

gain experience in 

handling and 

evaluating genotype 

and gene expression 

data. 

 We are working on 

a draft guidance for 

industry on the 

regulatory pathway for 

pharmacogenomic 

drug-device 

combinations. 

Counterterrorism 

biotechnology 

research 

We have used 

congressionally 

mandated special 

funding to initiate 

research in several 

areas relevant to 

counterterrorism. Our 

scientists are studying: 

 Microarray 

technologies, which 

could assist in 

identifying infectious 

biowarfare agents 

 Non-specific 

immune boosters, 

which could provide 

transient protection 

against such agents 

 Monoclonal 

antibodies as 

neutralizers of 

biological toxins 

 Various strategies to 

defend against anthrax 

By establishing a core 

of scientists 

experienced in several 

areas of bioterrorism, 

these projects 

anticipate high-priority 

regulatory submissions 

likely to require rapid 

science-based 

evaluation. 
CDER 2003 Report to the Nation 

10 

Biotechnology research 

Our new Office of Biotechnology Products was officially transferred in 

2003 from the Center for Biologics Evaluation and Research. The office 

consists of about 80 scientists who are responsible for evaluating 

therapeutic biotechnology product submissions as well as carrying out 

scientific research related to biologics regulatory issues. 

 We review many submissions aimed at inhibiting unwanted immune 

responses, such as autoimmune diseases or rejection of transplanted 

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

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

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

to another. 

 We study the mechanisms by which various regulated products induce 

their intended effects, as well as unintended adverse effects. Our 

investigations also examine various normal and pathogenic pathways 

that are targeted by regulated agents. 

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

risks and benefits of biotech products, to advise industry on difficult 

regulatory problems, such as potency assays, and to develop hands-on 

expertise in the modern technologies used by sponsors of biotech products. 

Informatics and computational safety analysis 

 Our cooperative research and development agreements with several 

commercial software developers have resulted in the development and 

marketing of new computer software to predict the cancer-causing 

potential of chemicals based on their molecular structure. The software 

makes use of our extensive rodent carcinogenicity database without 

compromising propriety information. 

 We have successfully developed computer models to estimate the safe 

starting dose for clinical trials of drugs based on their molecular 

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

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

based exclusively on an extrapolation from animal toxicity studies. We 

have begun studies to validate the new method. 

Laboratory 

support 

Last year our efforts 

included: 

 Assessment of the 

safety (cyanide release) 

and the efficacy 

(cesium binding) of 

Prussian blue in 

support of its approval 

as a medical 

countermeasure 

(page 16).

 Development of 

methods to evaluate 

quality attributes of 

drug products and raw 

materials by chemical 

imaging. These 

properties include 

polymorphic form, 

hydration state, 

stability and purity. 

 Rapid identification 

of counterfeit products 

using near-infrared 

spectroscopy and 

chemical imaging to 

discriminate drug 

products and raw 

materials. 

 Development of a 

methodology for the 

determining glove 

permeability to lindane 

shampoo and lotion, 

treatments for lice 

whose active ingredient 

is highly toxic. 

Pharmaceutical 

analysis 

We assure that 

analytical methods 

being developed by 

pharmaceutical 

companies are suitable 

for quality assurance 

and regulatory 

purposes. We assessed 

analytical methods for 

six new drugs and one 

generic drug. 

We collaborate with 

other organizations to 

ensure the availability 

of high quality 

standards and 

calibration materials. 

We collaborated with 

state pharmacy boards 

to evaluate Internet 

pharmaceuticals. 

We evaluated the 

quality of a select 

group of the mostoften-ordered 

pharmaceutical 

products from foreign 

Internet suppliers. 
Improving Public Health Through Human Drugs 

11 

1 

DRUG REVIEW

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

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

equivalents for both. 

We approved 21 new medicines that have never been marketed before in 

this country, known as new molecular entities. We approved 263 generic 

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

the counter without a prescription, and one of them can be used by 

children. 

We met or exceeded all 10 performance goals for the fiscal year 2002 

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

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

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

applications, we exceeded both goals for new molecular entities. 

We conducted 728 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: 

 Five cancer treatments. 

 Three new drugs for HIV infection, including the first in a class of 

antiretroviral drugs known as fusion inhibitors. 

 Three treatments for infections, including the first in a new class of 

antibiotics. 

 Six orphan new drugs and two orphan new uses to treat patient 

populations of fewer than 200,000. 

 One new drug for treating hepatitis in children and 15 labels with 

information for treating children. 

 Lower doses of estrogen-containing drugs for treating symptoms of 

menopause. 

 Expanded treatment options for children with depression and obsessive 

compulsive disorder. 

 New options for oral contraceptives, including a chewable version and 

one that reduces menstruations to once every three months. 

 The first over-the-counter treatment for frequent heartburn. 

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 2003 

 72 new drugs 

 21 new 

molecular entities 

 6 orphan new drugs 

 2 orphan new uses 

for existing drugs 

 131 new or 

expanded uses for 

already approved drugs 

 3 over-the-counter 

drugs or Rx-to OTC 

switches 

 263 generic 

equivalents 

for prescription 

and over-the counter 

drugs 
CDER 2003 Report to the Nation 

12 

Priority new drugs 

(N=NME)

 Abarelix (Plenaxis) 

(N) 

 Aprepitant (Emend) 

(N) 

 Atazanavir sulfate

(Reyataz) (N) 

 Bortezomib 

(Velcade) (N) 

 Daptomycin 

(Cubicin) (N) 

 Enfuvirtide 

(Fuzeon) (N) 

 Gefitinib (Iressa) 

(N) 

 Imatinib mesylate 

(Gleevec) 

New Drug Review 

Definitions 

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. 

Median times. Our charts show review and approval times as “medians.” 

The value for the median time is the number that falls in the middle of the 

group after the numbers are ranked in order. It provides a truer picture of 

our performance than average time, which can be unduly influenced by a 

few very long or short times. Our guide to understanding median approval 

time statistics is available at http://www.fda.gov/cder/present/

MedianAPtime/index.htm.

New molecular entities. NMEs contain an active substance that has never 

before been approved for marketing in any form in the United States. 

Because of high interest in truly new medicines, we report NMEs 

separately; however, the charts for NDAs include the NMEs as well. 

Priority new drugs 

 14 approvals 

(including 9 NMEs) 

 Median review time: 

7.7 months 

 Median approval 

time: 7.7 months 

 26 actions 

 19 filings 

 5 orphan approvals 

(including 3 NMEs) 

Priority NDA Approvals

Median times, approvals

6.06.07.87.86.26.46.26.46.16.16.06.06.06.013.819.17.77.7

29

11

20 28

10

14

20

15

25

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

15

30

Approvals

Median FDA review time Median total approval time Number approved

Priority NDAs

Actions, filings*, approval percentages

31244426353246274331412127718202619

57% 54%

61%

37%

49%

65%

54%

66% 48%

0

25

50

1995 1996 1997 1998 1999 2000 2001 2002 2003

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

Priority approval, 

review times down 

in 2003 

The median total 

approval and review 

times for priority 

NDAs were 7.7 months 

each, and the times for 

priority NMEs were 6.7 

months each. 

The much higher times 

shown in 2002 were 

caused by the approval 

of a number of older 

applications coupled 

with a decrease in the 

number of new 

applications received. 
Improving Public Health Through Human Drugs 

13 

Priority new drugs. These drugs represent significant improvements 

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

of these applications within six months. 

Standard new drugs. 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. 

Actions and filings. An application is “filed” when we determine it is 

complete and accept it for review. We make a filing decision within 60 

days of receiving an application. Approval is one of the actions that we can 

take once an application is filed. Other actions include seeking more 

information from the sponsor. There is no direct connection between 

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

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

Orphan drugs. We administer a program that provides incentives to 

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

of orphan drugs receive inducements that include seven-year marketing 

exclusivity, tax credit for the product-associated clinical research, research 

design assistance from FDA and grants of up to $200,000 per year. 

Priority new 

molecular entities 

 9 approvals 

 Median review time: 

6.7 months 

 Median approval 

time: 6.7 months 

 12 filings 

 3 orphan approvals 

Priority NME Approvals

Median times, approvals

6.06.07.79.66.46.76.26.26.36.96.06.06.06.013.816.36.76.7

7

7

9 9 9

18 16

19

9

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

10

20

Approvals

Median FDA review time Median total approval time Number approved

Priority NMEs

Filings*

16161715141551012

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

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

Number

Filings

Accelerated 

approval 

This program helps 

make products for 

serious or lifethreatening diseases 

available earlier in the 

development process. 

We base our approval 

on a promising effect of 

the drug that can be 

observed significantly 

sooner than a longterm clinical benefit. 

Sponsors perform 

additional studies to 

demonstrate long-term 

clinical benefit. 

Priority new drugs

(cont.) (N=NME)

 Olanzapine and 

fluoxetine 

hydrochloride 

(Symbyax) 

 Pegvisomant 

(Somavert) (N) 

 Prussian blue 

(Radiogardase) (N) 

 Pyridostigmine 

bromide 

(Pyridostigmine 

Bromide) 

 Ribavirin (Rebetol) 

 Sterile talc powder 

(Sterile Talc Powder) 
CDER 2003 Report to the Nation 

14 

Standard new 

drugs 

 58 approvals 

(including 12 NMEs) 

 Median review time: 

11.9 months 

 Median approval 

time: 15.4 months 

 139 actions 

 96 filings 

 1 orphan approval 

Standard NDAs

Actions, filings*, approval percentages

1859222590200921538714710119787143881547813996

51%

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

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

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

Number

0%

50%

100%

Percent

Actions Filings Percent of actions that are approvals

Standard NDA Approvals

Median times, approvals

16.218.715.117.814.715.012.012.012.013.812.012.012.014.012.715.311.915.4

67

102 101

65 55

78

56

67

58

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

60

120

Approvals

Median FDA review time Median total approval time Number approved

Notable 2003 new drug approvals 

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

disease and other disorders. 

People with cancer 

Abarelix (Plenaxis) is a palliative treatment for advanced prostate cancer 

for patients who cannot take other hormone therapies and who have refused 

surgical castration. Abarelix lowers the male hormone testosterone, which 

is involved in most prostate cancer growth. A study of 81 men showed they 

could avoid surgical castration by undergoing at least 12 weeks of 

treatment with the drug. Some also experienced other benefits, including 

decreased pain and relief from urinary problems. The drug is marketed 

under a risk management program because of an increased risk of serious 

and potentially life-threatening allergic reactions. (NME, P) 

Aprepitant (Emend) is used in combination with other anti-nausea and antivomiting drugs for prevention of acute and delayed nausea and vomiting 

associated with initial and repeat courses of highly emetogenic cancer 

chemotherapy, including high-dose cisplatin. (NME, P) 

New molecular 

entities 

 Abarelix (Plenaxis) 

 Alfuzosin 

hydrochloride 

(Uroxatral) 

 Aprepitant (Emend) 

 Atazanavir sulfate

(Reyataz) 

 Bortezomib 

(Velcade) 

 Daptomycin 

(Cubicin) 

 Emtricitabine 

(Emtriva) 

 Enfuvirtide 

(Fuzeon) 

 Epinastine 

hydrochloride 

(ELESTAT) 

 Gefitinib (Iressa) 

Internet resources 

for drug review 

statistics 

Other drug review 

statistics are available 

on our Web site at 

http://www.fda.gov/

cder/rdmt/default.htm.
Improving Public Health Through Human Drugs 

15 

Orphan new drug 

approvals 

(N=NME)

 Bortezomib 

(Velcade) (N) 

 Miglustat (Zavesca) 

(N) 

 Pegvisomant 

(Somavert) (N) 

 Prussian blue 

(Radiogardase) (N) 

 Ribavirin (Rebetol) 

 Sterile talc powder 

(Sterile Talc Powder) 

Standard new 

molecular entities 

 12 approvals 

 Median review time: 

13.8 months 

 Median approval 

time: 23.1 months 

 13 filings 

 1 orphan approval 

Standard NME Approvals

Median times, approvals

15.917.814.615.114.415.012.313.414.016.315.419.915.719.012.515.913.823.1

10 17 18

30

19

35

14

16 12

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

20

40

Number

Median FDA review time Median total approval time Number approved

Standard NMEs

Filings*

342925282212251312

0

20

40

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

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

Number

Filings

Gefitinib (Iressa) is a single-agent treatment for patients with advanced 

non-small cell lung cancer, whose cancer has continued to progress despite 

treatment with platinum-based chemotherapy and docetaxel. Gefitinib, 

which received accelerated approval, was developed to block growth 

stimulatory signals in cancer cells. (NME, P) 

Imatinib mesylate (Gleevec) received regular approval as a treatment for 

refractory chronic myeloid leukemia, a rare life threatening form of canceraffecting about 40,000 people in the United States. The drug was originally 

approved under the accelerated approval program in 2001. (NDA, P) 

Palonosetron hydrochloride (Aloxi) is an injectable drug for the prevention 

of acute nausea and vomiting associated with initial and repeat courses of 

moderately and highly emetogenic cancer chemotherapy and the prevention 

of delayed nausea and vomiting associated with initial and repeat courses 

of moderately emetogenic cancer chemotherapy. (NME, S) 

Notable 2003 new drug approvals (continued)

New molecular 

entities (cont.)

 Gemifloxacin 

mesylate (Factive) 

 Ibandronate sodium 

(Boniva) 

 Memantine 

hydrochloride 

(Namenda) 

 Miglustat (Zavesca) 

 Palonosetron 

hydrochloride (Aloxi) 

 Pegvisomant 

(Somavert) 

 Prussian blue 

(Radiogardase) 

 Rosuvastatin 

calcium (Crestor) 

 Sertaconazole 

nitrate (Ertaczo) 

 Tadalafil (Cialis) 

 Vardenafil 

hydrochloride (Levitra) 
CDER 2003 Report to the Nation 

16 

Notable 2003 new drug approvals (continued)

Bortezomib (Velcade), an orphan drug, is indicated for the treatment of 

multiple myeloma in patients who have received at least two prior therapies 

and have demonstrated disease progression on the last therapy. (Orphan, 

NME, P) 

Sterile talc powder (Sterile Talc Powder), an orphan drug, is indicated for 

administering intrapleurally via chest-tube as a sclerosing agent to decrease 

the recurrence of malignant pleural effusions in symptomatic patients. The 

pleura is a thin, transparent membrane that covers the lungs and also lines 

the inside of the chest wall. Normally, only a thin layer of fluid separates 

the two layers of the pleura. An excessive amount of fluid, called pleural 

effusion, may accumulate for many reasons, including heart failure, 

cirrhosis, pneumonia and cancer. (Orphan, NDA, P) 

People with HIV infection 

Atazanavir sulfate (Reyataz) is a protease inhibitor to be used in 

combination with other anti-retroviral agents for the treatment of adult 

patients with HIV infection. This drug is the first protease inhibitor that 

only can be taken once daily. It has a low “pill burden” of two pills each 

day. Protease inhibitors block the protease enzyme that HIV needs in order 

to make new viruses. When protease is blocked, HIV makes copies of itself 

that cannot infect new cells. (NME, P) 

Emtricitabine (Emtriva) is indicated for the treatment of HIV infection in 

adults. The drug belongs to the class of anti-HIV agents known as 

nucleoside reverse transcriptase inhibitors that, when used in combination 

with other anti-HIV drugs, can block the replication of HIV in a person’s 

blood. (NME, S) 

Enfuvirtide (Fuzeon) is an injectable drug indicated for the use in 

combination with other antiretroviral agents for the treatment of HIV 

infection in treatment-experienced patients who show evidence of HIV 

replication despite ongoing antiretroviral therapy. The first member of a 

new class of medications called fusion inhibitors, the drug received 

accelerated approval. Enfuvirtide interferes with the entry of HIV into cells 

by inhibiting fusion of viral and cellular membranes. (NME, P) 

People with heart disease 

Rosuvastatin calcium (Crestor) is an adjunct to diet to lower elevated 

cholesterol levels, a risk factor for heart disease. It belongs to the class of 

drugs called HMG-CoA reductase inhibitors, also known as statins. 

(NME, S) 

Drugs@FDA 

Drugs@FDA is a Web 

site where you can find 

official information 

about FDA approved 

brand name and 

generic drugs. Use 

Drugs@FDA to search 

for: 

 Approved and 

tentatively approved 

drug products 

 The regulatory 

history of an approved 

drug 

 Labels for approved 

drug products 

 All drugs with a 

specific active 

ingredient 

 Generic drug 

products for a brandname drug product 

 Therapeutically 

equivalent drug 

products for a brandname or generic drug 

product 

 Consumer 

information for drugs 

approved after 1998 

To use Drugs@FDA, go 

to our home page 

(http://www.fda.gov/

cder) and click on 

“Drugs@FDA.”

Counterterrorism 

treatments 

Insoluble Prussian blue 

(Radiogardase), an 

orphan drug, can be 

used to treat people 

exposed to radiation 

contamination due to 

harmful levels of 

cesium-137 or thallium 

poisoning. The drug 

works by increasing the 

rate of elimination of 

these substances from 

the body. More 

information is at http://

www.fda.gov/cder/

drug/infopage/

prussian_blue/. 

(Orphan, NME, P) 

Pyridostigmine bromide 

tablets (Pyridostigmine 

Bromide) are used as a 

pretreatment to 

increase survival after 

exposure to Soman 

“nerve gas” poisoning. 

The product is 

approved for combat 

use by U.S. armed 

forces. This 

application, sponsored 

by the U.S. Army, is the 

first drug approved 

under the animal 

efficacy rule (page 8).

That 2002 regulation 

allows for use of animal 

data for evidence of a 

drug’s effectiveness 

when the drug cannot 

be ethically or feasible 

tested in humans. 

(NDA, P) 
Improving Public Health Through Human Drugs 

17 

Infectious diseases 

Daptomycin (Cubicin) injection treats complicated skin and skin structure 

infections. These are serious infections, usually occurring in hospitalized 

patients and include major abscesses, post-surgical skin wound infections 

and infected ulcers. Daptomycin is the first approved product in a new class 

of antibiotics called cyclic lipopeptide antibacterial agents. The drug binds 

to bacterial membranes and rapidly upsets electrical balance. This leads to 

inhibition of protein, DNA and RNA synthesis, which results in bacterial 

cell death. (NME, P) 

Gemifloxacin mesylate (Factive) is indicated for the treatment of 

community-acquired pneumonia and acute bacterial exacerbation of 

chronic bronchitis. Gemifloxacin, a synthetic broad-spectrum antibacterial 

agent for oral administration, is related to the fluoroquinolone class of 

antibiotics. (NME, S) 

Sertaconazole nitrate (Ertaczo) cream is indicated for the topical treatment 

of athlete’s foot (interdigital tinea pedis) in immunocompetent patients 12 

years of age and older. Sertaconazole belongs to the imidazole class of 

antifungals. (NME, S) 

People with metabolic disorders 

Miglustat (Zavesca), an orphan drug, is indicated for the treatment of mild 

to moderate Type I Gaucher disease in adults for whom enzyme 

replacement therapy is not a therapeutic option due to constraints such as 

allergy, hypersensitivity or poor venous access. Type 1 Gaucher disease is 

an inborn error of metabolism that results in disease because of a defect in 

an enzyme needed to break down the chemical glucocerebroside. The 

enzyme defect leads to the progressive accumulation of glucocerebroside in 

the spleen, liver and lymph nodes. Miglustat reduces the body’s formation 

of glucocerebroside to a level that allows the residual activity of the 

deficient enzyme to be more effective. (Orphan, NME, S) 

Pegvisomant (Somavert), an orphan drug, is for the treatment of 

acromegaly in patients who have an inadequate response to existing 

therapies or for whom these therapies are not appropriate. Acromegaly is a 

potentially life-threatening disease caused by an excess of growth hormone. 

The drug is the first in a new class called growth hormone receptor 

antagonists. Acromegaly causes changes in facial features and enlarged 

hands, feet and jaw as well as headaches, profuse sweating, swelling and 

joint disorders. If untreated, patients with acromegaly often have a 

shortened life span because of heart and respiratory diseases, diabetes 

mellitus and cancer. (Orphan, NME, P) 

Notable 2003 new drug approvals (continued)

Therapeutic 

biologic reviews 

consolidated 

The review staff and 

review of some new 

biologic products were 

transferred to our 

center in 2003. 

This will enhance the 

efficiency and 

consistency of 

reviewing clinically 

similar products. 

Medicines transferred 

include monoclonal 

antibodies, cytokines, 

growth factors, 

enzymes and other 

therapeutic 

immunotherapies. 

BLA approval 

statistics 

This report will begin 

incorporating statistics 

on consolidated 

therapeutic biologic 

license approvals 

(BLAs) in 2004. 

The Center for 

Biologics Evaluation 

and Research is 

reporting these 

statistics for 2003. 

During the period 

Sept. 1 to Dec. 31, 2003, 

when we had official 

approval authority for 

therapeutic biologics, 

we approved one BLA: 

 Efalizumab 

(Raptiva) is a treatment 

for adult patients 18 

years or older with 

chronic moderate to 

severe plaque psoriasis 

who are candidates for 

systemic therapy or 

phototherapy. 
CDER 2003 Report to the Nation 

18 

People with allergic conjunctivitis 

Epinastine hydrochloride (ELESTAT) ophthalmic solution is an 

antihistamine indicated for the prevention of itching associated with 

allergic conjunctivitis. (NME, S) 

People with bipolar disorder 

Olanzapine and fluoxetine hydrochloride (Symbyax) is a combination of 

two psychotropic agents and is indicated for the treatment of depressive 

episodes associated with bipolar disorder. Olanzapine belongs to the 

thienobenzodiazepine class of drugs, and fluoxetine hydrochloride is a 

selective serotonin reuptake inhibitor. (NDA, P) 

Older people 

Memantine hydrochloride (Namenda) is the first drug approved for the 

treatment of patients with moderate to severe Alzheimer’s disease. Previous 

treatments have been studied in patients with mild to moderate disease. The 

drug is an N-methyl-D-asparate (NMDA) antagonist and is thought to work 

by blocking the action of the chemical glutamate. Although memantine 

hydrochloride helps treat the symptoms of Alzheimer’s disease, there is no 

evidence that it modifies the underlying pathology of the disease. (NME, S) 

Children 

Ribavirin (Rebetol) oral solution, an orphan drug, is to be used as part of 

combination therapy with interferon alpha-2b recombinant (Intron A) for 

the treatment of chronic hepatitis C among previously untreated pediatric 

patients at least 3 years of age or older. The drug, a nucleoside analog, was 

first approved in capsule form in 1998. (Orphan, NDA, P) 

Men 

Tadalafil (Cialis) and vardenafil (Levitra) are oral medications to treat 

erectile dysfunction in men. These are the second and third oral products 

approved for this condition. (Both NME, S) 

Alfuzosin hydrochloride (Uroxatral) is indicated for the treatment of the 

signs and symptoms of benign prostatic hyperplasia. The drug is an alphablocker and may help to relax the muscles in the prostate and the bladder, 

which may lessen the symptoms of BPH and improve urine flow. (NME, S) 

Notable 2003 new drug approvals (continued)

Women 

Ibandronate sodium 

(Boniva), indicated for 

the treatment and 

prevention of 

postmenopausal 

osteoporosis, is a 

bisphosphonate that 

inhibits bone 

resorption. (NME, S)

Estradiol (Estrasorb) 

topical emulsion is an 

estrogen therapy 

product in a topical 

form. The drug treats 

moderate to severe 

symptoms of hot 

flashes and night 

sweats associated with 

menopause. Current 

estrogen products 

available for treatment 

include oral pills, 

transdermal patches 

and a vaginal ring. 

(NDA, S) 

Women (cont.)

A combination of a 

progestin 

(norethindrone) and an 

estrogen (ethinyl 

estradiol) (Ovcon 35) is 

an oral, spearmintflavored contraceptive 

tablet that can be 

chewed or swallowed. 

This dosage form 

provides one more 

alternative to the many 

types of oral 

contraceptives 

currently on the 

market. (NDA, S) 

A combination of a 

progestin 

(levonorgestrel) and an 

estrogen (ethinyl 

estradiol) (Seasonale) 

provides a new 91-day 

oral contraceptive 

regimen. Tablets 

containing the active 

hormones are taken for 

12 weeks, followed by 

one week of inactive 

tablets. Conventional 

oral contraceptive use is 

based on a 28-day 

regimen (21 days of 

active tablets followed 

by seven days of 

inactive tablets). Under 

this drug’s dosing 

regimen, the number of 

expected menstrual 

periods is reduced from 

one a month to about 

one every three months. 

(NDA, S) 
Improving Public Health Through Human Drugs 

19 

New or Expanded Use Review 

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

treatment options, are formally called “efficacy supplements” to the 

original new drug application. 

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

priority supplements in six months. The new and expanded use review 

statistics on this page include figures for both priority and standard 

applications. 

Notable 2003 new or expanded use approvals 

Carvedilol (Coreg) is approved for the treatment of patients with left 

ventricular dysfunction following myocardial infarction. 

Conjugated estrogens and medroxyprogesterone acetate (Prempro) and 

conjugated estrogens (Premarin) are available in lower strength doses for 

the treatment of moderate-to-severe vasomotor symptoms associated with 

menopause and for the treatment of moderate to severe symptoms of vulvar 

and vaginal atrophy associated with the menopause. When prescribing 

solely for the treatment of symptoms of vulvar and vaginal atrophy, topical 

vaginal products should be considered. 

Eplerenone (Inspra) tablets improve the survival of congestive heart failure 

patients who are stablized following an acute heart attack. The drug is the 

first member of the aldosterone receptor blocker class of drugs to receive 

approval for this indication. 

Fondaparinux sodium (Arixtra) injection, used to prevent blood clots, is 

approved for extended prevention therapy in patients undergoing hip 

fracture surgery. In a clinical trial that compared 326 patients receiving the 

drug to 330 patients receiving placebo, blood clots occurred in 1.4 percent 

of those who received the drug compared to 35 percent of those who 

received placebo. During the three-week period of treatment, major 

bleeding rates were 2.4 percent for those administered the drug and 0.6 

percent for those administered placebo.

Leflunomide (Arava) tablets, a treatment for rheumatoid arthritis, had 

revised labeling to support the addition of a claim for improved physical 

function. 

Losartan potassium (Cozaar) has a new use to reduce the risk of stroke in 

patients with hypertension and left ventricular hypertrophy. The indications 

section of the label further notes that there is evidence that this benefit does 

not apply to black patients. 

Polifeprosan 20 with carmustine implant (Gliadel Wafer) had its indication 

expanded to include patients with malignant glioma undergoing primary 

surgical resection. 

Counterterroism 

treatment 

Atropine (AtroPen) 

autoinjector is now 

approved for use in 

children and 

adolescents exposed to 

certain nerve agents or 

insecticides. The 

atropine autoinjector, 

approved since 1973 

for use in adults, 

includes information to 

support two lowerstrength autoinjectors 

(0.5 mg and 1 mg) and 

a revised package 

insert for use in both 

adult and pediatric 

populations. 
CDER 2003 Report to the Nation 

20 

Sirolimus (Rapamune), first approved in 2000 for helping prevent organ 

rejection in transplant patients, will allow new kidney transplant patients at 

low to moderate immunologic risk of organ rejection to stop taking 

cyclosporine two to four months after transplantation. This is the first 

approval of a cyclosporine-sparing regimen for new kidney transplant 

patients. 

Valacyclovir hydrochloride (Valtrex), a treatment for herpes infections first 

approved in 1995, reduces the risk of heterosexual transmission of genital 

herpes to susceptible partners with healthy immune systems when used as 

suppressive therapy in combination with safer sex practices. 

Priority new or 

expanded uses 

(efficacy 

supplements) 

 21 approvals 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 33 actions 

 2 orphan new uses 

 5 priority reviews of 

pediatric labeling 

additions 

Priority New or Expanded Use Approvals

Median times, approvals

6.06.06.06.04.44.46.06.06.06.06.06.06.06.06.06.06.06.0

21 19

6

18

9

7

13

4

4

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

12

24

Approvals

Median FDA review time Median total approval time Number approved

Priority New or Expanded Uses

Actions, approval percentages

597131923103633

53% 64%

60%

80%

57%

78%

47%

100%

78%

0

20

40

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Actions

0%

50%

100% Percent

Actions Percentage of actions that are approvals

Priority new or 

expanded use 

reviews 

 Atovaquone and 

proguanil 

hydrochloride 

(Malarone) 

 Atropine (AtroPen) 

 Busulfan (Busulfex) 

 Carvedilol (Coreg) 

 Divalproex sodium 

(Depakote ER) 

 Eplerenone (Inspra) 

 Fentanyl 

(Duragesic) 

Notable 2003 new or expanded approvals (continued)

Priority new or 

expanded use 

reviews (cont.)

 Fondaparinux 

sodium (Arixtra) 

 Fosinopril sodium 

(Monopril) 

 Imatinib mesylate 

(Gleevec) [2 approvals] 

 Leflunomide 

(Arava) 

 Losartan potassium 

(Cozaar) 

 Orlistat (Xenical) 

 Polifeprosan 20 with 

carmustine implant 

(Gliadel Wafer) 

 Porfimer sodium 

(Photofrin) 
Improving Public Health Through Human Drugs 

21 

Orphan approvals 

Porfimer sodium (Photofrin), a cancer treatment first approved in 1995, is 

now approved for the ablation of precancerous lesions in Barrett’s 

esophagus patients who do not undergo surgery to remove the esophagus. 

The drug is a photosensitizing agent that can kill cells, including cancer 

cells, when they are exposed to a particular type of light. A small number 

of people with Barrett’s esophagus develop pre-cancerous lesions that 

progress to an often deadly type of cancer of the esophagus called 

esophageal adenocarcinoma. 

Somatropin rDNA origin (Zorbtive), a human growth hormone (hGH) 

produced by recombinant DNA technology, treats short bowel syndrome in 

patients receiving specialized nutritional support. In human clinical studies, 

the administration of growth hormone has been shown to enhance the 

transmucosal transport of water, electrolytes and nutrients. 

Standard New or Expanded Use Approvals

Median times, approvals

16.717.812.614.811.912.011.912.011.011.310.010.010.711.310.010.010.010.0

110

133

85

116

88

111 111 104

65

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

80

160

Approvals

Median FDA review time Median total approval time Number approved

Standard New or Expanded Uses

Actions, approval percentages

180187182160165182203237177

37%

47%

32% 36%

36%

61%

39%

69%

59%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Actions

0%

50%

100% Percent

Actions Percentage of actions that are approvals

Standard new or 

expanded uses 

(efficacy 

supplements) 

 110 approvals 

 Median review 

time: 10.0 months 

 Median approval 

time: 10.0 months 

 177 actions 

Notable 2003 new or expanded approvals (continued)
CDER 2003 Report to the Nation 

22 

Notable pediatric new or expanded uses 

Atovaquone and proguanil hydrochloride (Malarone Pediatric Tablets) can 

be used for the treatment of Plasmodium falciparum malaria in pediatric 

patients weighing 11 pounds to 24.2 pounds. 

Budesonide (Pulmicort) is approved for use in asthma patients 6 to 12 

months; safety information from the study supports the finding that use of 

the drug in this population may result in systemic effects such as growth 

suppression. 

Busulfan (Busulfex) injection, a treatmnent for leukemia, incorporates new 

pediatric information on dosing, pharmacokinetics and safety. 

Divalproex (Depakote ER) is now approved for use in pediatric patients for 

epilepsy. 

Fentanyl (Duragesic) transdermal system is approved to treat pain in 

opioid-tolerant pediatric patients 2 years of age and older. The label 

contains new warning that the drug should only be administered to children 

if they are opioid-tolerant and 2 years or older. 

Fluticasone propionate (Flonase and Cutivate). A new study with Flonase 

nasal spray revealed no significant effect on growth as compared to 

placebo. Cutivate ointment is only indicated for use in adults; in a pediatric 

study a lower than normal adrenal function was observed. 

Fluoxetine hydrochloride (Prozac) was approved to treat children and 

adolescents 7 to 17 years old for depression (major depressive disorder) 

and obsessive compulsive disorder. The studies revealed a decrease in both 

height and weight gain as compared to placebo. 

Fosinopril sodium (Monopril) incorporates pediatric labeling changes in 

clinical pharmacology, precautions, adverse reactions, overdosage, and 

dosage and administration sections of the labeling. 

Imatinib mesylate (Gleevec) is approved for pediatric patients with Ph+ 

chronic phase chronic phase chronic myeloid leukemia whose disease has 

recurred after stem cell transplant or who are resistant to interferon alpha 

therapy. The clinical benefit for pediatric patients was extrapolated from 

adult data. 

Lisinopril (Prinivil and Zestril) is labeled for treatment of hypertension in 

patients 6 to 16 years of age; information on the preparation of a 

suspension is provided. 

Orlistat (Xenical) has revised labeling to provide for use in the 

management of obesity in adolescent patients aged 12 to 16 years. 

Pediatric Research 

Equity Act of 2003 

This law gives FDA the 

authority to require 

pediatric studies of new 

drugs and biologics 

when such studies are 

needed to ensure the 

safe and effective use of 

these products in 

children. 

Internet resources 

Our Web site for up-todate pediatric labeling 

changes is at http://

www.fda.gov/cder/

pediatric/index.htm. 

Priority pediatric 

labeling changes 

An efficacy supplement 

may change labeling to 

reflect new information 

about pediatric use, 

even if there are no 

new or expanded uses. 

Consistent with the 

mandate in the Best 

Pharmaceuticals for 

Children Act, these 

pediatric supplements 

received priority 

reviews last year: 

 Atovaquone/

proguanil 

 Fentanyl 

 Fexofenadine 

hydrochloride 

(2 approvals) 

 Fexofenadine 

hydrochloride and 

pseudoephedrine 

hydrochloride 

 Fludarabine 

phosphate 

 Fluticasone 

 Fosinopril 
Improving Public Health Through Human Drugs 

23 

Conditions with 

approved pediatric 

labeling 

 Abnormal heart 

rhythms 

 Allergies 

 Anesthesia and 

sedation 

 Asthma 

 Atopic dermatitis 

 Attention deficit/

hyperactivity disorder 

 Diabetes mellitus 

(Type 1 and Type 2) 

 Gastroesophageal 

reflux 

 High blood pressure 

 High cholesterol 

 High eye pressure 

 HIV infection 

 Infectious diseases 

 Juvenile rheumatoid 

arthritis 

 Low levels of 

calcium associated with 

severe kidney disease 

 Malaria 

 Obesity 

 Obsessive 

compulsive disorder 

 Pain 

 Seizures 

 Severe recalcitrant 

nodular acne 

 Nerve agent 

poisoning 

Pediatric Drug Development 

The Best Pharmaceuticals for Children Act of 2002 renewed our authority 

to grant six months of additional marketing exclusivity to manufacturers 

who conduct and submit pediatric studies in response to our written 

requests. Last year, we approved 15 pediatric labeling changes as a result of 

the exclusivity provision. Also, we approved one new molecular entity for 

use in children (page 18). 

As of March 31, 2004, we had received 346 proposed pediatric study 

requests from manufacturers, issued 284 written requests, made 109 

exclusivity determinations and added new pediatric information to 71 

labels. 

Approximately one-fourth of the new pediatric labels have important 

dosing or safety information. Important differences in clearance and 

metabolism of products are being discovered. This is important because 

underdosing leads to ineffective treatment and overdosing poses a greater 

risk of adverse reactions. Pediatric safety signals that have been identified 

include effects on growth, school behavior and suppression of the adrenal 

gland. As a result of this pediatric testing we now have eight drugs with 

new pediatric formulations and six drugs with recipes in their label that 

provide directions for the pharmacist to compound an age-appropriate 

formulation. The failure to produce drugs in dosage forms that can be taken 

by young children such as liquids or chewable tablets can also deny them 

access to important medications. 

The BPCA also established a publicly funded contracting process to study 

drugs that lack patent protection or market exclusivity, referred to as “offpatent.” In consultation with FDA and other pediatric experts, the National 

Institutes of Health has published three lists of off-patent drugs for which 

additional pediatric studies are needed. We have issued and forwarded 

seven written requests for these off-patent drugs to NIH for study through 

their contracting process. In addition, we have forwarded four written 

requests for on-patent drugs, which were declined by sponsors, to the 

Foundation for the National Institutes of Health for study. 

Pediatric Drug Development

4 12 17 23 20 23

2 3

11 12 19 15

31

98

45

69

21 24

0

60

120

1998 1999 2000 2001 2002 2003

Calendar year

Pediatric exclusivity determinations Pediatric exclusivity labeling changes

Written requests issued

2003 pediatric drug 

statistics 

 23 exclusivity 

determinations made 

 15 pediatric 

exclusivity labeling 

changes granted 

 24 written requests 

issued 

FDA 

commissioner’s 

office oversees 

pediatric issues 

The Best 

Pharmaceuticals for 

Children Act of 2002 

mandated the creation 

of the Office of 

Pediatric Therapeutics, 

which began operations 

in October 2002 in the 

Commissioner’s office. 

This office oversees all 

pediatric issues within 

FDA including 

institutional review 

board referrals to FDA, 

safety issues, ethical 

issues and pediatric 

trial oversight. 

The office is also 

responsible for the new 

Pediatric Advisory 

Committee that was 

authorized as part of 

the Pediatric Research 

Equity Act. 
CDER 2003 Report to the Nation 

24 

User Fee Program 

Americans deserve timely access to potentially lifesaving new drugs as 

soon as possible once they are proven safe and effective. The Prescription 

Drug User Fee Act of 1992 received its third five-year extension in 2002, 

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

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

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

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

includes increased consultations with drug sponsors and provided for 

earlier feedback on their submissions. Although our resources from 

PDUFA III are higher than from PDUFA II, our total resources for new 

drug review have not increased as much as we expected. 

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

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

proportion of submissions whose fees were waived. The expectation that 

the reauthorization would put the user fee program on a sound financial 

basis has only been partially met. 

We are concerned about the safety of new medicines following approval. In 

recent years, 50 percent of all new drugs worldwide have been launched in 

the United States, and American patients have had access to 78 percent of 

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

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

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

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

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

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

trials. 

Full information on PDUFA III, including the latest performance and 

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

PDUFA3.html. 

User fee 

performance 

Under legislation 

authorizing us to 

collect user fees for 

drug reviews, we 

agreed to specific 

performance goals for 

the prompt review of 

submissions. 

 We met or exceeded 

all our performance 

goals for the fiscal year 

2002 receipt cohort. 

 We are on track for 

meeting or exceeding 

all user-fee 

performance goals for 

fiscal year 2003. 

Internet resources 

for user fees 

Our user fee Web site 

has links to more 

documents and 

information including 

our user fee 

performance report to 

Congress. 

The page is at http://

www.fda.gov/cder/

pdufa/default.htm.

End-of-Phase-2A-Meeting Pilot 

Making better use of data collected early in drug development could help 

sponsors avoid some pitfalls that lead to either an extra cycle of review or 

Phase 4 commitments. We are undertaking a pilot program to discuss this 

early data with drug sponsors voluntarily at an End-of-Phase-2A meeting. 

We think this will improve dose selection and study design for subsequent 

clinical trials. More information is available in a concept paper we issued in 

October 2003 (http://www.fda.gov/ohrms/dockets/ac/03/

briefing/3998B1_01_Topic%201-Part%20A.pdf). 
Improving Public Health Through Human Drugs 

25 

Over-the-Counter Drug Review 

We approved one new Rx-to-OTC switch. We approved two supplemental 

applications for existing OTC products, one of which can be used by 

children. The approvals are: 

 Omeprazole magnesium (Prilosec OTC) is the first OTC treatment for 

frequent heartburn in consumers 18 years of age and older. This 

previously prescription-only drug stops acid production at its source in 

the stomach. It works differently than the other two classes of OTC 

heartburn treatments: antacids and acid reducers. 

 Famotidine (Pepcid AC) prevents and temporarily relieves heartburn in 

consumers 12 years of age and older. This approval was for a higher 

OTC dose. 

 Loratadine hydrochloride (Claritin Hives Relief) temporarily relieves 

itching due to hives for adults and children 6 years and older. This 

antihistamine was first approved OTC for the temporary relief of 

allergy symptoms in 2002. This approval was a new use to be marketed 

under the brand name Claritin Hives Relief. 

Education campaign on safe use of OTCs 

We developed a national education campaign to provide advice on the safe 

use of over-the-counter pain and fever reducers. 

The campaign focuses on OTC drug products that contain acetaminophen 

and non-steroidal anti-inflammatory agents, which include products such as 

aspirin, ibuprofen, naproxen sodium and ketoprofen. 

Many OTC medicines sold for different uses have the same active 

ingredients. To minimize the risks of an accidental overdose, we are trying 

to educate consumers to avoid taking multiple medications that contain the 

same active ingredient at the same time. 

You can learn more about this educational campaign at our Web site: 

http://www.fda.gov/cder/drug/analgesics/. 

Over-the-counter 

drug statistics 

 1 new Rx-to-OTC 

switch 

 2 new uses 

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. 

More information 

about the OTC drug 

review process is at 

http://www.fda.gov/

cder/about/smallbiz/

OTC.htm. 

Improved labels 

for OTC medicines 

American consumers 

are benefiting from 

easy-to-understand 

labels on drugs they 

buy without a 

prescription. 

A mandatory 

changeover to the new 

labels, titled “Drug 

Facts,” began in 2002. 

OTC New Approvals & New Uses

8

13

1 1

7

2

5

9

6

8

20

3

1 1

3

0

12

24

1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

New approvals or Rx-to-OTC switches New uses
CDER 2003 Report to the Nation 

26 

Notable 2003 generic drug approvals 

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

 Paroxetine (Paxil) used to treat depression. 

 Gabapentin (Neurontin) used to treat certain kinds of seizures. 

 Mirtazapine (Remeron) used to treat depression. 

 Quinapril (Accupril) used to treat hypertension. 

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. 

Tentative vs. full approval 

We also issued 101 tentative approvals. While full approvals decreased 

from 321 to 263, the tentative approvals increased from 63 to 101. The 

review of an application that is tentatively approved requires the same 

amount of work as a review that results in a full approval. 

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 263 approvals in 2003 represent 

conversions of tentative approvals granted in 2003 or previous years. 

Electronic 

submissions 

Through public 

presentations, we are 

encouraging the 

generic drug industry 

to submit their 

applications 

electronically. 

More information 

electronic submissions 

is on page 29.

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. 

For many products 

such as tablets and 

capsules, the generics 

must show 

bioequivalence to the 

brand-name reference 

listed drug. This means 

that the generic version 

must deliver the same 

amount of active 

ingredient into a 

patient’s bloodstream 

and in the same time as 

the brand-name 

reference listed drug. 

The rate and extent of 

absorption is called 

bioavailability. The 

bioavailability of the 

generic drug is then 

compared to that of the 

brand-name. This 

comparison is 

bioequivalence. 

Brand-name drugs are 

subject to the same 

bioequivalency tests as 

generics when their 

manufacturers 

reformulate them. 

Generic drug 

Web site 

You can find more 

information about our 

generic drug program 

at http://www.fda.gov/

cder/ogd/.

Generic Drug Review 

We approved 263 generic drug products in 2003, including a substantial 

number of products that represent the first time a generic drug was available for the brand-name product. The median approval time for generic 

drugs was 17 months. 

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

months for six years. We made changes to decrease the overall time to approval of applications by three months over the next three to five years. We 

are improving the efficiency of our generic drug review process and increasing the number of chemistry reviewers by one-third. 
Improving Public Health Through Human Drugs 

27 

Generic drug 

statistics 

 263 generic drug 

approvals 

 Median approval 

time: 17.0 months 

 101 tentative 

approvals 

 479 receipts 

Generic Drug Approvals

Median times, approvals

27.023.019.318.018.618.218.118.317.0

321

244 234

186

225

273 212

207

263

0

18

36

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Months

0

200

400

Number

Median approval times Number of generic approvals

Generic Drug Tentative Approvals 

1525404056617363101

0

60

120

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Tentative approvals

New law aims to speed approval of generics 

Provisions of the Medicare Prescription Drug, Improvement and 

Modernization Act of 2003, which became law on Dec. 3, 2003, are 

expected to decrease time-consuming legal delays in the approval and 

marketing of generic products. 

The law incorporates much of the substance of our final regulation issued 

in 2002, particularly the limitation on 30-month stays that may delay 

availability of generic drugs. The law codifies several points regarding 

patent notification and forfeiture of 180-day exclusivity on the part of a 

generic applicant. 

We are working on new regulations to implement the law. 
CDER 2003 Report to the Nation 

28 

Generic Drug Applications Received

283307330345296365320392479

0

250

500

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Applications received (workload in future years)

Consumer 

communication 

Our efforts to build 

consumer confidence in 

generic drug products 

are continuing through 

our Generic Drug 

Quality Awareness 

program. 

We have partnered 

with a number of 

professional and 

consumer 

organizations to launch 

programs about the 

quality and benefits of 

generic drugs. We have 

helped design messages 

that appear on 

prescription bags in 

CVS and Kmart. We 

have partnered with 

Express Scripts to get 

the word out to their 

consumers about the 

quality and value of 

generic products. 

Radio public service 

announcements with 

the generic drug 

quality message will be 

appearing in several 

geographic areas. 

Our generic drug 

public service 

announcements are at 

http://www.fda.gov/

cder/consumerinfo/

generic_info/

default.htm. 

Generic drug review efficiencies 

Receipts of generic drug application increased more than one-fifth in 2003 

to 479 from 392 in 2002. This dramatic increase in applications makes it 

imperative that we have the ability to process generic drug applications 

more efficiently 

We are continue to look for ways to improve our process and also to 

provide communication and guidance to industry, with the overall goal of 

getting generic drug products to the consumer as efficiently as possible. 

We are taking steps aimed at improving the content and completeness of 

generic drug applications and assuring that the applications contain the 

needed information to be evaluated successfully in one cycle. These steps 

include: 

 Enhanced communication with individual applicants during the review 

process. 

 A collaborative effort with the Generic Pharmaceutical Association to 

assist the industry. Over the past year, this project has already resulted 

in six important meetings between us and members of the generic drug 

industry. 

 Two “ANDA Basics” workshops held to assist generic drug makers in 

understanding the review process and provide training on how to 

prepare a generic drug application, known formally as an abbreviated 

new drug application or ANDA. 

 Efforts to encourage submission of applications in an electronic format 

for greater efficiency. 

Increased generic 

drug review staff 

We have constituted a 

third chemistry review 

division for generic 

drugs. 

We are augmenting our 

clinical review staff to 

further speed our 

review of generic drug 

applications. 

Scientific basis for 

generic drug 

review 

We have continued to 

articulate the scientific 

underpinnings of our 

review process and to 

work to define 

mechanisms to evaluate 

equivalence of certain 

unique products. 
Improving Public Health Through Human Drugs 

29 

Antimicrobial resistance 

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

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

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

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

inappropriate prescription of antibiotics to children and adults for common 

ailments such as ear infections and chronic coughs. 

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

drug/antimicrobial/default.htm. 

Antimicrobial 

resistance 

education 

campaign 

Last year, we joined 

with the Centers for 

Disease Control and 

Prevention to launch 

an education campaign 

on antibiotic resistance. 

The campaign includes 

print, radio and TV 

public service 

announcements and 

brochures. 

We are both now 

working on materials 

for the Spanishspeaking audience. 

Electronic Submissions 

The number of new drug applications submitted electronically, the number 

of participating companies and the number of applications with electronic 

components continues to grow. 

The major change last year was the inclusion of two additional types of 

submissions that can be provided in electronic format: investigational new 

drug applications and drug master files. 

Electronic submissions following the electronic Common Technical 

Document (page 45) specifications provide our reviewers significant

advantages over paper submissions and electronic submissions following 

past specifications. 

The eCTD allows our reviewers to build a cumulative table of contents for 

viewing the entire life cycle of the applications. The CTD and eCTD 

standardized table of contents puts the same information in the same place 

every time regardless of application type. 

This reduces the amount of time reviewers spend trying to find where 

information is located. It not only improves the efficiency of finding 

documents but also provides a comprehensive picture of the changes to the 

application over time. This is particularly useful in the efficient reviewing 

continuous marketing applications under PDUFA. 

Last year, we made further strides in establishing standards for the 

submission of clinical and animal toxicity study data and annotated 

electrocardiogram waveform data. 

We cooperation with outside organizations working to publish standards 

for the submission of study data. These groups include the Clinical Data 

Interchange Standards Consortium and the Standard for Exchange of Nonclinical Data consortium working through Health Level Seven. 

We continue to receive individual case safety reports and other postmarketing reports from manufacturers in electronic format, including 

adverse event reports (page 35).

All submissions 

can use eCTD 

As of August 2003, we 

are able to receive all 

applications and 

related submissions in 

electronic format 

following the electronic 

Common Technical 

Document 

specifications. This 

includes: 

 New drug 

applications 

 Generic drug 

applications 

 Biologics licensing 

applications 

 Investigational new 

drug applications 

 Drug master files 

Internet resources 

 The guidance and 

specifications for the 

eCTD may be found at 

http://www.fda.gov/

cder/regulatory/

guidance

 More information 

on our electronic 

submissions program is 

at http://www.fda.gov/

cder/regulatory/ersr/
CDER 2003 Report to the Nation 

30 

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. 

We are working with medical review divisions and pharmaceutical 

companies to update product labels with available data regarding human 

pregnancies exposed to drugs during pregnancy. 

Improving knowledge about use of drugs in pregnancy 

In many cases, a disease or condition left untreated may be more harmful to 

a woman and her fetus or baby than a drug treatment. To improve our 

knowledge of how drugs work during pregnancy and when women are 

nursing, we have provided guidance to industry and our reviewers as well 

as sponsored research. 

 In 2002, we published a final guidance that provides sponsors with 

advice on how to establish pregnancy exposure registries. Registries 

that prospectively monitor the outcomes of pregnancies in women 

exposed to a specific drug can provide clinically relevant human data 

for treating or counseling patients who are pregnant or anticipating 

pregnancy. 

 We are working to finalize a guidance for our reviewers on how to 

evaluate the outcomes of human pregnancies exposed to drug products 

during pregnancy. This guidance was published in draft form in 1999. 

 We are working on numerous guidances that address study design 

issues for determining the appropriate dose of a drug for pregnant 

women and nursing mothers. These pharmacokinetic studies evaluate 

the action of a drug over time during pregnancy and lactation, including 

the processes of absorption, distribution, localization in tissues, 

biotransformation and excretion. 

 We have funded several studies to evaluate whether or not the dose a 

drug should be adjusted for pregnant women. Pharmacodynamic studies 

evaluate the biochemical and physiological effects of a drug and the 

mechanism of its actions, including the correlation of actions and 

effects of a drug with its chemical structure. 

 We funded studies to look at specific anti-infective drug products that 

would be used to treat specific bioterrorism agents in special 

populations, such as children, women who are pregnant or nursing and 

the elderly. 

Research on high 

blood pressure in 

pregnancy 

FDA’s Office of 

Women’s Health has 

funded studies to look 

at specific 

antihypertensive agents 

used to treat high blood 

pressure in pregnancy. 
Improving Public Health Through Human Drugs 

31 

Assessing Data Quality, Research Risks 

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

rely on human volunteers to take part in clinical studies and high quality 

laboratory studies. Protecting volunteers from research risks is a critical 

responsibility for us and all involved in clinical trials. 

We perform on-site inspections to protect the rights and welfare of 

volunteers and verify the quality and integrity of data submitted for our 

review. We inspect domestic and foreign clinical trial study sites; 

institutional review boards; sponsors, monitors and organizations 

conducting research; laboratories that obtain data; and sites performing 

bioequivalence studies in humans (see “How we approve generic drugs,” 

page 26) and preclinical studies in animals. 

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. 

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 for 

data quality, 

research risks 

in 2003 

We conducted a total of 

728 inspections in 2003 

compared to 589 in 

2002: 

 324 U.S. clinical 

investigators 

 44 foreign clinical 

investigators 

 154 institutional 

review boards 

 17 sponsors, 

monitors or contract 

research organizations 

 87 good laboratory 

practices 

 102 in-vivo

bioequivalence 

International 

inspections of 

clinical research 

We have conducted 510 

inspections of clinical 

research in 53 

countries from 1980 to 

2004. 

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 46) and the 

Declaration of Helsinki. 

Inspections for Data Quality, Research Risks

297

64

61

49

38

30

191

155

139

154

1

4

10

2828

15

52

5454

47

50

32

88

83

91

75

61

70

102

246

293

324

276

258

296

42

44

166

184

143

17

87

0

400

1997 1998 1999 2000 2001 2002 2003

Calendar year

U.S. clinical investigators Foreign clinical investigators Institutional review boards

Sponsors, monitors, CROs Good laboratory practices In-vivo bioequivalence
CDER 2003 Report to the Nation 

32 

Drug Review Team 

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

individual special technical expertise to review applications: 

 Biologists, biochemists and immunologists evaluate the manufacturing 

processes for biological products to ensure the continued purity, 

potency and safety of these products. They also provide insights to the 

review team regarding the mechanism of action and potential and 

observed adverse events associated with specific products. 

 Chemists focus on how a 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. 

 Clinical pharmacologists and biopharmaceutists evaluate factors that 

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

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

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

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

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

relationships and check for interactions between drugs. 

 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. 

 Pharmacologists and toxicologists evaluate the effects of the drug on 

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

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

cancer in humans. 

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

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

outweigh its known risks at the doses proposed. 

 Project managers orchestrate and coordinate the drug review team’s 

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

expert for the review team and as the primary contact for the drug 

industry. 

 Statisticians evaluate the designs and results for each important clinical 

study. 

Scientific training 

for reviewers 

Our systematic, 

internal training 

program is based on 

core competencies, 

learning pathways and 

individual development 

plans. 

 The program grew 

from seven activities 

offered in 1997 to more 

than 40 in science and 

science policy. 

 We offer 44 courses 

in job skills, research 

tools, leadership and 

management. 

 Reviewer 

participants increased 

six-fold, from about 

250 in 1997 to 1,500 

currently. 

 Last year, we 

brought in 40 visiting 

professors to talk 

directly to individual 

review divisions about 

critical, new drugrelated research and 

techniques. 

Advanced 

scientific 

education 

A committee of our 

scientists oversees a 

program of scientific 

training, seminars, case 

study rounds and guest 

lectures. 

This multidisciplinary 

program helps keep 

our scientists up-todate on the latest 

developments in their 

fields and current 

industry practices. 

Academics to 

CDER 

Each spring, we 

collaborate with five 

local universities to 

present special courses 

on the most critical 

needs and interest of 

our reviewers. Recent 

topics were: 

 2004: Applying 

exposure-response 

concepts to drug 

development 

 2003: Drug safety 

assessment tools 

 2002: Pharmacogenetics 

 2001: Assessment of 

QT prolongation 

(cardiac arrhythmia) in 

drug development 
Improving Public Health Through Human Drugs 

33 

2 

DRUG SAFETY

AND QUALITY

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

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

degree of uncertainty always exists about the risks of drugs. This 

uncertainty requires our continued vigilance, along with that of the 

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

We monitor the quality of marketed drugs and their promotional materials 

through product testing and surveillance. As Americans are increasingly 

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

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

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

drug labeling, current good manufacturing practices, clinical and good 

laboratory practices and industry practices to demonstrate the safety and 

effectiveness of drugs. 

Highlights of drug safety and quality activities in 2003 include: 

 Processing and evaluating 370,887 reports of adverse drug events, 

including 29,955 submitted directly from individuals. 

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

due to error-prone labeling. 

 We held a public workshop to gather consumer and scientific input on 

our proposals for risk management strategies during drug development 

and after a drug is marketed. 

 Signing a cooperative research and development agreement to develop 

advanced software tools for quantitative analysis of drug safety data. 

 Proposing a regulation that calls for over-the-counter medicines 

commonly used in hospitals and all prescription medicines to have a bar 

code. The rule became final in 2004. 

 Issuing 737 letters to help ensure that the promotion of drug products 

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

misleading. 

 Clarifying our policy on prescription drugs that are sold without a 

prescription and providing an incentive to have them incorporated into 

the U.S. drug regulatory system. 

 Developing technology for the rapid identification of counterfeit drug 

products. 

 Conducting shelf-life extensions for stockpiled drugs. 

Mission 

We protect the public 

health by ensuring that 

human drugs are safe 

and effective. 
CDER 2003 Report to the Nation 

34 

Known side effects 

Unavoidable Avoidable 

Medication 

errors 

Product quality 

defects 

Preventable 

adverse 

events 

Injury 

or death 

Remaining 

uncertainties 

 Unexpected side effects 

 Unstudied uses 

 Unstudied populations 

Sources of Risk from Drug Products 

Types of Risks from Medicines 

Product quality defects. These are controlled through good manufacturing 

practices, monitoring and surveillance. 

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

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

medicines. Some are avoidable, and others are unavoidable. 

 Avoidable. In many cases drug therapy requires an individualized 

treatment plan and careful monitoring. Other avoidable side effects are 

known drug-drug interactions. 

 Unavoidable. Some known side effects occur with the best medical 

practice even when the drug is used appropriately. Examples include 

nausea from antibiotics or bone marrow suppression from 

chemotherapy. 

Medication errors. For example, the drug is administered incorrectly or the 

wrong drug or dose is administered. 

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

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

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

premarket testing. 

Drug Safety 

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

variety of tools and disciplines. We maintain a system of postmarketing 

surveillance and risk assessment programs to identify adverse events that 

did not appear during the drug development process. We monitor adverse 

events such as adverse reactions, drug-drug interactions and medication 

errors. 

Risk management 

public workshop, 

concept papers 

We held a three-day 

public workshop to 

discuss riskmanagement activities 

in April 2003. Before 

the workshop, we 

issued three concept 

papers for discussion: 

 Premarketing Risk 

Assessment 

 Risk Management 

Programs 

 Risk Assessment of 

Observational Data: 

Good Pharmacovigilance Practices 

The concept papers, 

presentations and 

transcripts of the 

workshops served as 

the basis for draft 

guidances issued in 

May 2004 at http://

www.fda.gov/bbs/

topics/news/2004/

new01059.html.
Improving Public Health Through Human Drugs 

35 

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

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

public health significance of adverse event reports we receive. 

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

assessments and decisions about the most appropriate way to manage any 

new risk or new perspective on a previously known risk. Risk management 

methods may include new labeling, drug names, packaging, “Dear Health 

Care Practitioner” letters, education or special risk communications, 

restricted distribution programs or product marketing termination. 

Adverse Event Reporting System 

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

computerized system combines the voluntary adverse drug reaction reports 

from MedWatch and the required reports from manufacturers. These 

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

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

further testing of the hypothesis is undertaken using various 

epidemiological and analytic databases, studies and other instruments and 

resources. AERS offers paper and electronic submission options, 

international compatibility and pharmacovigilance screening. 

Electronic submissions 

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

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

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

accepting electronic individual case safety reports from six major drug 

firms. Electronic submissions into AERS represent 21 percent of the total 

expedited reports we received in 2003. We estimate the cost of receiving a 

report is reduced at least 30 percent per report for those submitted 

electronically. 

Adverse event 

reporting 

In 2003, we received 

370,887 reports of 

suspected drug-related 

adverse events: 

 22,955 MedWatch 

reports directly from 

individuals 

 144,310 

manufacturer 15-day 

(expedited) reports 

 58,998 serious 

manufacturer periodic 

reports 

 144,624 nonserious 

manufacturer periodic 

reports

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 serious and 

unexpected adverse 

events to us as soon as 

possible but 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

370,887 322,681

278,143 266,971 286,738

247,604

212,843

191,865 156,477

0

250,000

500,000

1995 1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Direct (MedWatch) 15-day Periodic Nonserious periodic
CDER 2003 Report to the Nation 

36 

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/elist.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, product quality problems and 

medication errors for all FDA-regulated medical products. Reports can 

be filed by mail, fax, telephone or the Internet. Direct reports, primarily 

from healthcare professionals, have increased by 51 percent from 1998 

to 2003. 

 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. 

Individual healthcare professional and consumer subscribers to our e-mail 

notification service increased to more than 40,000. We also have 170 

MedWatch Partner organizations. Last year, These individuals and groups 

received: 

 33 safety alerts for drugs. 

 25 to 45 safety-related labeling changes for drugs each month. 

Medication Guides 

We may require specific written patient information for selected 

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

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

distributed to patients with each prescription dispensed. We require 

Medication Guides when the information is necessary for patients to use 

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

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

innovator product and generic lindane and isotretinoin products: 

 Mefloquine hydrochloride (Lariam). 

 Lindane Shampoo (generic product). 

 Lindane Lotion (generic product). 

 Isotretinoin (Claravis) and Isotretinoin (Sotret), Medication Guide 

previously approved for Accutane and Amnesteem. 

Drugs with special 

safety restrictions 

Controls on 10 

prescription drugs 

include limiting 

distribution to specific 

facilities; limiting 

prescription to 

physicians with special 

training or expertise; 

or requiring certain 

medical tests with their 

use. 

Consumers should not 

buy these drugs over 

the Internet. 

As of April 30, 2003, 

these drugs are: 

 Alosetron 

 Bosentan 

 Clozapine 

 Dofetilide 

 Fentanyl citrate 

 Isotretinoin 

 Mifepristone 

 Sodium oxybate 

 Thalidomide 

 Trovafloxacin 

mesylate or 

alatrofloxacin mesylate 

injection 

More information is at 

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

buyonline/

consumeralert120902.

html. 

Data mining 

We signed a two-year 

data mining 

cooperative research 

and development 

agreement with a 

commercial firm to 

develop advanced 

software tools for 

quantitative analysis of 

drug safety data. 

Data mining for simple 

drug-event signal 

generation is one part 

of the potential 

contribution data 

mining and related 

quantitative methods 

can make to increase 

our awareness and 

understanding of 

trends and patterns in 

adverse drug reactions. 
Improving Public Health Through Human Drugs 

37 

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.

Estrogen labeling 

safety changes 

We made safety 

changes to the labeling 

of all estrogen and 

estrogen with progestin 

products for use by 

postmenopausal 

women to incorporate 

new risk information 

and to emphasize 

individualized decisions 

that appropriately 

balance the benefits 

and the potential risks 

of these products. 

These changes, 

including a boxed 

warning, reflect our 

analysis of the 

landmark Women’s 

Health Initiative study, 

sponsored by the 

National Institutes of 

Health. The study 

showed that 

postmenopausal 

women taking estrogen 

plus progestin have an 

increased risk of heart 

attack, stroke, breast 

cancer and blood clots. 

Complete information 

is at http://

www.fda.gov/cder/

drug/infopage/

estrogens_progestins/

default.htm. 

Medication Error Prevention 

Avoiding name, label, packaging confusion 

We work hard to ensure the safe use of drugs we approve by weeding out 

brand names that look or sound like the names of existing products. We 

identify and avoid brand names, labels and packaging that might contribute 

to problems or confusion in prescribing, dispensing or administering. 

We review about 250 reports of medication errors each month. About half 

are due to error-prone labeling such as look-alike labels, poor package 

design and confusing names. We provide a root cause analysis of these 

reports that may result in revisions to the label, labeling, and/or packaging 

of these products to avert further error. 

Our comprehensive Web site on medication errors is at 

http://www.fda.gov/cder/drug/MedErrors/default.htm.

Bar codes to be required on medicines in hospitals

In March 2003, we proposed a regulation that called for over-the-counter 

medicines commonly used in hospitals and all prescription medicines to 

have a bar code. The rule became final in February 2004. 

The bar-code rule aims to protect patients from preventable medication 

errors by helping ensure that health professionals give patients the right 

drugs at the appropriate dosages and at the right time. The rule will support 

and encourage widespread adoption of advanced information systems that, 

in some hospitals, have reduced medication error rates by as much as 85 

percent. 

We estimate that the rule will help prevent nearly 500,000 adverse events 

and transfusion errors while saving $93 billion in health costs over 20 

years. 

DailyMed update 

We are collaborating 

on a multi-agency 

effort to improve 

patient safety through 

accessible medication 

information. Called 

DailyMed and still in 

development, the 

project will enable us—

through the National 

Library of Medicine—

to provide an up-todate electronic 

repository of 

medication labeling in 

a standard format. 

This information will 

be useable in computer 

systems that support 

patient safety, such as 

electronic prescribing 

and decision-support 

systems. 
CDER 2003 Report to the Nation 

38 

Top 10 reasons for 

drug recalls in 

fiscal year 2003: 

 cGMP deviations 

 Subpotency 

 Stability data does 

not support expiration 

date 

 Generic drug or 

new drug application 

discrepancies 

 Dissolution failure 

 Label mix-ups 

 Content uniformity 

failure 

 Presence of foreign 

substance 

 pH failures 

 Microbial 

contamination of nonsterile products 

Drug Recalls 

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

in the manufacture or distribution of the product that may present a 

significant risk to public health. These problems usually, but not always, 

occur in one or a small number of batches of the drug. The most common 

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

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

must be withdrawn completely. 

Manufacturers or distributors usually implement voluntary recalls in order 

to carry out their responsibilities to protect the public health when they 

need to remove a marketed drug product that presents a risk of injury to 

consumers or to correct a defective drug product. A voluntary recall of a 

drug product is more efficient and effective in assuring timely consumer 

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

How we coordinate drug recalls 

We coordinate drug recall information, assist manufacturers or distributors 

in developing recall plans and prepare health hazard evaluations to 

determine the risk posed to the public by products being recalled. 

We classify recall actions in accordance to the level of risk. We participate 

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

product and other factors including the extent of distribution of the product 

to be recalled. 

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

with public notification about the recall. 

Drug Recalls

191

226 248 254

60 53 34

88 72 83 88

352 354

176

316

248

156

72

0

200

400

1995 1996 1997 1998 1999 2000 2001 2002 2003

Fiscal year

Prescription Over-the-counter

Drug recalls in 

fiscal year 2003 

 254 prescription 

drugs 

 88 over-the-counter 

drugs 
Improving Public Health Through Human Drugs 

39 

Safety-based Drug Withdrawals 

No safety-based withdrawals in 2003 

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

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

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

Record of safety-based market withdrawals 

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

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

period. 

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 April 30, 2004, we approved 

303 NMEs, and 7 (2.3 percent) have been withdrawn. Nearly all drugs we 

approved in this period were reviewed under PDUFA goals. 

Recent safetybased drug 

withdrawals 

Drug name 

(year approved/ 

year withdrawn)

 Phenylpro- 

 panolamine 

 (—/2000) 

(never approved 

 by FDA) 

 Fenfluramine

(1973/1997) 

 Azaribine 

 (1975/1976) 

 Ticrynafen 

 (1979/1980) 

 Zomepirac 

 (1980/1983) 

 Benoxaprofen 

 (1982/1982) 

 Nomifensine 

 (1984/1986) 

 Suprofen 

 (1985/1987) 

 Terfenadine 

 (1985/1998) 

 Encainide 

 (1986/1991) 

 Astemizole 

 (1988/1999) 

 Flosequinan 

 (1992/1993) 

 Temafloxacin 

 (1992/1992) 

 Cisapride 

 (1993/2000) 

 Dexfenfluramine 

 (1996/1997) 

(not an NME)

 Bromfenac 

 (1997/1998) 

 Cerivastatin 

 (1997/2001) 

 Grepafloxin 

 (1997/1999) 

 Mibefradil 

 (1997/1998) 

 Troglitazone 

 (1997/2000) 

 Rapacuronium 

 (1999/2001) 

 Alosetron* 

 (2000/2000) 

*Returned to market in 

2002 with restricted 

distribution.

Recent safetybased drug 

withdrawals 

(cont.)

Safety-Based NME Withdrawals

Based on year of approval

2.7% 2.3%

0.0%

1.5%

3.0%

Pre-PDUFA PDUFA

(13) (7)

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

Percentage

Percentage withdrawn
CDER 2003 Report to the Nation 

40 

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 calendar year 2003, we issued 185 advisory 

letters to companies regarding their promotional materials for launch 

campaigns. 

We issued 346 other advisory letters to the industry regarding proposed 

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

we issued 159 other types of correspondence to the pharmaceutical 

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

letters. 

Regulatory actions 

We issued 42 regulatory action letters to companies for prescription drug 

promotions determined to be false, misleading, lacking in fair balance of 

risks and benefits or that promoted a product or indication before approval. 

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

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

promotions include promotional exhibit hall displays, oral representations, 

Internet sites, plus traditional materials such as journal advertisements and 

sales brochures. 

Direct-to-consumer promotion 

Included in our letters were 254 regarding direct-to-consumer promotion. 

This compares with 188 letters in 2002. Included in last year’s letters were 

47 for launch campaigns and 163 for non-launch advisories. Ten were 

regulatory letters. 

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

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

other entities consistently shows that DTC ads encourage some patients to 

seek care for undertreated conditions. This often results in a different 

treatment that is more appropriate for the patient than the advertised drug. 

But physicians and others are concerned that consumers may not always 

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

DTC letters 

 2003: 254 

 2002: 188 

 2001: 190 

 2000: 215 

 1999: 247 

 1998: 282 

 1997: 240 
Improving Public Health Through Human Drugs 

41 

Drug promotion 

review statistics 

We issued a total of 737 

drug promotion letters 

last year. 

 42 regulatory action 

letters 

 185 launch 

campaigns 

 510 advisory 

acknowledgement or 

closure letters DTC advertising surveys 

We completed two national telephone surveys and conducted preliminary 

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

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

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

behaviors associated with direct-to-consumer advertisements. 

Preliminary findings of the two surveys indicate that: 

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

DTC advertising encourages information seeking about potentially 

serious medical conditions. 

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

advertising creates awareness of new treatments. 

 About 42 percent of patients and 75 percent of physicians feel DTC 

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

the patients think the drug works better than it does. 

 About 40 percent of physicians believe that patients understand the 

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

believe patients understand the benefits and positive effects. 

 Slightly less than half (47%) of physicians report feeling at least a little 

pressure to prescribe when asked for a prescription. 

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

index.htm.

DTC public meeting 

To explore DTC advertising issues, we held a two-day public meeting 

where we presented information from our two patient and one physician 

surveys. We heard from researchers who have investigated the promotion 

of prescription drugs directed to consumers through print, broadcast and 

other types of media. 

Drug Promotion Review

129539773276515597465185510

42

237171117

105

37

417220558245399350178186

0

400

800

1995 1996 1997 1998 1999 2000 2001 2002 2003

Cale ndar ye ar

Regulatory actions Launch campaigns Other letters

Proposed rule to 

revise prescription 

drug labeling 

We continued to work 

on a final rule, based 

on comments from the 

public to our proposal 

in 2001. 

The main purpose of 

labeling is to 

communicate essential 

information about 

prescription drugs to 

health care providers.
CDER 2003 Report to the Nation 

42 

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 and 

evaluate for regulatory action all reports of FDA inspections of foreign 

drug manufacturing facilities. We determine which foreign manufacturers 

are acceptable to supply active pharmaceutical ingredients or finished drug 

products to the U.S. market. 

Reporting systems for drug quality problems 

Two important post-marketing tools help us rapidly identify significant 

health hazards and quality problems associated with the manufacturing and 

packaging of drugs: 

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

receive reports of observed or suspected drug quality defects associated 

with marketed drugs. We evaluate and prioritize the reports to 

determine potential health hazards and industry trends. These reports 

significantly assist us in targeting potential manufacturing quality 

problems and identifying candidates for further sampling and analysis. 

We identify significant health hazards associated with drug 

manufacturing, packaging and labeling and initiate field inspection 

assignments. We review inspection reports and recommend appropriate 

corrective action. We maintain a central reporting system to detect 

problem areas and trends. 

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

possible problems that may represent safety hazards for their marketed 

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

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

to determine if firms are complying with reporting requirements. We 

review and approve enforcement recommendations for failure to meet 

these requirements. 

Risk-based 

surveillance 

sampling of drugs 

We monitor the quality 

of the nation’s drug 

supply through 

surveillance and 

sampling of foreign and 

domestic finished 

dosage forms and bulk 

shipments of active 

ingredients. 

The drug products 

surveyed are selected 

according to a riskbased strategy that 

targets products with 

the greatest potential to 

harm the public health. 

FDA district offices 

conduct follow-up 

inspections to 

determine the cause of 

sample failures and to 

assure corrective action 

by the firms. 

Sampling criteria 

 Microbial/endotoxin 

concerns 

 Stability concerns 

 Sterility issues 

 Dissolution issues 

 Impurities/

contaminants 

 Product quality 

history 

 Counterfeit drugs 

 History of violations 

Prescription drugs 

sold without 

approved 

applications 

We identify drugs that 

are marketed without 

an approved new or 

generic drug 

application. 

We estimate that there 

are several thousand 

illegally marketed drug 

products in the United 

States, comprising 

several hundred unique 

molecules. 

We issued a draft 

guidance in October 

that describes how we 

intend to: 

 Exercise our 

enforcement discretion 

regarding these 

products. 

 Provide an incentive 

to be the first 

manufacturer to obtain 

approval for one of 

these drugs. After a 

grace period, we will 

consider taking 

enforcement action 

against unapproved 

competitors, which 

may result in de facto 

exclusivity. 

 Avoid unnecessarily 

restricting patient 

access to useful 

medicines. 

 Reiterate our riskbased criteria for 

enforcement action. 
Improving Public Health Through Human Drugs 

43 

Manufacturing plant inspections 

FDA field offices conduct inspections of domestic and foreign plants that 

manufacture, test, package and label drugs. Before a drug is approved, 

FDA investigators must determine if data submitted in the firm’s 

application are authentic and if the plant is in compliance with good 

manufacturing practices. After a drug is approved, FDA conducts periodic 

inspections to make sure a firm can consistently manufacture the product 

with the required quality. We develop compliance programs to guide the 

investigators in conducting these inspections, and we identify facilities that 

are high priority for inspection based on their identified risk potential. 

Misbranded drugs, unsubstantiated claims 

Mislabeled, fraudulent, hazardous products. We often encounter 

mislabeled and fraudulent products that make unsubstantiated claims. 

Consumers may use these products inappropriately or incorrectly. They 

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

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

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

claims may pose a significant health risk. 

Occasionally, fraudulent products may also contain toxic compounds that 

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

products that lack required FDA approval threatens to undermine the U.S. 

drug development and approval process as well as the ongoing over-thecounter drug review process. 

FDA Inspections of Manufacturing Plants

7731,7751,8441,1441,0851,4368221,2681,4978901,2761,5195898641,512

0

1,000

2,000

1999 2000 2001 2002 2003

Fiscal year

New drug preapproval Generic preapproval Current good manufacturing practice

Preapproval 

inspections 

During fiscal year 2003, 

FDA evaluated: 

 589 plants in 

support of new drug 

applications 

 864 domestic firms 

in support of generic 

drug applications 

Good 

manufacturing 

practice 

inspections 

There were 1,512 good 

manufacturing practice 

inspections in fiscal 

year 2003. 

 We reviewed 51 

field recommendations 

for regulatory action 

and approved 34. These 

included 27 warning 

letters, four injunctions 

and three seizures. 

 We reviewed 184 

foreign establishment 

inspection reports, 

resulting in one 

warning letter and one 

import alert. 

Protecting 

consumers from 

misbranded or 

fraudulent drugs 

We protect consumers 

from mislabeled, 

fraudulent or 

hazardous products. 

We locate and identify 

these products for sale 

on the Internet as well 

as from traditional 

retail outlets, and we 

take steps to remove 

them from the market. 

These steps include 

issuing enforcement 

letters and pursuing 

enforcement actions, 

such as seizures of 

violative products and 

injunctions against 

firms or individuals. 

International 

commerce in 

pharmaceuticals 

continues to be an 

important regulatory 

topic. We work with 

the FDA field force to 

implement legal 

requirements 

establishing which 

drugs may be imported 

by manufacturers, 

distributors and 

consumers. 

We protect the public 

health by ensuring that 

imported drugs are not 

counterfeit and meet 

applicable legal 

requirements relating 

to safety and 

effectiveness. 
CDER 2003 Report to the Nation 

44 

Drug Product Quality Science 

Process analytical technologies initiative 

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

emerging technologies that will improve the capability and efficiency of the 

pharmaceutical manufacturing process while maintaining or improving 

product quality. Known as process analytical technologies (PAT), these are 

systems for continuous analysis and control of manufacturing processes 

based on real-time or rapid measurements during processing. They can also 

be non-destructive. These systems involve in-line, on-line or at-line 

monitoring, measuring and controlling in manufacture of drug substance 

and drug products. 

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

bringing together experts in the areas of analytical and physical chemistry, 

pharmaceutical technology, regulatory compliance, chemical engineering 

and international pharmaceutical manufacturing. These include experts 

from industry and academia along with our own and those from other FDA 

components. 

We are encouraging the adoption of this technology in drug manufacturing 

because it can enhance process understanding, improve overall product 

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

objectives of the Pharmaceutical cGMPs for the 21st Century Initiative. 

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

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

special review team is now in place to evaluate process analytical 

technologies as the pharmaceutical industry begins implementation in 

existing and new manufacturing processes. On the team, our own 

chemistry reviewers and compliance officers will join FDA's field 

investigators on inspections. 

By organizing public meetings and workshops, we have gathered 

information related to development and use of process analytical 

technologies and shared our own research data. 

We entered into a a cooperative research and development contract with a 

major pharmaceutical company to develop and implement chemical 

imaging as a process analytical technology tool. 

Process analytical technologies Web site launched 

FDA’s effort to facilitate the introduction of new technologies to the 

manufacturing sector of the pharmaceutical industry now has its own Web 

page at http://www.fda.gov/cder/OPS/PAT.htm.

Laboratory 

support 

We assessed several 

analytical technologies 

for characterizing 

active pharmaceutical 

ingredients and 

guarding against 

counterfeit product 

marketing. We applied 

near infrared, Raman, 

Isotope ratio mass 

spectrometry to the 

problem of 

distinguishing between 

production sources of 

active pharmaceutical 

ingredients and 

finished dosage forms. 

We developed 

methodology to better 

characterize nasal 

spray products. We 

evaluated a new 

aerodynamic particle 

size analyzer 

We evaluated 

instrumentation for the 

determination of 

particle size and 

particle size 

distribution for 

cyclosporin drug 

products. 

We are developing 

physicochemical 

methods to assess 

quality changes in 

liposomal drug 

products. 

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 46). 

We have a new 

program to advance 

rapid microbiology test 

methods. 
Improving Public Health Through Human Drugs 

45 

3 

INTERNATIONAL

ACTIVITIES

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 is making 

new drugs available with minimum delays not only to American consumers 

but also to patients in other parts of the world. 

The drug regulatory systems in all three regions share the same 

fundamental concerns for the safety, efficacy and quality of drug products. 

Before ICH, many time-consuming and expensive technical tests had to be 

repeated in all three regions. The ICH goal is to minimize unnecessary 

duplicate testing during the research and development of new drugs. The 

ICH process results in guidance documents that create consistency in the 

requirements for product registration. 

Common Technical Document 

The ICH Common Technical Document allows data in the same format to 

be submitted to drug review authorities in all three ICH regions. 

Specifications for electronic submission of the CTD, known as the eCTD, 

were completed in 2002. 

eCTD improves review efficiency 

Electronic submissions using the eCTD specifications can be used to 

submit all applications and related submissions (page 30) such as 

promotional materials and adverse events. 

Among other things, the eCTD allows reviewers to: 

 Create an up-to-date, cumulative table of contents for the entire 

application at any time. 

 Access any electronic submission from a single screen. 

 Download files so submissions can be used even when the reviewer’s 

computer is disconnected from the network. 

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. 

ICH guidance 

documents 

As of April 30, 2004, we 

had published: 

 47 final ICH 

documents 

 8 draft documents. 

We publish ICH 

documents as 

guidances to industry 

on our Web site at 

http://www.fda.gov/

cder/guidance/

index.htm.

Sixth International 

Conference on 

Harmonization 

At this biannual 

meeting in Osaka, 

Japan, the ICH 

members focused on 

areas such as: 

 New technologies in 

the discovery of 

innovative drugs. 

 Opportunities and 

new challenges for 

regulatory 

harmonization. 

 Pharmacovigilance 

and global cooperation 

with regulatory 

harmonization 

initiatives outside the 

ICH regions. 

 Practical 

implementation of the 

Common Technical 

Document. 
CDER 2003 Report to the Nation 

46 

International information-sharing agreements 

In an era of enhanced cooperation among regulators around the world, FDA 

entered new international agreements in which we play a critical role in 

implementing. We have a growing list of regulatory partners worldwide 

with whom we can pursue more open dialogue on emerging issues as well 

as exchange routine information on scientific review, policy development 

and enforcement. New information-sharing agreements with Canada, 

Switzerland and the European Union add to those already in effect with 

Japan and Australia. 

Japan and Australia 

We routinely exchange recall information about products of interest to 

Japan and Australia and communicate emerging enforcement activities of 

mutual interest. We met several times with our counterparts regarding the 

exchange of site inspection information. With limited inspection resources 

of our own, we increasingly depend on foreign regulatory inspections and 

incorporate their inspection findings into a risk-based program for future 

inspection. 

European Agency for the Evaluation of Medicinals 

This agreement establishes a basis for exchanging confidential information 

with the European Union agency primarily responsible for approving drugs. 

It will permit our review and compliance staff to share important 

information about pending approvals, post-marketing surveillance and 

enforcement actions concerning products and facilities under the oversight 

of the EMEA. Implementation will be phased in and includes activities 

designed to build understanding and mutual confidence in each another’s 

systems. 

Canada 

This agreement provides for the exchange of information about pending 

approvals, post-marketing surveillance and enforcement actions. It expands 

on information-sharing activities that began years ago as well as those 

developed more recently with Mexico and Canada. Exchanges of emerging 

compliance issues and site-specific information have already begun. 

Switzerland 

The working arrangement with Switzerland began several years ago. The 

present agreement addresses the need for protection of confidential 

information and provides for the exchange of information about marketing 

approval decisions, post-market surveillance, policy developments and 

compliance or enforcement activities of mutual interest. Progress is being 

made in implementing this arrangement, including the exchange of 

technical staff and training opportunities. 

Swedish reviewer 

exchange program 

in development 

We are developing a 

reviewer exchange 

program with the 

Swedish Medical 

Products Agency to 

provide continued 

improvement of quality 

reviews. 
Improving Public Health Through Human Drugs 

47 

Internet resources 

More information 

about our international 

activities, including 

Spanish language 

materials, is at http://

www.fda.gov/cder/

audiences/iact/

iachome.htm.

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 2003: 

 5,474 

Export Certificates Issued

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

4,7335,474

0

3,000

6,000

1995 1996 1997 1998 1999 2000 2001 2002 2003

Fiscal year

Export certificates issued
CDER 2003 Report to the Nation 

48 

4 

COMMUNICATIONS

Highlights from 2003 include: 

 Meeting almost weekly with outside experts on difficult scientific and 

public health issues. 

 Receiving more than 12 million visits and more than 205 million hits on 

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

five databases and 250,000 hyperlinks. 

Public participation 

 We confer with panels of outside experts in science, medicine and 

public health in meetings open to the public. 

 We assure that patient representatives are included on advisory 

committees considering medicines for HIV, AIDS, cancer and other 

serious disorders. 

 We analyze public comments on proposed new rules, and we seek and 

receive comments on our guidances to industry. 

We held large public meetings and workshops to gather a wide variety of 

viewpoints on major scientific and regulatory issues, including: 

 Risk management (page 34).

 Direct-to-consumer advertising (page 41).

 Evaluating drug names for similarities (page 37).

 Pharmaceutical good manufacturing practices initiative (page 6).

 Process analytical technologies (page 44).

Consumer and industry outreach 

 Regulations. We published four final regulations, and we sought public 

comment on another three proposed regulations. 

 Guidances. We published 32 guidances for industry that explain our 

position on best practices in scientific and technical areas. We 

published another 24 in draft form seeking public comment. 

 Manual of Policies and Procedures. To foster transparency of our 

operations, we publish our internal operating policies and procedures on 

the Internet. We added 23 documents last year. 

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

more than 1,500 approved drugs or new uses for approved drugs. 

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 

We 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 more than 

24,000 subscribers to 

our service that 

provides daily e-mail 

updates of new content 

on our Web site and 

nearly 25,000 

subscribers to our 

weekly e-mail updates. 

To subscribe, visit 

http://www.fda.gov/

cder/cdernew/

listserv.html.
Improving Public Health Through Human Drugs 

49 

 Trade press. We responded to about 2,200 telephone and e-mail 

requests from the specialized press covering the pharmaceutical 

industry. 

 Exhibits. We exhibited at 31 conferences, reaching an estimated 

audience of more than 108,000 consumers, educators and health care 

professionals. 

 Videoconferencing. We held 144 domestic and foreign 

videoconferences for academia, industry and associations. 

 CDER Live! We produced one satellite television broadcasts and Web 

transmission for a largely pharmaceutical audience estimated at about 

5,000 viewers. The first part of the program featured a discussion of the 

broad science-based issues that form the basis of the pharmaceutical 

cGMP initiative; the second part presented a discussion of electronic 

signatures and records. 

 Freedom of Information requests. We responded to nearly 4,000 

requests under the Freedom of Information Act. 

 General information requests. We answered more than 36,000 

telephone inquiries, 26,000 e-mails and 1,800 letters from consumers, 

health professionals and industry. 

Ombudsman activities 

Our ombudsman’s office changed management; however, the overall tenor 

of the office did not change. Our ombudsman serves as a portal for 

consumers, regulated industry and small business for, among other things, 

comment on programs, drug development and FDA center jurisdictional 

advice, general information on drug regulation, and adverse drug 

experience reporting. 

Several people contacted the office to report irregularities and possible 

fraud in conducting and reporting clinical trials, promotional activities and 

violations in pharmaceutical manufacturing. Several hundred people 

contacted the office to express their opinions on advisory committee 

members, on whether we should approve specific therapies and unwanted 

e-mail promotion by on-line pharmacies. 

Public education 

programs 

Our programs educate 

and empower 

consumers to make 

wise choices about their 

medications. Our 

messages, which 

reached many millions 

of Americans last year, 

include science-based 

information on: 

 Antibiotic resistance 

 Benefits vs. risks of 

medication use 

 Buying drugs from 

outside the United 

States 

 Buying prescription 

drugs online 

 Counterfeit drugs 

 Drug interactions 

 Generic drug 

quality 

 Misuse of 

prescription pain 

relievers 

 Over-the-counter 

medicine labels 

 Safe use of aspirin 

These are available on 

the Internet at http://

www.fda.gov/cder/

consumerinfo/

DPAdefaultv.htm.

Average Monthly Use of CDER Internet Site

0.8 1.0

0.1 0.0 0.2 0.2 0.4 0.5

0 1

3 3

7

9

14

17

0.0

0.6

1.2

1996 1997 1998 1999 2000 2001 2002 2003

Calendar year

Visitors (millions)

0

10

20

Hits (millions)

Visitors (millions) Hits (millions)
CDER 2003 Report to the Nation 

50 

Where to Find More Information 

We support multiple ways to obtain information about drug products and 

the laws, regulations and guidances concerning them. 

Internet site 

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

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

Division Drug Information

HFD-240, Room 12B-05 

5600 Fishers Lane 

Rockville, MD 20857 

The ombudsman’s topic of the year was FDA’s enforcement against 

importing drugs from Canada. 

The e-mail account ombudsman@cder.fda.gov has become a preferred 

method of contacting us with more than 1,500 contacts. Approximately 570 

of these were forwarded to our druginfo@cder.fda.gov account. We 

received approximately 400 specific issue contacts by telephone. Examples 

of our cases were: 

 Review/drug development delay. 

 Freedom of Information Act access. 

 Docket posting dispute. 

 User fees dispute. 

 Intellectual property dispute. 

 Management/employee disagreement. 

 NDA priority designation dispute. 

 Perceived retaliation complaint. 

 Repackaging/expiration dating dispute. 

 Import/export issues. 

Jurisdictional 

issues 

Our ombudsman serves 

as our jurisdiction 

officer. Many times it is 

not readily apparent 

where proposed 

products will be 

reviewed and regulated 

either within the center 

or between FDA 

centers. 

Our ombudsman is a 

member of a steering 

committee that advises 

the congressionally 

created the FDA Office 

of Combination 

Products. The office, 

created in December 

2002, has a mandate to 

define or clarify 

regulations in the area 

of combination 

products such as: 

 Primary mode of 

action 

 Single-separate 

applications 

 User fees 

 cGMPs 

Our ombudsman is also 

a member of the 

working group for the 

FDA’s initiative in the 

area of novel drug 

delivery systems and in 

the agency’s dispute 

resolution processes. 
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 

Office of Executive Programs 

 Executive Operations Staff 

 Quality Assurance Staff 

 Advisors & Consultants Staff 

 International Program 

 Ombudsman 

 Organizational Development & Strategic 

Planning 

Office of Medical Policy 

 Div. of Scientific Investigations 

 Div. of Drug Marketing Advertising 

& Communications 

Office of New Drugs 

 Pharmacology/Toxicology Staff 

 Program Management Team 

 Study Endpoints & Labeling Team 

 Pregnancy Labeling Team 

 Guidance Policy Team 

 Regulatory Affairs Team 

Office of Pharmacoepidemiology 

& Statistical Science 

Office of Pharmaceutical Science 

 Informatic Computation Safety Analysis 

Staff 

 Process Analytical Technologies 

 Quality Implementation Staff 

 New Drug Microbiology Team 

Office of Counter-Terrorism & 

Pediatric Drug Development 

 Div. of Pediatric Drug Dev. 

 Div. of Counter-Terrorism 

Office of Drug Evaluation I 

 Div. of Neuropharmacological 

Drug Products 

 Div. of Oncology Drug Products 

 Div. of Cardio-Renal Drug 

Products 

Office of Drug Evaluation II 

 Div. of Pulmonary Drug Products 

 Div. of Metabolic & Endocrine 

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& Addiction Drug Products 

Office of Drug Evaluation III 

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& Radiopharmaceutical Drug 

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Products 

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& Research Staff 

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Staff 

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Management 

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Policy 

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& Communications 

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Office of Biotechnology 

Products 

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Office of Drug Evaluation VI 

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Oncology Products 

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Internal Medicine Products 

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Staff 

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U.S. Department of Health and Human Services

Food and Drug Administration 

Center for Drug Evaluation and Research