Center for Drug Evaluation and Research 2004

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 2004 Report to the Nation 

MISSION

The Center for Drug Evaluation and Research promotes and protects public 

health by ensuring 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/2004/rtn2004.pdf.

 HTML: http://www.fda.gov/cder/reports/rtn/2004/rtn2004.htm.

 Slides: http://www.fda.gov/cder/reports/rtn/2004/rtn2004.ppt.

Suggested citation: U.S. Food and Drug Administration. CDER 2004 

Report to the Nation: Improving Public Health Through Human Drugs.

Rockville, Maryland. 2005. 
Improving Public Health Through Human Drugs 

i 

CONTENTS

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

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

HIGHLIGHTS AND INITIATIVES ...................................................3 

 Drug Safety Initiative ..........................................................4 

 Critical Path Initiative..........................................................6 

 Improving Manufacturing Practices ....................................8 

 Counterterrorism..................................................................9 

 Scientific Research ............................................................11 

1 DRUG REVIEW.......................................................................13 

 New Drug and Biologic Review........................................14 

 New or Expanded Use Review..........................................21 

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

 Pregnancy and Lactation Labeling ....................................26 

 Over-the-Counter Drug Review ........................................27 

 Generic Drug Review........................................................28 

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

 Electronic Submissions .....................................................32 

 User Fee Program..............................................................33 

 Drug Review Team............................................................34 

2 DRUG SAFETY AND QUALITY...............................................35 

 Safety System for Medicines.............................................36 

 Drug Safety Surveillance...................................................37 

 Public Health Advisories in 2004......................................38 

 MedWatch Outreach and Reporting..................................39 

 Medication Error Prevention .............................................41 

 Drug Recalls ......................................................................42 

 Safety-Based Drug Withdrawals .......................................43 

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

 Compliance Oversight.......................................................46 

 Product Quality Science ....................................................50 

3 INTERNATIONAL ACTIVITIES ...............................................51 

 President’s Emergency Plan for AIDS Relief ...................51 

4 COMMUNICATIONS................................................................55 

 Ombudsman’s Activities ...................................................57 

 Where to Find More Information ......................................58 
CDER 2004 Report to the Nation 

ii 

Graphs and Charts 

Critical Path..................................................................................7 

Priority NDA & BLA Approvals ...............................................14 

Priority NME & New BLA Approvals ......................................15 

Standard NDA & BLA Approvals .............................................16 

Standard NME and New BLA Approvals..................................17 

Priority New or Expanded Use Approvals.................................22 

Standard New or Expanded Use Approvals...............................23 

Pediatric Drug Development......................................................25 

OTC New Approvals & New Uses ............................................27 

Generic Drug Approvals ............................................................29 

Generic Drug Tentative Approvals ............................................29 

Generic Drug Applications Received.........................................30 

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

Sources of Risk from Medicine..................................................36 

Adverse Event Reports...............................................................37 

Drug Recalls...............................................................................42 

Safety-Based Withdrawals .........................................................43 

Letters Issued on Drug Promotion Compliance .........................45 

FDA Inspections of Manufacturing Plants.................................47 

Drug Quality Reports .................................................................49 

Reported Drug Quality Defects..................................................49 

Modular Structure of Common Technical Document................53 

Export Certificates Issued ..........................................................54 

Average Monthly Use of CDER Internet Site............................56 

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

iii 

Director’s Message 

Last year, the staff in the Center for Drug Evaluation and Research worked 

hard to protect and promote public health. Our highly trained and dedicated 

staff supports a unique mission to ensure availability of effective 

pharmaceutical products while maximizing patient safety. The health of 

millions of Americans and the global leadership of the United States in drug 

development depends on the quality and timeliness of this critical work. To 

manage this effort is a solemn honor. 

Modern drugs provide unmistakable and significant health benefits. However, 

as we move into the 21st century with an armamentarium of medicines 

unimaginable 100 years ago, we are finding that the scientific tools of the 20th 

century are not adequate to achieve our goals of: 

 Developing new medicines efficiently without lowering our standards of 

safety and effectiveness. 

 Identifying and managing issues related to the safe use of approved 

medicines. 

Because we can’t solve 21st century problems with 20th century policies and 

scientific tools, we realize we can’t continue with business as usual to develop 

new medicines, and we are working on several initiatives that hold much 

promise for: 

 Streamlining the path for developing new drugs, including drugs for 

children, orphan diseases and medical countermeasures to terrorist attacks. 

 Improving the science of drug manufacturing. 

 Improving our methods for identifying, analyzing and responding to 

emerging safety issues and communicating those results to physicians and 

patients. 

We believe we can make important contributions to the public health by 

aggressively following up on these initiatives. 

Improving our scientific tools for analysis and prediction 

The Critical Path Initiative is our effort to address the fact that developing new 

medicines has become increasingly expensive and time-consuming, with 

likelihood of success more uncertain than ever before. We need to work to 

assure that the promise of ongoing basic science research is translated into 

efficient assessment of new medicines for patients. 

We are proposing collaborative research to improve predictability and 

efficiency and to get much needed treatments to patients faster. We are seeking 

development of a versatile applied science toolkit containing such methods as 

animal- and computer-based predictive models, greater use of biomarkers for 

assessing safety and effectiveness and new clinical evaluation techniques. 
CDER 2004 Report to the Nation 

iv 

Encouraging innovation in manufacturing 

Good manufacturing practices are as important to public health as they are to 

making best use of government and industry resources. Our overhaul of the 

pharmaceutical good manufacturing practices encourages manufacturers to 

modernize their methods, equipment and facilities to eliminate both production 

inefficiencies and undue risks for consumers. Our improved polices are also 

making better use of our limited resources through more targeted and effective 

inspections. 

Addressing public concerns about drug safety 

Concerns about high-profile products with safety questions should not distort 

the fact that drugs are safer today than they have ever been before and that 

millions of Americans each day benefit from them. Nonetheless, too many 

Americans suffer from unexpected and unpreventable adverse events from the 

medicines they use. We have undertaken several new initiatives to improve the 

ways that we detect, analyze and respond to emerging safety signals and then 

to communicate those signals to patients and health care professionals 

effectively. A new, independent Drug Safety Oversight Board will oversee the 

management of important drug safety issues and assist in the timely release of 

emerging safety information. 

Speeding the development of medical countermeasures 

We recognize the clear need to facilitate the development of countermeasures 

to protect Americans from biological, chemical, nuclear and radiological 

agents of terrorism. To do this, we are working with other parts of the 

Department of Health and Human Services to provide guidance that will 

facilitate their development. 

We are extremely proud of our work outlined in this report and will continue to 

work on our initiatives as we look forward to the Agency’s 100th anniversary 

in 2006. 

Steven Galson, M.D., MPH

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 U.S. 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 2,200 

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

scientists. 

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 safe and effective new drugs to American consumers 

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

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

prescription drugs.

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

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

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

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

a drug is used or even remove it from the market. We monitor changes in 

manufacturing to make sure they won’t adversely affect safety or efficacy. 

We evaluate reports about suspected problems from manufacturers, health 

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

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

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 2004 Report to the Nation 

2 

Monitoring drug information and advertising. Accurate and complete 

information is vital to the safe use of drugs. We regulate information that 

accompanies or is displayed with an over-the-counter drug. In the past, 

drug companies promoted their products almost entirely to physicians. 

More frequently now, they are advertising directly to consumers. We 

oversee advertising of prescription drugs, whether to physicians or 

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

a great many consumers. The Federal Trade Commission regulates 

advertising of over-the-counter drugs. Advertisements for a drug must 

contain a truthful summary of information about its effectiveness, side 

effects and circumstances when its use should be avoided.

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 over-thecounter 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 but 

usually considerably 

less expensive. 

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 

HIGHLIGHTS 

AND INITIATIVES

We are pleased to present our ninth performance report. Our work in 2004 

offered many Americans new or improved choices for protecting and 

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

We worked hard at our mission of ensuring that Americans have safe and 

effective drugs and also developed these initiatives to bring the latest 

science and technology to bear on our mission: 

 Reforming our drug safety oversight. 

 Identifying steps to improve the science of drug development. 

 Improving manufacturing practices. 

 Protecting the homeland with improved medical countermeasures to be 

used in event of a terrorist attack or disaster. 

 Conducting targeted scientific research to improve our regulatory 

practices. 

We accomplished our work on these initiatives while maintaining our 

performance on our reviews of safety and efficacy and our oversight and 

surveillance of the safety of products sold to Americans. 

 Reviews. We approved 119 new medicines, including 36 truly new 

medicines that had not been marketed in any form before in this 

country. We approved 147 new or expanded uses for already approved 

medicines. We approved 380 generic versions of existing drugs. 

 User fee performance. We exceeded our goals for review performance. 

 Drug safety surveillance. We processed and evaluated more than 

400,000 reports of adverse drug events, including more than 20,000 

submitted directly from individuals. 

 Drug promotion and advertising. We issued more than 800 letters to 

help ensure manufacturers comply with regulations concerning drug 

promotion. 

 Bar codes on medicines. We promulgated a regulation that calls for bar 

codes on over-the-counter medicines commonly used in hospitals and 

most prescription medicines. 

 Public health advisories. We issued warnings on non-steroidal antiinflammatory pain medicines and on antidepressant use in children, 

adolescents and adults. 

 Manufacturing. We implemented our initiative that encourages 

adoption of state-of-the-art manufacturing processes. 
CDER 2004 Report to the Nation 

4 

Drug Safety Initiative 

Americans are rightly concerned about the safety of their drugs. Too many 

suffer from unexpected and unpreventable adverse events from the 

medicines they need. Some have worried about “dangerous” drugs, while 

others have worried that an “overemphasis” on safety will delay developing 

new therapies. 

The most important concern for many Americans, however, has been the 

gap between the time a safety issue emerges and the time we know enough 

to make a regulatory decision. Our reforms of our drug safety efforts will: 

 Give patients, healthcare professionals and consumers quick and easy 

access to the most up-to-date and accurate information on medicines. 

 Make our drug review, approval and monitoring programs as 

transparent as possible. 

Drug safety has been and will continue to be a top priority for us. A recent 

internal audit showed that our professional staff spends about one-half its 

time addressing safety issues. Drug safety involves more than watching for 

problems once we approve a drug. Other important areas where the 

evaluation of drug safety takes place include: 

 Oversight of clinical trials. 

 Evaluation of safety and efficacy of new therapies and new or expanded 

uses for existing therapies. Because all drugs have risks, our evaluation 

must balance those risks against expected benefits. 

 Regulation of manufacturing, distribution and promotional activities. 

 Prevention of medication errors by evaluating proposed proprietary 

names, labeling and packaging. 

 Development of proactive risk management strategies both before and 

after approval. 

Oversight board 

The new, independent Drug Safety Oversight Board will oversee the 

management of drug safety issues and will provide emerging information to 

doctors and patients about the risks and benefits of medicines. It will: 

 Recommend information and updates for placement on the proposed 

Drug Watch Web page. 

 Resolve disagreements over approaches to drug safety issues. 

 Assess the need for MedGuides. 

 Oversee development and implementation of Centerwide drug safety 

policies. 

Institute of 

Medicine Study 

We have contracted 

with the IOM to study 

the effectiveness of 

the nation’s drug 

safety system. The 

study will have an 

emphasis on the postmarket phase and 

assess what additional 

steps could be taken 

to learn more about 

the side effects of 

drugs as they are 

actually used. The 

IOM is the nation’s 

foremost body for 

science-based advice 

on matters of 

biomedical science, 

medicine and health. 
Improving Public Health Through Human Drugs 

5 

Oversight Board members don’t directly supervise approvals 

The board consists of FDA supervisors, staff and medical experts from 

other medical agencies in the Department of Health and Human Services 

and other government departments such as the Department of Veterans 

Affairs. The board will consult with outside medical experts and 

representatives of patient and consumer groups. To avoid conflicts of 

interest, the board members have no direct supervision of approval 

decisions. Because board members are government employees, they will be 

able to freely discuss confidential and proprietary information. 

New communications channels 

We will share drug safety information sooner, more broadly and more 

conveniently through tailored drug safety information sheets for healthcare 

professionals and patients. 

We expect these new and direct communication channels will enhance 

knowledge and understanding of safety issues. Emerging or potential safety 

problems can be discussed even before we have reached conclusions that 

would prompt a regulatory action. 

The new communication channels include: 

 Drug Safety Web site. Consumers will find a variety of new information 

on specific drug products, including information sheets for patients and 

healthcare professionals (described below), the product’s regulatory 

history and its prescribing information. The site is http://www.fda.gov/

cder/drugsafety.htm.

 Proposed Drug Watch Web site. The Drug Safety Oversight Board will 

place “emerging” drug safety information on this site, such as possible 

serious side effects of particular drugs, before we have fully determined 

that the drug was responsible. This information will also include risks 

that might alter the benefit and risk analysis of a drug, affect patient 

selection, change monitoring decisions or could otherwise be avoided. 

 Healthcare professional information sheets. These will be one-page 

information sheets for all drugs on FDA’s Drug Watch and all drugs 

with Medication Guides. They will contain the most important new 

information for safe and effective product use, such as known and 

potential safety issues based on reports of adverse events, new 

information that may affect prescribing of the drug and the approved 

indications and benefits of the drug. 

 Patient information sheets. These one-page information sheets in a 

consumer friendly format will contain new safety information as well as 

basic information about how to use the drug for all products on Drug 

Watch. Ultimately, such sheets will be made available for every new 

drug that is approved. 

Differences 

of professional 

opinion 

In most cases, free 

and open discussion 

of scientific issues 

among review teams 

and with supervisors, 

managers and 

external advisors, 

leads to an agreed 

course of action. 

Sometimes, however, 

consensus cannot be 

reached. We normally 

document these 

differences and their 

resolution in the official 

file of an action. 

An employee may 

sometimes feel that 

the normal process 

was inadequate and 

the decision made will 

have a significant 

negative impact on the 

public health. 

We have implemented 

a pilot process, 

coordinated by our 

ombudsman 

(page 57), to provide 

for expeditious review 

and resolution of these 

differences by 

qualified staff not 

directly involved in the 

decisions. 
CDER 2004 Report to the Nation 

6 

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 has been a slowdown—instead of the 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. 

Personalized medicine 

The Critical Path recognizes the importance of “pharmacogenomics” and 

encourages its use in drug development. 

 Pharmacogenomics allows health care providers to identify differences 

in people’s drug response profiles and predict the best possible 

treatment options for them. 

Instead of a hit-or-miss approach to treating patients where it can take 

multiple attempts to find the right drug and the right dose, 

pharmacogenomics holds the promise that doctors will be able to analyze a 

patient’s genetic profile and prescribe the best available drug therapy and 

dose from the start. 

The field has experienced significant growth over the last few years. The 

sequencing of the human genome and the advent of new tools and 

technologies have already opened new possibilities in drug discovery and 

development. 

Research needed 

to improve 

development tools 

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. We 

need 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 play 

a major role in this 

effort because of: 

 Our experience 

overseeing medical 

product development, 

assessment and 

manufacturing/

marketing. 

 Our vast clinical 

and animal databases. 

 Our close 

interactions with all the 

major players in the 

critical path process. 

Public support 

for Critical Path 

We have heard from 

patient groups, the 

drug and biotech 

industry, and industry 

groups. They concur 

with the scientific 

infrastructure problem 

and the focus on 

research, sciencebased standards and 

collaboration. 

Areas of major 

concern are: 

Clinical trials 

 Statistical tools to 

support innovative trial 

design. 

 Disease modeling 

and trial simulation. 

 Standardization of 

trial administration. 

 Development of 

consistent electronic 

data collection, 

monitoring and 

reporting. 

Biomarkers 

and endpoints 

 Clarification of the 

process for validating 

surrogate endpoints. 

 Evidence needed to 

use biomarkers for 

other purposes, such 

as patient selection. 

 Standards for 

imaging as a 

biomarker. 
Improving Public Health Through Human Drugs 

7 

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 

Personalized medicine for cancer 

Genomic tests are helping to identify cancers that have a good chance of 

responding to a particular medication or regimen. This has enabled the 

development of targeted therapies like trastuzumab for metastatic breast 

cancer, imatinib mesylate for chronic myeloid leukemia and cetuximab for 

metastatic colorectal cancer. 

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 Critical Path report is available at http://www.fda.gov/oc/

initiatives/criticalpath/whitepaper.html.

 You can view public comments to our proposal at http://www.fda.gov/

ohrms/dockets/dockets/04n0181/04n0181.htm.

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 wellcharacterized medical 

product that can be 

mass produced. 
CDER 2004 Report to the Nation 

8 

Emerging 

technologies in 

process validation 

recognized 

We revised a longstanding policy 

document regarding 

the validation of 

pharmaceutical 

manufacturing 

processes. New to this 

version is the 

recognition of the role 

of emerging advanced 

engineering principles 

and control 

technologies in 

ensuring batch quality. 

For drugs produced 

using these new 

principles and 

technologies, we 

provide for possible 

exceptions to the need 

for manufacturing 

multiple conformance 

batches prior to initial 

marketing. 

Improving Manufacturing Practices 

Our overhaul of the regulatory and quality control systems for 

pharmaceutical products encourages manufacturers to modernize their 

methods, equipment and facilities. Our goal is to help eliminate both 

production inefficiencies and undue risks for consumers. Our initiative 

implements improved policies that are making better use of our limited 

resources through more targeted and effective inspections. 

Collectively, our policies are known as “current good manufacturing 

practices” or cGMPs, and our last comprehensive revisions to them took 

place nearly a quarter of a century ago. 

Pharmaceutical cGMPs for the 21st Century is the umbrella name for this 

strategic initiative, and more information is available at http://

www.fda.gov/cder/gmp/. 

Pharmaceutical cGMP initiative final report issued 

In 2004, we moved into an implementation phase and issued a final report 

on: 

 Our assessment of our regulations, current manufacturing practices as 

well the new tools in manufacturing science that will enable a 

progression to controls based on quality systems and risk management. 

 Specific steps we have taken and will take to develop and implement 

quality systems management and a risk-based product quality 

regulatory system. 

The report is available at http://www.fda.gov/cder/gmp/gmp2004/

GMP_finalreport2004.htm#_Toc84065734. 

Process analytical technologies initiative 

A key element of the cGMP initiative is our effort to encourage adoption of 

state-of-the-art quality control systems in manufacturing. This work is 

based on the premise that quality cannot be tested into products; it should 

be built into products by design. 

Process analytical technology is a system for design, analysis and control of 

manufacturing with the goal of ensuring final product quality. It does this 

through timely measurements—during processing—of critical quality and 

performance attributes of raw and in-process materials and processes. 

Effective use of the most current pharmaceutical science and engineering 

principles and knowledge—throughout the life cycle of a product—can 

improve the efficiencies of both the manufacturing and regulatory 

processes. More information is on page 50.
Improving Public Health Through Human Drugs 

9 

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 terrorist events. These steps include: 

 Assuring the availability of medicines to treat victims of terrorist 

attacks. 

 Leveraging resources with other federal agencies to answer scientific 

questions concerning therapies to treat conditions caused by chemical, 

biological or radioactive agents. 

 Preparing ourselves to continue operations during a crisis. 

 Protecting the nation’s drug supply from attack or deliberate 

contamination. 

Medical countermeasure approvals 

 The infant atropine autoinjector (Pediatric AtroPen) provides an 

automatic injection of a potentially life-saving nerve agent antidote to 

children as young as 6 months. Doses and dosage forms of the AtroPen 

for adults and older children had been approved previously. 

 Pentetate calcium trisodium injection (Calcium DTPA) and pentetate 

zinc trisodium injection (Zinc DTPA) treat people who have become 

internally contaminated with certain radioactive isotopes (plutonium, 

americium or curium). The label includes information on pediatric 

dosing. These new molecular entities received priority approval and 

have orphan drug status. A second manufacturer received tentative 

approvals for these two drugs. 

 A second manufacturer of insoluble Prussian blue (Manoplex), to treat 

people internally contaminated with radioactive cesium-137 or thallium, 

received tentative approval in 2004. The first approval for insoluble 

Prussian blue was in 2003, and the product received orphan exclusivity. 

 We updated the ciprofloxacin (Cipro) label to include human 

information based on its use to prevent inhalational anthrax during the 

attacks in 2001. The label previously referenced only animal efficacy 

data for this indication. 

 Levofloxacin (Levaquin) is now approved to treat inhalational anthrax 

(post exposure prophylaxis) in adults. Levaquin is similar to 

ciprofloxacin, except it can be dosed once daily. 

 Fifteen new generic ciprofloxacin drug products were approved. Each 

will be indicated for prevention of inhalational anthrax post-exposure. 

 Penicillin G procaine injectable suspension (Wycillin) was approved to 

prevent the occurrence or progression of anthrax disease following 

exposure to Bacillus anthracis (including inhalational anthrax). 

Emergency 

preparedness 

We participated in four 

emergency response 

exercises. Threat 

agents were smallpox, 

anthrax, radiological 

contamination from a 

dirty bomb and 

cyanide. We also 

engaged in continuity 

of operations 

exercises, including an 

“at home” test to 

assure maintenance of 

vital operations and 

services in an 

emergency. 

Emergency use 

authorization 

Under the 2004 

Project BioShield Act, 

we worked with the 

Centers for Disease 

Control and 

Prevention to identify 

potential medical 

countermeasures in 

the Strategic National 

Stockpile that we 

could authorize for 

emergency use for an 

unapproved indication. 

We also outlined the 

internal processes and 

procedures we need to 

handle an emergency 

use authorization. 

Strategic National 

Stockpile 

regulatory, policy 

issues working 

group 

We participated in this 

internal FDA working 

group to address 

issues such as: 

 Compounding 

medical 

countermeasures 

during a mass 

casualty situation. 

 Labeling and 

dispensing medical 

countermeasures 

during a mass 

casualty. 

 FDA-shelf-life 

extension program 

and re-labeling. 

 Cities Readiness 

Initiative (mass 

prophylaxis 

dispensing). 

 Availability and 

vulnerability of 

products in the 

stockpile. 

 Risk assessment 

and enforcement 

discretion. 

 Proactive facilities 

inspections. 

 Patient access to 

life-saving therapies 

through investigational 

applications for 

countermeasures. 
CDER 2004 Report to the Nation 

10 

Facilitating medical countermeasure development 

 Plague. The Centers for Disease Control and Prevention began 

enrolling patients in an FDA-funded clinical trial to assess the efficacy 

of the antibiotic gentamicin for endemic plague in two African 

countries where antimicrobial options for plague are extremely limited. 

We contributed to protocol design and the formation of a data safety 

monitoring board to oversee study safety concerns. We are continuing 

our collaboration with the Center for Devices and Radiological Health 

to evaluate the performance of a novel, rapid bedside plague diagnostic 

test kit under study conditions. 

 Pneumonic plague. We also continued our collaboration with the 

National Institute of Allergy and Infectious Diseases and the U.S. Army 

Medical Research Institute of Infectious Diseases to evaluate the safety 

and efficacy of five antibiotics (gentamicin, ciprofloxacin, levofloxacin, 

doxycycline and ceftriaxone) to treat pneumonic plague in a non-human 

primate model. Natural history studies, pharmacokinetic and toxicology 

studies to support efficacy studies and efficacy studies with high-dose 

and a humanized (lower) dose of gentamicin have been completed and 

analyzed. 

 Radiological and nuclear threats. We began another collaboration with 

the National Institute of Allergy and Infectious Diseases to identify 

promising new products for use against radiological and nuclear threats. 

We discuss scientific and regulatory issues with manufacturers of such 

products and inform them about possible funding sources, both for early 

development and for procurement by the federal government. 

Interagency collaborations 

 Post-event surveillance planning. Along with the FDA’s other medical 

centers and the CDC, we developed a plan to identify processes for 

collecting adverse event and outcome data on medical products 

distributed in response to an emergency. 

 Project BioShield prioritization. We participated in many interagency 

working groups engaged in counter-terrorism efforts. These groups 

have contributed to gap analyses in medical countermeasures and have 

authored many of the requirements documents that will be used to 

prioritize products for development and eventual procurement under 

BioShield. 

Counterterrorism guidances published in 2004 

 Guidance for Federal Agencies and State and Local Governments: 

Potassium Iodide Tablets Shelf Life Extension. 

 Draft Guidance for Industry: Vaccinia Virus—Developing Drugs to 

Mitigate Complications from Smallpox Vaccination. 

Internet resources 

We provide links at 

http://www.fda.gov/

cder/drugprepare/

default.htm 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. 

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 sciencebased evaluation. 
Improving Public Health Through Human Drugs 

11 

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 

 Biomarkers for organ damage. We are identifying, evaluating and 

establishing relevant protein biomarkers in blood in both animal models 

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

be caused by certain drugs to the heart, kidney, immune system and 

liver. 

 Biomarkers for inflammation. To enhance safety within broad segments 

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

we are working on the identification and elucidation of associated 

serum biomarkers and mechanisms responsible for the development of 

vascular inflammation in specific organ systems. 

 Evaluation of microarrays. 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. 

 Medicinal plants, herbs. We established scientific research capabilities 

in the analyses of medicinal plant and herbal products. 

 Imaging drug targets. We continue to explore noninvasive imaging 

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

accurate dose-concentration-response principles by viewing drugs and 

their actions directly at the level of the drug target, rather than indirectly 

via plasma concentrations. 

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

approach for using exposure-response information to help evaluate the 

risks and benefits of drug therapies and recommending dose 

adjustments in special populations. 

 Pediatric pharmacokinetics. We are developing a pediatric population 

pharmacokinetics study design template to facilitate implementation of 

sparse sample strategies in pediatric drug development. 

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: ExposureResponse 

Relationships: Study 

Design, Data Analysis 

and Regulatory 

Applications

 We cosponsored 

an open workshop on 

pharmacogenomics in 

drug development and 

regulatory decisionmaking. 

 We published a 

draft guidance, 

Pharmacogenomic 

Data Submissions, to 

provide a better 

understanding on the 

current use of 

pharmacogenomics in 

drug development and 

to 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. 
CDER 2004 Report to the Nation 

12 

Biotechnology research 

Our new Office of Biotechnology Products was officially transferred to our 

center in 2003 from the Center for Biologics Evaluation and Research. The 

office consists of about 80 scientists and other staff who are responsible for 

evaluating therapeutic biotechnology product submissions as well as 

carrying out scientific research related to biologics regulatory issues. 

 Immune responses. We review many submissions aimed at inhibiting 

unwanted immune responses, such as autoimmune diseases or rejection 

of transplanted organs, or aimed at enhancing desired immune 

responses, such as those against infections or cancer. To facilitate 

review of such immunology-related submissions, we study the 

mechanisms by which immune cells are activated, suppressed or 

channeled from one kind of active response to another. 

 Metabolic pathways. We study the mechanisms by which various 

regulated products induce their intended effects, as well as unintended 

adverse effects. Our investigations also examine various normal and 

pathogenic pathways that are targeted by regulated agents. 

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

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

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

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

Informatics and computational safety analysis 

 Cancer toxicity predictive software. Our cooperative research and 

development agreements with several commercial software developers 

have resulted in the development and marketing of new computer 

software to predict the cancer-causing potential of chemicals based on 

their molecular structure. The software makes use of our extensive 

rodent carcinogenicity database without compromising proprietary 

information. 

 Safe starting dose models. We have successfully developed computer 

models to estimate the safe starting dose for clinical trials of drugs 

based on their molecular structure. The current method for estimating 

the starting dose is highly inexact and requires the use of multiple safety 

factors because it is based exclusively on an extrapolation from animal 

toxicity studies. We have begun studies to validate the new method. 

Scientific research in pregnancy and lactation 

See page 26 for studies to evaluate fetal safety from drug exposure or 

whether the dose of a drug should be adjusted during pregnancy or 

lactation. 

Laboratory 

support 

Our efforts included: 

 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 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 

13 

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. When we review a medicine, we use the best science 

available to determine if a medicine’s benefits outweigh its risks for its 

intended use. An internal study showed that about half of our professional 

staff time is spent on safety assessment. We oversee the development of 

new medicines in the United States, and our paramount concern is the 

safety of patient volunteers in clinical trials. 

Highlights for 2004 include: 

 119 new medicines. We approved 113 drugs and six biologics (29 

priority and 90 standard reviews). 

 36 truly new medicines. We approved 31 drugs and five new biologics 

that had never been marketed before in any form in this country (21 

priority and 15 standard reviews). 

 147 new treatment options. We approved new or expanded uses for 133 

already approved drugs and 14 already approved biologics (48 priority 

and 99 standard reviews). 

 13 medicines for cancer. Our approvals included seven priority new 

medicines and six priority new or expanded uses for existing medicines. 

 8 over-the-counter drugs. Our approvals included five new medicines to 

be sold over the counter without a prescription, and four of them can be 

used by children. We approved three new uses for existing OTCs, all of 

which can be used by children. 

 15 “orphan” medicines. Our approvals included 11 new medicines and 

four new or expanded uses for patient populations of 200,000 or fewer. 

 Medicines for children. We provided 23 priority reviews of pediatric 

studies of already approved medicines. These resulted in seven 

medicines gaining approval for new or expanded uses in children. 

 380 generic drugs. We gave final approval to 380 generic versions of 

existing drugs and tentative approval to another 95. We received 635 

marketing applications for generic drugs. 

 User fee goals. We exceeded all our performance goals for the fiscal 

year 2003 receipt cohort, the latest year for which we have full 

statistics. We are on track for exceeding all user-fee performance goals 

for the fiscal year 2004 cohort. 

 730 clinical trial inspections. We conducted foreign and domestic 

inspections that help protect volunteers in clinical trials from research 

risks and validate the quality and integrity of data submitted to us. 
CDER 2004 Report to the Nation 

14 

New Drug and Biologic 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. 

Priority approvals. These products represent significant improvements 

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

of these applications within six months. 

Standard approvals. These products have therapeutic qualities similar to 

those of already marketed products. We have a goal of reviewing 90 

percent of these applications within 10 months. 

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

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

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

take once an application is filed. 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. 

Priority new drugs 

and biologics 

 29 total approvals 

 25 drugs 

 4 biologics 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 31 filings 

 42 actions 

 9 orphan approvals 

(includes 8 NMEs) 

New drug 

applications 

NDAs are the formal 

submissions of data 

that sponsors send us 

when they are seeking 

approval to market a 

“new drug” in the 

United States. Some 

NDAs are NMEs; 

however, “new drugs” 

can also include an 

active substance 

previously sold in a 

different form. 

New molecular 

entities 

NMEs contain an 

active substance that 

has never before been 

approved for 

marketing in any form 

in the United States. 

Because of high 

interest in truly new 

medicines, we report 

approvals of NMEs 

and “new BLAs.” The 

charts for all NDAs 

and all BLAs include 

NMEs and new BLAs. 

Priority NDA & BLA Approvals

Median times, approvals

7.97.97.87.86.26.46.26.46.16.16.06.06.06.013.819.17.77.76.06.0

29 29

11

20 28

10

14

20

16

25

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

15

30

Approvals

Median FDA review time Median total approval time Number approved

Priority NDAs & BLAs

Filings, actions, approval percentages

24 32 44 35 46 43 41 27 18 26 26 21 32 27 31 7 19 18 31 42

69%

50% 66% 54%

65%

49%

37%

61% 54%

57%

0

25

50

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year *Includes therapeutic BLAs

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

Number

0%

50%

100% Percent

Filings Actions Percent of actions that are approvals
Improving Public Health Through Human Drugs 

15 

Definitions (cont.)

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 a year. 

Accelerated approval. This program helps make products for serious or 

life-threatening 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 long-term clinical benefit. Sponsors perform 

additional studies to demonstrate long-term clinical benefit. 

Fast track development. This program facilitates the development and 

expedites our review of new drugs and biologics that demonstrate the 

potential to address unmet medical needs for serious or life-threatening 

conditions. Fast track emphasizes our close, early communication with 

sponsors. 

2002 data. The higher review and approval times in 2002 resulted from the 

approval of some older applications and a decrease in applications filed. 

Priority new 

molecular entities 

and new biologics 

 21 total approvals 

 17 NMEs 

 4 new BLAs 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 17 filings 

 8 orphan approvals 

Biologic license 

applications 

BLAs are the formal 

submissions of data 

that sponsors send us 

when they are seeking 

approval to market a 

biologic in the United 

States. A “new BLA” is 

a biologic that has 

never been approved 

for marketing in the 

United States. 

Priority NME & New BLA Approvals

Median times, approvals

7.97.97.79.66.46.76.26.26.36.96.06.06.06.013.816.36.76.76.06.0

18

9

16

19

9 7

7

9

21

10

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

12

24

Approvals

Median FDA review time Median total approval time Number approved

Priority NMEs & New BLAs

Filings

16 17

10

5

15 14 14 16 16 16

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes therapeutic BLAs

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

Number

Approval totals 

 119 drugs and 

biologics 

 113 drugs 

 6 biologics 

 36 truly new 

medicines 

 31 NMEs 

 5 new BLAs 

 15 orphan 

approvals 

 11 NDAs (includes 

9 NMEs) 

 4 new or expanded 

uses 
CDER 2004 Report to the Nation 

16 

Standard drugs 

and biologics 

 90 total approvals 

 88 drugs 

 2 biologics 

 Median review 

time: 11.9 months 

 Median approval 

time: 12.9 months 

 77 filings 

 162 actions 

 2 orphan approvals 

(including 1 NME) 

Notable 2004 New Approvals 

Last year’s approvals benefited people with diabetes, neurological 

disorders, infections, cancer, heart disease and other disorders. 

People with diabetes 

Insulin glulisine (Apidra) is a rapid-acting, synthetic insulin that starts 

working faster than regular insulin but does not work as long. It is approved 

for adults and is used with a longer-acting insulin or by itself in an insulin 

pump to maintain proper blood sugar control. (NME) 

People with depression 

Duloxetine hydrochloride (Cymbalta) treats depression. It belongs to a 

class of medicines called serotonin and norepinephrine reuptake inhibitors. 

The label carries our warning (page 38) about suicidal thoughts or actions 

in children, adolescents and adults. (NME) 

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. 

Standard NDA & BLA Approvals

Median times, approvals

16.218.715.117.814.715.012.012.012.013.812.012.012.014.012.715.311.915.411.912.9

90

67

102 101

65 55

78

56

67

58

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

60

120

Approvals

Median FDA review time Median total approval time Number approved

Standard NDAs & BLAs

Filings, actions, approval percentages

921859022592200871531011478719788143791548913977162

56%

51%

44% 42%

37% 40% 39%

42% 45%

36%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year *Includes therapeutic BLAs

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

Number

0%

50%

100% Percent

Filings Actions Percent of actions that are approvals
Improving Public Health Through Human Drugs 

17 

Standard new 

molecular entities 

and new biologics 

 15 total approvals 

 14 NMEs 

 1 new BLA 

 Median review 

time: 16.0 months 

 Median approval 

time: 24.7 months 

 16 filings 

 1 orphan approval 

People with neurological disorders 

Apomorphine hydrochloride (Apokyn) treats loss of control of body 

movements in people with advanced Parkinson’s disease. (NME, priority, 

orphan) 

Natalizumab (Tysabri), which received accelerated approval in November 

2004, represented a new approach to treating patients with relapsing forms 

of multiple sclerosis. In February 2005, however, we issued a public health 

advisory to inform patients and health care providers about natalizumab’s

suspended marketing while we and the manufacturer evaluate serious 

adverse events reported with its use. (biologic, priority) 

People with pain

Ziconotide (Prialt) helps in the management of severe chronic pain in 

people who are intolerant of or refractory to other treatment. It is used with 

an implanted pump that injects the drug into the space around the spinal 

cord. (NME, priority)

Pregabalin (Lyrica) helps manage pain associated with diabetic peripheral 

neuropathy. (NME, priority) 

Therapeutic BLAs 

included starting 

with 2004 data 

Beginning with 2004, 

our charts incorporate 

data on the review of 

therapeutic biologics 

transferred to us in 

late 2003. These 

include: 

 Monoclonal 

antibodies. 

 Cytokines. 

 Growth factors. 

 Enzymes. 

 Other therapeutic 

immunotherapies. 

Additional 

statistics 

More review statistics 

are available at http://

www.fda.gov/cder/

rdmt/default.htm. 

Data updated 

You should be aware 

that these data may 

differ from those in 

previous issues of this 

report. We have 

revised data from 

previous years. 

Standard NME & New BLA Approvals

Median times, approvals

15.917.814.615.114.415.012.313.414.016.315.419.915.719.012.515.913.823.116.024.7

15 17 10 18

30

19

35

14 16 12

0

15

30

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

20

40

Number

Median FDA review time Median total approval time Number approved

Standard NMEs & New BLAs

Filings

16 13 12

25

12

22 28 25 29 34

0

20

40

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

 *Includes therapeutic BLAs

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

Number
CDER 2004 Report to the Nation 

18 

Notable 2004 new drug approvals (continued)

People with cancer 

Azacitidine (Vidaza) treats patients with myelodysplastic syndrome, a 

group of conditions caused by a problem in the blood-forming cells of bone 

marrow. (NME, priority, orphan) 

Bevacizumab (Avastin) is used with intravenous 5-FU based chemotherapy 

as a first-line treatment for patients with cancer of the colon or rectum that 

has spread to other areas of the body. (biologic, priority)

Cetuximab (Erbitux) treats a type of cancer of the colon or rectum that has 

spread to other areas of the body and is known as EGFR-expressing 

metastatic colorectal carcinoma. It is the first monoclonal antibody 

approved to treat this type of cancer and is given intravenously in 

combination with irinotecan, another drug approved to fight colorectal 

cancer, or alone if patients cannot tolerate irinotecan. (biologic, priority) 

Clofarabine (Clolar) treats 1- to 21-year-old patients with acute 

lymphoblastic leukemia that has relapsed after at least two treatments or is 

unresponsive to treatment. Also known as ALL, the disease is responsible 

for 80 percent of the acute leukemias of childhood. (NME, priority, orphan) 

Erlotinib hydrochloride (Tarceva) treats non small-cell lung cancer that has 

spread within the lung or other parts of the body after failure of at least one 

prior chemotherapy regimen. (NME, priority) 

Palifermin (Kepivance) is used to reduce the chances of developing 

mucositis, a severe injury to the cells lining the mouth, and to shorten the 

time with severe mucositis in patients with cancer who receive high doses 

of chemotherapy and radiation therapy followed by stem cell rescue. It is a 

modified version of a naturally occurring human growth factor that helps 

maintain the normal structure of the skin and gastrointestinal surface.

(biologic, priority) 

Pemetrexed (Alimta) in combination with cisplatin treats patients with 

malignant pleural mesothelioma. It is an orphan drug and the first approved 

for cancer of the mesothelium, a membrane that covers and protects most 

of the internal organs of the body. The disease is rare and usually 

associated with a history of asbestos exposure. (NME, priority, orphan) 

People with alcoholism 

Acamprosate calcium (Campral) helps patients with alcoholism stay 

alcohol-free after they have stopped drinking. (NME, priority)

NMEs 

(P=priority, 

S=standard, 

O=orphan) 

 Acamprosate 

calcium (P) 

 Apomorphine 

hydrochloride (P, O) 

 Azacitidine (P, O) 

 Cinacalcet 

hydrochloride (P, O) 

 Clofarabine (P, O) 

 Darifenacin 

hydrobromide (S) 

 Duloxetine 

hydrochloride (S) 

 Erlotinib 

hydrochloride (P) 

 Eszopiclone (S) 

 Gadobenate 

dimeglumine (S) 

 Human secretin (P) 

 Hyaluronidase (P) 

 Iloprost (P, O) 

 Insulin glulisine (S) 

 Lanthanum 

carbonate (S) 

NMEs (cont.)

 L-Glutamine (S, O) 

 Omega-3-acid ethyl 

esters (S) 

 Ovine 

hyaluronidase (P) 

 Pegaptanib sodium 

(P) 

 Pemetrexed 

disodium (P, O) 

 Pentetate calcium 

trisodium (P, O) 

 Pentetate zinc 

trisodium (P, O) 

 Pregabalin (P) 

 Rifaximin (S) 

 Solifenacin 

succinate (S) 

 Telithromycin (S) 

 Tinidazole (S) 

 Tiotropium bromide 

(S) 

 Trospium chloride 

(S) 

 Trypan blue (P) 

 Ziconotide (P) 
Improving Public Health Through Human Drugs 

19 

Infectious diseases 

Nitazoxanide (Alinia) treats diarrhea caused by parasites. For diarrhea 

caused by Giardia lamblia, an oral suspension can be used for patients 1 

year of age and older and tablets can be used for patients older than 12. The 

oral suspension can also treat diarrhea caused by Cryptosporidium parvum

in patients 1 to 11 years of age. (priority) 

Rifaximin (Xifaxan) is a nonsystemic antibiotic used to treat traveler’s

diarrhea caused by Escherichia coli. The drug does not enter the 

bloodstream. (NME) 

Tinidazole (Tindamax) treats infections caused by parasites in both adults 

and pediatric patients older than 3 years of age. It treats trichomoniasis, a 

sexually transmitted disease, and the intestinal infections, giardiasis and 

amebiasis. (NME) 

Telithromycin (Ketek) is an antibiotic to treat certain respiratory infections 

in adults 18 years of age and older. (NME) 

People with lung disease 

Tiotropium bromide (Spiriva HandiHaler) is for the long-term, once-daily, 

maintenance treatment of bronchospasm associated with chronic 

obstructive pulmonary disease, including chronic bronchitis and 

emphysema. (NME) 

People with pulmonary hypertension 

Iloprost (Ventavis) treats pulmonary arterial hypertension, high blood 

pressure in the artery that carries oxygen-poor blood from the heart to the 

lungs. The inhaled drug helps dilate blood vessels in the lungs. (NME, 

priority, orphan) 

People with macular degeneration 

Pegaptanib sodium (Macugen) slows vision loss in people with the eye 

disease known as neovascular (wet) age-related macular degeneration. The 

drug is a selective vascular endothelial growth factor antagonist and is 

among the first treatments to target the underlying biology of this disease.

(NME, priority)

People with end-stage kidney disease

Lanthanum carbonate (Fosrenol) is used to reduce the buildup of 

phosphates in patients with end-stage kidney disease. Fosrenol mixes with 

phosphates from food in the stomach to stop the phosphates from passing 

into the body. While small amounts of phosphates are needed by all cells in 

the body for them to work the right way, normal kidneys remove excess 

phosphate that can weaken bones. (NME) 

Notable 2004 new drug approvals (continued)

Counterterrorism 

treatments 

For NME and new 

drug tentative 

approvals see page 9. 

New BLAs 

 Bevacizumab (P) 

 Cetuximab (P) 

 Natalizumab (P) 

 Palifermin (P) 

 Technetium 99m Tc 

fanolesomab (S) 

Other NDA 

priority approvals 

(T=tentative)

 Acetylcysteine 

 Desloratadine 

 Emtricitabine; 

tenofovir disoproxil 

fumarate 

 Insoluble Prussian 

blue (T) 

 Nitazoxanide 

 Pentetate calcium 

trisodium (T) 

 Pentetate zinc 

trisodium (T) 

 Saquinavir 

mesylate 

People with HIV 

infection 

Saquinavir mesylate 

(Invirase) and the 

combination of 

emtricitabine and 

tenofovir disoproxil 

fumarate (Truvada), in 

combination with other 

antiretroviral agents, 

treat adults with HIV. 

(both priority)

Children with 

allergies, hives 

Desloratadine 

(Clarinex Syrup), a 

new pediatric 

formulation, treats 

allergy symptoms and 

hives in children from 

6 months old to 2 

years old. (priority) 
CDER 2004 Report to the Nation 

20 

People with other disorders 

Acetylcysteine (Acetadote) prevents or lessens injury to the liver when 

administered within 8 to 10 hours after swallowing a potentially liverdamaging quantity of acetaminophen. (priority, orphan)

Cinacalcet hydrochloride (Sensipar) treats patients with high levels of 

parathyroid hormone in their blood due to chronic kidney disease that 

requires dialysis or with high levels of calcium in their blood due to cancer 

of the parathyroid gland. (NME, priority, orphan) 

Darifenacin hydrobromide (Enablex), solifenacin succinate (VESIcare) and 

trospium chloride (Sanctura) treat an overactive bladder. (NMEs) 

Eszopiclone (Lunesta) treats insomnia. (NME) 

L-glutamine (NutreStore) treats short bowel syndrome in patients receiving 

specialized nutritional support when used with a recombinant human 

growth hormone approved for this indication. The manufacturer 

discontinued this product. (NME, orphan) 

Omega-3-acid ethyl esters (Omacor) are used along with diet to lower very 

high triglyceride levels in adults. Elevated blood levels of triglycerides 

appear to increase the risk of developing heart disease. (NME)

Diagnostic and treatment aids 

Gadobenate dimeglumine (Multihance) is a contrast agent used in magnetic 

resonance imaging of the central nervous system. (NME) 

Human secretin (ChiRhoStim) can be used to stimulate the pancreas as an 

aid in the diagnosis of pancreatic disease. (NME, priority) 

Hyaluronidase (Amphadase) and Ovine hyaluronidase (Vitrase) help to 

increase the absorption and dispersion of other injected drugs. (NME, 

priority) 

Technetium 99m Tc fanolesomab (NeutroSpec) helps in the imaging of 

patients with equivocal signs and symptoms of appendicitis who are 5 years 

of age or older. It is a kit to prepare a radiolabled monoclonal antibody. 

(biologic) 

Trypan blue (VisionBlue) helps in eye surgery by staining the part of the 

eye that holds the lens in place. (NME, priority)

Notable 2004 new drug approvals (continued)

Drugs@FDA 

Drugs@FDA—the 

most frequently used 

application on the FDA 

Web site—has official 

information about FDA 

approved brand-name 

and generic drugs 

such as: 

 Approved and 

tentatively approved 

drug products. 

 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.” 
Improving Public Health Through Human Drugs 

21 

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. 

Notable 2004 new or expanded use approvals 

People with cancer 

Docetaxel (Taxotere), in combination with the steroid prednisone, treats 

advanced metastatic prostate cancer. This is the first drug for hormone 

refractory prostate cancer that has shown a survival benefit. The drug’s 

uses were also expanded for use in combination with other chemotherapy 

for treatment of patients with operable node positive breast cancer. 

(priority)

Gemcitabine hydrochloride (Gemzar), in combination with the cancer 

chemotherapy paclitaxel, is a first-line treatment for patients with breast 

cancer that has spread and who have had a failure of prior anthracyclinecontaining adjuvant chemotherapy, unless anthracyclines were clinically 

contraindicated. (priority)

Interferon gamma-1b (Actimmune), a treatment to reduce the frequency and 

severity of serious infections in people with chronic granulomatous disease, 

now has safety and efficacy data for pediatric patients. (biologic, priority)

Letrozole (Femara) can now be used with other chemotherapy for the 

extended treatment of early breast cancer in postmenopausal women who 

have received five years of tamoxifen therapy. (priority)

Oxaliplatin (Eloxatin), in combination with other chemotherapy, can now 

be used to treat patients previously untreated for advanced cancer of the 

colon and rectum. (priority) 

Tositumomab and iodine I 131 tositumomab (Bexxar) can now treat 

patients with relapsed or refractory, low grade, follicular or transformed 

CD20 positive non-Hodgkin’s lymphoma who have not received rituximab. 

(biologic, priority)

People with diabetes 

Duloxetine hydrochloride (Cymbalta), a treatment for depression (page 16),

can now be used for the management of neuropathic pain associated with 

diabetic peripheral neuropathy. It carries our warning (page 38) about 

suicidal thoughts or actions in children, adolescents and adults. (priority)

Counterterrorism 

treatment 

See page 9 for the 

expanded use of

Penicillin G procaine 

to prevent the 

occurrence or 

progression of anthrax 

disease following 

exposure to Bacillus 

anthracis (including 

inhalational anthrax). 

(priority) 

Pediatric new 

or expanded uses 

See page 25 for the 

drugs with new or 

expanded uses in 

children approved 

under priority review 

required by the Best 

Pharmaceuticals for 

Children Act. 
CDER 2004 Report to the Nation 

22 

People on artificial feeding 

Multi-vitamin infusion without vitamin K (MVI-12) is used to prevent 

vitamin deficiency and complications from blood clots in people receiving 

home parenteral nutrition who also receive warfarin-type blood thinning 

therapy. (priority, orphan)

People on dialysis 

Icodextrin (Extraneal Peritoneal Dialysis Solution), used for continuous 

ambulatory peritoneal dialysis or automated peritoneal dialysis for the 

management of chronic renal failure, is an improvement over normal 

solutions in certain patients. (priority)

Priority new or 

expanded uses 

(efficacy 

supplements)

 48 total approvals 

 46 drugs 

 2 biologics 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 64 actions 

 23 pediatric 

approvals (page 25)

 2 orphan approvals 

Priority New or Expanded Use Approvals

Median times, approvals

6.06.06.06.04.44.46.06.06.06.06.06.06.06.06.06.06.06.06.06.0

48

21 19

6

18

7 9 13

4 4

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

25

50

Approvals

Median FDA review time Median total approval time Number approved

Priority New or Expanded Uses

Actions, approval percentages

33

64

5 9 7 13 19 23

10

36

78% 100%

47%

78%

57%

80%

60%

53%

64%

72%

0

40

80

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Actions

0%

50%

100% Percent

Actions Percentage of actions that are approvals

25 priority 

approvals 

[number of approvals]

(See page 25 for 23 

pediatric priority 

approvals) 

 Docetaxel [2] 

 Duloxetine [1] 

 Gatifloxacin [2] 

 Gemcitabine 

hydrochloride [1] 

 Icodextrin [1] 

 Interferon 

gamma-1b [1] 

(biologic)

 Leflunomide [1] 

Notable 2004 new or expanded use approvals (cont.)
Improving Public Health Through Human Drugs 

23 

Standard new or 

expanded uses 

(efficacy 

supplements)

 99 total approvals 

 87 drugs 

 12 biologics 

 Median review 

time: 10.0 months 

 Median approval 

time: 10.0 months 

 161 actions 

 2 orphan approvals 

Antimicrobial Resistance 

Drug-resistant bacteria continue to be a major threat to the public health. 

In an effort to help protect public health, we provided priority reviews of 

new or expanded uses for four antibiotics to treat community acquired 

pneumonia due to multi-drug resistant Streptococcus pneumoniae. The 

antibiotics are Gatifloxacin (Tequin), Levofloxacin (Levaquin), Linezolid 

(Zyvox) and Moxifloxacin hydrochloride (Avelox). Linezolid was also 

approved to treat hospital-acquired pneumonia caused by Streptococcus 

pneumoniae, including multi-drug resistant strains. 

Education campaign 

We continued our antimicrobial resistance education campaign partnership 

with the Centers for Disease Control and Prevention and jointly released 

two new print public service announcements—one English and one 

Spanish. In addition to the print public service announcements, a Spanishlanguage brochure also was produced. 

Standard New or Expanded Use Approvals

Median times, approvals

16.717.812.614.811.912.011.912.011.011.310.010.010.711.310.010.010.010.010.010.0

99 110

133

85

116

88

111 111 104 65

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Months

0

80

160

Approvals

Median FDA review time Median total approval time Number approved

Standard New or Expanded Uses

Actions, approval percentages

178 161

237 203 182 160 165 180 187 182

62% 62%

56%

42%

36% 57% 64%

53%

69%

59%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004*

Calendar year

*Includes BLAs for therapeutic biologics

Actions

0%

50%

100% Percent

Actions Percentage of actions that are approvals

25 priority 

approvals (cont.)

[number of approvals]

 Letrozole [1] 

 Levofloxacin [5] 

 Linezolid [3] 

 Moxifloxacin 

hydrochloride [2] 

 Multi-vitamin 

infusion without 

vitamin K [1] 

 Oxaliplatin [1] 

 Rofecoxib [2] 

 Tositumomab and 

iodine I 131 

tositumomab [1] 

(biologic)

Approval totals 

 147 drugs and 

biologics 

 133 drugs 

 14 biologics 
CDER 2004 Report to the Nation 

24 

Some conditions 

with approved 

pediatric labeling 

 Abnormal heart 

rhythms 

 Allergies 

 Anesthesia and 

sedation 

 Asthma 

 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 in severe 

kidney disease 

 Malaria 

 Nerve agent 

poisoning 

 Obesity 

 Obsessive 

compulsive disorder 

 Pain 

 Seizures 

 Severe recalcitrant 

nodular acne 

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. In calendar year 2004, we approved 25 pediatric labeling changes 

as a result of the exclusivity provision. 

NME approval. We provided a priority review and orphan status to one 

new molecular entity—clofarabine (Clolar)—for use in children (page 18). 

Exclusivity. As of April 30, 2005, we had received 374 proposed pediatric 

study requests from manufacturers, issued 300 written requests, made 121 

exclusivity determinations, granted exclusivity to 111 drugs and added new 

pediatric information to 90 labels. 

Improved safety, dosing information. About one-fourth of the new pediatric 

labels have safety or dosing information. We are discovering important 

differences between adults and children in the clearance and metabolism of 

drugs. Underdosing leads to ineffective treatment, and overdosing poses a 

greater risk of adverse reactions. Pediatric safety signals identified in these 

studies include effects on growth, school behavior, suppression of the 

adrenal gland and suicidal ideation. As a result of this pediatric testing we 

now have 10 drugs with new pediatric formulations and six drugs with 

recipes in their labels to 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. 

Off-patent drugs. The law also established a publicly funded contracting 

process to study drugs that lack patent protection or market exclusivity, 

referred to as “off-patent.” In consultation with FDA and other pediatric 

experts, the National Institutes of Health has published four lists of offpatent drugs for which additional pediatric studies are needed. We have 

issued and forwarded 11 written requests—four in 2004—for these offpatent drugs. We also forwarded five written requests for on-patent drugs, 

for which sponsors declined pediatric studies. 

Public disclosure. We publish a summary of the medical and clinical 

pharmacology reviews of the pediatric studies conducted under the law. We 

have posted 49 summaries, regardless of the regulatory action, at http://

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

Adverse events reported. The act mandates review of all adult and pediatric 

adverse event reports for a one-year period after pediatric exclusivity is 

granted and presentation of these reports to a pediatric advisory committee. 

As of February 2005, reports for 34 drugs have been presented. Significant 

pediatric safety signals have been found, including neonatal withdrawal 

with antidepressant use during pregnancy and serious adverse events, 

including deaths, due to fentanyl transdermal use in children. 

Pediatric Research 

Equity Act of 2003 

This law gave us the 

authority to require 

pediatric studies of 

certain new drugs and 

biological products 

when such studies are 

needed to ensure the 

safe and effective use 

of the products in 

children. However, the 

law does not require 

the same public 

disclosure of pediatric 

studies required under 

the Best 

Pharmaceuticals for 

Children Act. 
Improving Public Health Through Human Drugs 

25 

Notable 2004 pediatric new or expanded uses 

The Best Pharmaceuticals for Children Act requires us to provide priority 

reviews to pediatric supplements for drugs submitted under the law. 

Reviews of 10 supplements for seven drugs resulted in new or expanded 

medication opportunities for children [number of approvals]: 

 Ciprofloxacin (Cipro) can treat complicated urinary tract infections and 

pyelonephritis for pediatric patients 1 to 17 years of age. [4] 

 Fenoldopam mesylate (Corlopam) is for in-hospital, short-term (up to 4 

hours) reduction in blood pressure in pediatric patients. [1] 

 Lansoprazole (Prevacid) can be used to treat symptomatic 

gastroesophageal reflux disease, nonerosive esophagitis and erosive 

esophagitis in pediatric patients between 12 and 17 years of age. [1] 

 Methylphenidate (Concerta) extended-release tablets (previously 

approved for pediatric patients 6 to 12 years of age) can be used in 

adolescents with attention deficit hyperactivity disorder. Labeling has 

been expanded to include a 72 mg dose. [1] 

 Nelfinavir mesylate (Viracept) in combination with other antiretroviral 

agents can be used to treat HIV-1 infection in pediatric patients from 2 

to 13 years of age. [3] 

 Paricalcitol (Zemplar) can be used in pediatric patients with end-stage 

kidney disease. [1] 

 Sodium ferric gluconate complex in sucrose (Ferrlecit) can be used to 

treat iron deficiency anemia in pediatric patients age 6 years and older 

who are undergoing chronic hemodialysis and receiving supplemental 

erythropoietin therapy. [1] 

Pediatric study information in labeling 

We work with sponsors to put more information on pediatric studies into 

their labels even when the studies did not show efficacy for the indication 

studied. 

Internet resources 

Our Web site for up-todate pediatric labeling 

changes is at http://

www.fda.gov/cder/

pediatric/index.htm. 

2004 pediatric drug 

statistics 

 19 written requests 

issued 

 25 pediatric 

exclusivity labeling 

changes granted 

 17 exclusivity 

determinations made 

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 

Best Pharmaceuticals 

for Children Act, we 

gave priority reviews 

to these pediatric 

supplements [number 

of approvals] 

 Anagrelide 

hydrochloride [1] 

 Benazepril 

hydrochloride [1] 

 Dorzolamide 

hydrochloride [1] 

 Glyburide and 

metformin 

hydrochloride [1] 

 Irinotecan 

hydrochloride [1] 

 Lansoprazole [2] 

 Tolterodine [1] 

 Venlafaxine 

hydrochloride [2] 

 Zolmitriptan [1] 

Pediatric Drug Development

12 17 23 20 23 17

11 12 19 15 25

98

45

69

21 24 19

4

2 3

31

0

60

120

1998 1999 2000 2001 2002 2003 2004

Calendar year

Pediatric exclusivity determinations Pediatric exclusivity labeling changes

Written requests issued
CDER 2004 Report to the Nation 

26 

Pregnancy and Lactation Labeling 

To improve our knowledge of the use of drugs during pregnancy and 

lactation, we sponsor research and provide scientific guidance to industry 

and our reviewers. 

Women who are pregnant often need to use prescription medicines. In 

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

woman and her fetus or nursing baby than a drug treatment. In other cases, 

a different drug treatment than she is already on may be safer. 

We have reviewed the current system of labeling drugs for use by pregnant 

and lactating women and are developing an improved, more comprehensive 

and clinically meaningful approach. We are consulting with government 

agencies, medical experts, consumer groups and the pharmaceutical 

industry to develop this new labeling format. We work with our reviewers 

and pharmaceutical companies to update product labels with available 

human data regarding exposure to drugs during pregnancy and lactation. 

Scientific guidance 

 Risks of drug exposure in human pregnancies. In 2005, we issued our 

final guidance for our reviewers on how to evaluate human data on the 

effects of in utero drug exposure on the developing fetus.

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

industry that provides the basic framework for designing, conducting 

and analyzing clinical lactation studies. 

 Determining the appropriate dose of a drug for pregnant women. In 

2004, we published a draft guidance for industry that provides the basic 

framework for designing, conducting and analyzing pharmacokinetic 

and pharmacodynamic studies in pregnant women. 

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

for industry that provides advice on how to establish registries that 

prospectively monitor the outcomes of pregnancies in women exposed 

to a specific drug. These registries can provide clinically relevant 

human data for treating or counseling patients who are pregnant or 

anticipating pregnancy. 

Research on drugs for high blood pressure, depression 

FDA’s Office of Women’s Health funded studies to look at specific drugs 

used to treat high blood pressure and depression and determine if the doses 

of these drugs should be adjusted during pregnancy. 

Scientific research 

in pregnancy and 

lactation 

We funded several 

studies to evaluate 

either fetal safety from 

drug exposure or 

whether the dose of a 

drug should be 

adjusted during 

pregnancy or lactation: 

 Counter-terrorism. 

These studies look at 

specific anti-infective 

drug products that 

would be used for 

treatment following 

exposure to specific 

bioterrorism agents. 

They focus on use in 

special patient 

populations, such as 

women who are 

pregnant or lactating 

and the elderly. They 

evaluate either the 

need for dose 

adjustments in these 

special patient 

populations or fetal 

safety following in 

utero drug exposure. 

 Liver enzymes.

These studies look at 

the effects of 

pregnancy on specific 

drug-metabolizing 

enzymes in the liver. 
Improving Public Health Through Human Drugs 

27 

Over-the-Counter Drug Review 

We approved five drugs for first-time over-the-counter sale: 

 Guaifenesin 600 mg/pseudoephedrine hydrochloride 60 mg tablets and 

guaifenesin 1200 mg/pseudoephedrine 120 mg tablets (Mucinex-D 

Extended Release) for use as an expectorant and nasal decongestant in 

adults and children 12 years and older. 

 Guaifenesin 600 mg/dextromethorphan 30 mg tablets and guaifenesin 

1200 mg/dextromethorphan 60 mg tablets (Mucinex-DM) for use as an 

expectorant and cough suppressant in adults and children 12 years and 

older. 

 Ibuprofen 100 mg/pseudoephedrine hydrochloride 15 mg/

chlorpheniramine maleate 1 mg per 5 mL (Children’s Advil Allergy & 

Sinus Elixir) for the relief of symptoms of allergic rhinitis and the 

common cold in children 6 years and older. 

 Ibuprofen 100 mg per 5 mL oral suspension (Children’s Elixsure IB)

for the relief of minor aches and pains and fever in children 2 years of 

age and older. 

 Ranitidine hydrochloride 150 mg (Zantac 150 Tablets) for prevention 

and relief of heartburn in adults. 

We also approved three new uses for existing OTC products, all of which 

can be used in children 12 years and older: 

 Loratadine 5 mg/pseudoephedrine hydrochloride 120 mg (Claritin-D 

12 Hr. Extended Release Tablets) and loratadine 10 mg/

pseudoephedrine hydrochloride 240 mg (Claritin-D 24 Hr. Extended 

Release Tablets) for the nasal congestion due to the common cold in 

adults and adolescents 12 years and older. 

 Miconazole nitrate (Monistat 1 Combination Pack) for anytime use in 

the treatment of vaginal yeast infections in adults and adolescents 12 

years and older. 

Over-the-counter 

drug statistics 

 5 approvals for 

first-time OTC sale 

 3 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 also can 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 

and is now complete 

for all products, with a 

few exceptions, as of 

May 2005. 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 (http://

www.fda.gov/cder/

drug/analgesics/).

Because many OTC 

medicines for different 

uses have the same 

active ingredients, an 

unintentional overdose 

is possible. We are 

focusing on OTC drug 

products that contain 

acetaminophen and 

non-steroidal antiinflammatory agents, 

which include products 

such as aspirin, 

ibuprofen, naproxen 

sodium and 

ketoprofen. 

OTC New Approvals & New Uses

5 6

1

5

1 1

1

2

3 13

9 9 8

20

8

3

3

1

7

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

New approvals or Rx-to-OTC switches New uses
CDER 2004 Report to the Nation 

28 

Notable 2004 generic drug approvals 

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

 Fluconazole (Diflucan) in several dosage forms for use as an antifungal 

agent. 

 Benazepril hydrochloride (Lotensin) used to treat high blood pressure. 

 Ciprofloxacin (Cipro) for antibiotic use, particularly as an agent to treat 

anthrax exposure. 

 Ribavirin (Rebetol) used in combination with interferon alpha 2-A for 

several indications, including the treatment of chronic hepatitis C. 

 Metformin hydrochloride extended release tablets (Glucophage XR) 

used to treat Type 2 diabetes mellitus. 

Our approval of generic versions of these drugs could save American 

consumers and the federal government hundreds of millions of dollars each 

year. 

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 380 generic drug products in 2004, 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 was 15.7 

months. 

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

months for six years. We made changes that decrease the overall time to 

approval of applications by three months. We are improving the efficiency 

of our generic drug review process and increasing the number of our 

chemistry reviewers by one-third. 

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 

chain drug stores. 

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. 

Improving 

manufacturing 

practices 

Our strategic initiative, 

Pharmaceutical 

cGMPs for the 21st 

Century, also applies 

to generic drugs (see 

page 8 and page 50).
Improving Public Health Through Human Drugs 

29 

Generic drugs 

 380 generic drug 

approvals 

 Median approval 

time: 15.7 months 

 95 tentative 

approvals 

 635 receipts 

Scientific basis 

for generic drug 

review 

We continue to 

articulate the scientific 

underpinnings of our 

review process and to 

work to define 

mechanisms to 

evaluate equivalence 

of certain unique 

products. 

Online education 

We are offering a free 

online educational 

tutorial on the generic 

drug approval process 

that offers one hour of 

continuing education 

credit for certain health 

professionals. 

The course, available 

at http://www.connectlive.com/events/

genericdrugs/, 

educates health 

professionals on how 

our approval assures 

that generic drugs are 

safe, effective and 

high quality products. 

Tentative vs. 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. 

The review of an application that is tentatively approved requires the same 

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

While tentative approvals represent a full workload for us, they are only 

displayed in our approvals chart once they are converted to full approvals. 

For example, some of 2004’s approvals represent conversions of tentative 

approvals granted in 2003 or previous years. 

Tentative approvals key to affordable, worldwide AIDS relief 

Tentative approval is a key regulatory mechanism to support the 

availability of drugs for the President’s Emergency Plan for AIDS Relief 

(page 51).

Generic Drug Approvals

Median times, approvals

18.3 17.0 15.7 18.6 18.1

23.0

18.0 18.2

27.0

19.3

380 321

244 234

186

225

273 212

207 263

0

18

36

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

Months

0

200

400

Number

Median approval times Number of generic approvals

Generic Drug Tentative Approvals 

56 61 73 63

101 95

40

15 25

40

0

60

120

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year
CDER 2004 Report to the Nation 

30 

Generic drug review efficiencies 

The dramatic increase in receipts of generic drug applications makes it 

imperative that we process generic drug applications more efficiently. With 

the overall goal of getting generic drug products to the consumer as 

efficiently as possible, we continue to look for ways to improve our 

processes and also to provide communication and guidance to industry. 

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. 

 Working with the generic drug industry association to help their 

members submit applications that can be reviewed more efficiently. 

 Exploring further enhancements to the review process. 

 Holding joint meetings and workshops with industry to enhance 

knowledge of topics of interest. 

 Efforts to encourage submission of applications in an electronic format 

for greater efficiency (page 32).

Electronic submissions 

Through public presentations, we are encouraging the generic drug industry 

to submit their applications electronically. 

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. 

Generic Drug Applications Received

296 365 320 392

479

635

345 283 307 330

0

350

700

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

Applications received (workload in future years)

Reducing legal 

hurdles to generic 

drug availability 

We are working on 

regulations to 

decrease timeconsuming legal 

delays in the approval 

and marketing of 

generic products. 

These rules, 

implementing 

provisions of the 2003 

Medicare Prescription 

Drug, Improvement 

and Modernization 

Act, will: 

 Limit an innovator 

firm to one 30-month 

delay for courts to 

resolve patents 

challenged by a 

generic manufacturer. 

 Prevent a generic 

manufacturer with 

180-day exclusivity 

from delaying 

marketing in order to 

deny other generic 

firms entry into the 

market. 
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 high quality laboratory studies and human volunteers to take part in 

clinical studies. Protecting volunteers from research risks is a critical 

responsibility for us and all involved in clinical trials. 

We perform on-site inspections to protect the rights 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 28) 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 and 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. 

2004 top 5 

deficiencies in 

inspections 

of clinical 

investigators 

 Failure to follow the 

protocol 

 Failure to keep 

adequate and accurate 

records 

 Failure to account 

for the disposition of 

study drugs 

 Failure to report 

adverse events 

 Problems with the 

informed consent form 

Inspections 

for data quality, 

research risks 

in 2004 

We conducted a total 

of 730 inspections in 

2004: 

 242 U.S. clinical 

investigators 

 82 foreign clinical 

investigators 

 178 institutional 

review boards 

 18 sponsors, 

monitors or contract 

research organizations 

 74 good laboratory 

practices 

 136 in-vivo

bioequivalence 

International 

inspections 

of clinical research 

We have conducted 

592 inspections of 

clinical research in 55 

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. This 

includes our work with 

the International 

Conference on 

Harmonization 

(page 53) and the 

Declaration of 

Helsinki. 

Internet resources 

More information on 

data integrity and 

patient safety is at 

http://www.fda.gov/

cder/offices/dsi/

index.htm.

Inspections of Clinical Research

623 635 700 728 730

589 574

650

0

400

800

1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

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

Sponsors, monitors, CROs Good laboratory practices In-vivo bioequivalence
CDER 2004 Report to the Nation 

32 

Electronic Submissions 

We cooperated with outside organizations working to publish standards for 

submitting study data. These groups include the Clinical Data Interchange 

Standards Consortium and Health Level 7. Some of these projects are: 

 Clinical trial data. We adopted the consortium’s Study Data Tabulation 

Model version 1.0 for submission of information from clinical trials. 

 Preclinical data. The consortium is working to extend the model to 

handle animal toxicity and microbiology data. 

 Database development. We completed a database model for storing and 

accessing both clinical and animal toxicity data submitted using the 

Study Data Tabulation Model. We are collaborating with the National 

Cancer Institute and software vendors to implement the database and 

develop “smart” tools for accessing the data. 

 Electrocardiogram data. We adopted the Health Level 7 standard for 

annotated electrocardiogram waveform data. We are working with a 

vendor to develop software for analyzing the data and a warehouse for 

storing it. 

 Structured product labeling. We are accepting Health Level 7 

Structured Product Labeling for content of labeling submissions. We 

are developing a repository for storing the data and software to improve 

the processing and reviewing of labeling changes. This is part of our 

effort to improve patient safety through access to the most recent 

information about medicines (page 41).

We continue to receive electronic submissions using the specifications of 

the electronic Common Technical Document (page 53).

Internet resources 

More information on our electronic submissions program is at 

http://www.fda.gov/cder/regulatory/ersr/.
Improving Public Health Through Human Drugs 

33 

User Fee Program 

Americans deserve timely access to potentially lifesaving new drugs as 

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

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

known as PDUFA III. This reauthorization is helping us 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. The 

current user fee law maintains our high review performance goals, includes 

increased consultations with drug sponsors and provides for earlier 

feedback on their submissions. 

User fee performance 

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

agreed to specific performance goals for the prompt review of submissions. 

 We exceeded all our performance goals for the fiscal year 2003 receipt 

cohort. 

 We are on track for exceeding all user-fee performance goals for the 

fiscal year 2004 cohort. 

Continuous marketing application pilot programs 

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

of marketing applications and of more extensive feedback to sponsors 

during their development programs. Two pilots for “continuous marketing 

applications” apply to drugs and biologics in our fast track program: 

 Pilot 1 allows applicants to submit predefined portions of their 

marketing applications called “reviewable units” before submitting the 

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

issuing a discipline (page 34) review letter. In fiscal year 2004, we met 

our goals for all 14 reviewable unit submissions for seven different 

products. 

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

scientific feedback and interactions during the clinical trial phase of 

product development. As of Aug. 1, 2005, there were nine development 

projects entered in the Pilot 2 program. 

The pilots have limitations and specific criteria for entry. More information 

is available at http://www.fda.gov/cder/pdufa/CMA.htm.

User fees support risk assessment and minimization 

The reauthorization allows user fees to support some safety activities, both 

during development and for newly approved medicines (page 40).

Internet resources 

for user fees 

Our user fee Web site 

at http://www.fda.gov/

cder/pdufa/default.htm 

has links to PDUFA: 

 Legislation 

 Federal Register 

documents 

 Guidances 

 Letters 

 Performance 

reports 
CDER 2004 Report to the Nation 

34 

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. In 2004: 

 We presented 51 

scientific seminars and 

scientific rounds. 

 We offered a strong 

and innovative 

curriculum of 28 

scientific courses. 

 We brought in 45 

visiting professors to 

talk directly to 

individual review 

divisions about critical, 

new drug-related 

research and 

techniques. 

 We offered 

additional courses in 

job skills, research 

tools, leadership and 

management. 

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 an up-to-date 

course on a 

compelling scientific 

topic. Recent topics 

were: 

 2005: Critical path 

science 

 2004: Exposureresponse concepts 

 2003: Drug safety 

 2002: Pharmacogenetics 

 2001: QT 

prolongation 
Improving Public Health Through Human Drugs 

35 

2 

DRUG SAFETY

AND QUALITY

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

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

a degree of uncertainty always exists about the risks of a medicine, not only 

when we approve it but also after we approve it. This uncertainty requires 

our continued vigilance, along with that of the industry, to collect and 

assess safety data for medicines on the market. 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. 

We also monitor the quality of marketed drugs and their promotional 

materials through product testing and 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 medication safety and quality activities in 2004 include: 

 Processing and evaluating more than 400,000 reports of adverse drug 

events, including more than 20,000 submitted directly from individuals. 

 Reviewing about more than 35,000 reports of medication errors. 

 Issuing more than 800 letters to help ensure manufacturers comply with 

regulations concerning drug promotion. Included in the total were more 

than 200 concerning direct-to-consumer advertising. 

 Evaluating more than 3,000 reports concerning problems that occur in 

the manufacturing, processing, packing, labeling, storage or distribution 

of drugs. 

 Promulgating a regulation that calls for bar codes on over-the-counter 

medicines commonly used in hospitals and most prescription 

medicines. 

 Issuing Public Health Advisories on non-steroidal anti-inflammatory 

pain medicines and on antidepressant use in children, adolescents and 

adults. 

 Approving Medication Guides for two drugs. 

 Implementing our initiative to encourage adoption of state-of-the-art 

manufacturing processes. 
CDER 2004 Report to the Nation 

36 

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 Medicine 

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. Drug therapy requires an individualized treatment plan and 

careful monitoring. Other avoidable side effects are caused by 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 cancer 

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 1 in 10,000 persons won’t be identified in normal premarket 

testing. 

Capacities 

of current 

safety system 

 Profile of common 

adverse events in 

populations studied 

during development. 

 Understanding of 

medication metabolism 

and common 

metabolism-based 

drug-drug interactions. 

 Management and 

evaluation of certain 

anticipated risks. 

 Identification of rare 

serious adverse 

events that occur after 

marketing. 

Safety System for Medicines 

Our current system for evaluating drug safety provides: 

 Extensive premarket testing with rigorous review, including evaluation 

of remaining uncertainties. 

 Risk management strategies before and after approval. 

 Voluntary adverse event reporting systems with additional populationbased information. 

 Proposed user-friendly communication through an improved drug label 

compatible with e-prescribing and electronic decision support. 

Knowledge gaps 

in current 

safety system 

 Detection of 

differences in the 

frequency of events 

occurring both in those 

who take a drug and 

those who don’t take 

the drug. 

 Time-dependent 

events. 

 Adverse events that 

occur more frequently 

in populations not 

normally studied in 

trials such as those 

who are very sick or 

on multiple drugs. 

 Adverse events that 

occur more frequently 

with off-label use. 

 A tendency for 

medical errors or 

abuse. 

Approaches 

to resolving 

knowledge gaps 

 Use emerging 

electronic medical 

record systems for 

surveillance. 

 Randomized trials 

or registries conducted 

in practice settings 

after marketing. 

 More surveillance 

systems in specialized 

settings such as 

emergency rooms or 

nursing homes. 
Improving Public Health Through Human Drugs 

37 

Drug Safety Surveillance 

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

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

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, known 

as AERS. 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. 

Adverse event 

reporting 

In 2004, we received 

422,889 reports of 

suspected drugrelated adverse 

events: 

 21,493 MedWatch 

reports directly from 

individuals. 

 162,107 

manufacturer 15-day 

(expedited) reports. 

 89,960 serious 

manufacturer periodic 

reports. 

 149,329 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. 

Adverse Event Reports

422,889 370,904 322,694

286,751 278,259 266,981 247,632 213,031

191,865 156,477

0

250,000

500,000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

Direct (MedWatch) 15-day Periodic Nonserious periodic

Chart data 

available 

Data for this chart and 

others is available as 

comments in the PDF 

version of the report. 
CDER 2004 Report to the Nation 

38 

Adverse event reporting compliance 

We monitor the pharmaceutical industry’s submission of adverse event 

reports. A firm’s procedures for collection, evaluation and submission may 

affect the transfer and quality of safety data that we have for analysis. Our 

surveillance of industry is based upon the risks associated with specific 

drug products and specific data processing procedures. 

Risk-based inspections 

We inspect drug firms’ adverse event reporting based upon risk criteria 

associated with specific drug products and corporate performance. These 

include: 

 Newly marketed drugs. 

 Emerging safety signals. 

 Previous violations. 

 Corporate transitions. 

Inspection outcome 

In fiscal year 2004, our field investigators inspected 68 domestic and 10 

foreign firms to assess compliance with our regulations for adverse event 

reporting. We sent 10 firms official notification that they had significant 

uncorrected deficiencies. We were able to work with other firms to obtain 

voluntary correction of deficiencies identified by our monitoring. 

Outreach 

and education 

In addition to our 

inspectional program 

for adverse event 

compliance, we 

improve safety 

reporting through 

educational 

presentations to 

industry. 

These provide industry 

with a direct 

opportunity to expand 

their understanding of 

reporting requirements 

and best practices in 

drug safety and to 

alert them to pending 

regulatory changes. 

These meetings also 

serve to expand our 

own knowledge of 

industry’s worldwide 

pharmacovigilance 

activities. 

Our educational 

activities include 

formal presentations at 

global industry 

meetings and training 

for FDA field 

investigators. 

Adverse event 

electronic 

submissions 

Electronic submission 

of adverse event 

reports permits more 

timely receipt and 

evaluation at 

considerable cost 

savings for us and 

industry. 

Our initiative to 

encourage electronic 

reports continues to 

make progress and 

remains a high priority. 

We provide useful 

information on 

electronic adverse 

event reports at http://

www.fda.gov/cder/

aerssub/default.htm.

Public Health Advisories in 2004 

Non-steroidal anti-inflammatory pain medicines 

In December, we issued a Public Health Advisory recommending limited 

use of non-steroidal anti-inflammatory drug products, including those 

known as COX-2 selective agents. This was an interim measure pending 

our further review of data about the increased risk of heart disease. Shortly 

after the advisory, the manufacturer of one withdrew it voluntarily from the 

market. In 2005, after further review and a public meeting, we withdrew 

another and required a boxed warning about heart disease risks on all 

prescription NSAIDs (page 43). We concluded that over-the-counter 

NSAIDs are safe for short-term pain relief when used as directed on the 

package labeling. 

Antidepressant use in children, adolescents and adults 

We asked manufacturers of all antidepressant drugs to include in their 

labeling a boxed warning and expanded warning statements that alert health 

care providers to an increased risk of suicidality (suicidal thinking and 

behavior) in children and adolescents being treated with these agents and 

additional information about the results of pediatric studies. 
Improving Public Health Through Human Drugs 

39 

MedWatch Internet 

resources 

 You can find the 

latest medical product 

safety information 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 

product use errors for all FDA-regulated medical products. Reports can 

be filed by mail, fax, telephone or the Internet. 

 Educating health professionals and consumers about the importance of 

recognizing and reporting serious adverse events and product problems, 

including medication errors. Our education program includes Internet 

outreach, speeches, articles and exhibits. 

Individual healthcare professional and consumer subscribers to our e-mail 

notification service increased to more than 50,000. We also have 160 

MedWatch Partner organizations. In 2004, these individuals and groups 

received: 

 50 safety alerts for drugs and therapeutic biologics. 

 25 to 70 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. 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. 

In 2004, we approved Medication Guides for two drugs: 

 Abacavir sulfate and lamivudine combination (Epzicom). 

 Amiodarone (Cordarone) and seven generic versions. 

These Medication Guides must be provided to patients with each 

prescription dispensed. 

Drugs with special 

safety restrictions 

Controls on 12 

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. They should not 

be bought over the 

Internet. 

As of June 23, 2005, 

these drugs are: 

 Abarelix 

 Alosetron 

 Bosentan 

 Clozapine 

 Dofetilide 

 Fentanyl citrate 

 Isotretinoin 

 Mifepristone 

 Sodium oxybate 

 Somatropin 

(rDNA origin) 

 Thalidomide 

 Trovafloxacin 

mesylate or 

alatrofloxacin mesylate 

injection 

More information is at 

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

buyonline/

consumeralert120902. 

html. 

Data mining 

We continued work 

under our 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. In 

particular, the software 

developed under the 

agreement was piloted 

in a small group of 

users. 

Data mining for simple 

drug-event signal 

generation is one 

potential contribution 

data mining and 

related quantitative 

methods can make to 

increase our 

awareness and 

understanding of 

trends and patterns in 

adverse drug 

reactions. 
CDER 2004 Report to the Nation 

40 

User fees support risk assessment, minimization 

In recent years, about half of all new medicines worldwide have been 

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

about three-quarters of the world’s new medicines within the first year of 

their introduction. 

The law authorizing us to collect user fees (page 33) allows us to spend 

some of those funds to increase our assessment and minimization of risks 

of medicines both before they are approved and after approval: 

 Preapproval. Sponsors are invited to submit proposed risk management 

plans before they submit an application for a new drug or biologic. Our 

drug safety experts carefully review the proposals and begin discussions 

with sponsors at this early stage that continue through application 

review and after approval. 

 Postapproval. User fees also fund 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. 

Risk management guidances published 

We published three risk management draft guidances for industry in 2004: 

 Premarketing Risk Assessment focuses on measures companies might 

consider throughout all stages of a medicine’s clinical development.

 Development and Use of Risk Minimization Action Plans describes how 

to address specific risk-related goals and objectives and also suggests 

various tools to minimize the risks of drug and biological products. 

 Good Pharmacovigilance Practices and Pharmacoepidemiologic 

Assessment identifies recommended reporting and analytical practices 

to monitor the safety concerns and risks of medicines in general use. 

The three guidances—finalized in 2005—fulfill our commitment to the risk 

management performance goals that are part of the 2002 reauthorization of 

the Prescription Drug User Fee Act. The guidances are based on three 

concept papers released in 2003, on input from a subsequent public 

workshop and on comments received on the draft guidances. 
Improving Public Health Through Human Drugs 

41 

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 to improve 

professional labeling 

so that it better 

communicates 

essential information 

about prescription 

drugs to health care 

providers.

Drug Shortages 

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

products. Drug shortages occur for a variety of reasons including 

manufacturing difficulties, bulk supplier problems and corporate decisions 

to discontinue drugs. 

Because drug shortages can have significant public health consequences, 

we work with all parties involved to make sure all medically necessary 

products are available within the United States. 

Drug shortage program aids counterterrorism effort 

Utilizing data obtained from manufacturers and distributors, our drug 

shortage program provides supply and production information in response 

to federal government requests in relation to counterterrorism efforts. 

Drug shortages 

on the Internet 

We have a Web site 

that lists current drug 

shortages, describes 

efforts to resolve them 

and explains how to 

report them. 

 The site is at http://

www.fda.gov/cder/

drug/shortages.

 We have an e-mail 

address to provide the 

public a communication tool for drug 

shortage information 

at DrugShortages 

@cder.fda.gov.

Medication Error Prevention 

Avoiding name, label, labeling and 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, labeling and packaging that might 

contribute to problems or confusion in prescribing, dispensing or 

administering drug products. 

We review about 300 post-marketing reports of medication errors each 

month. About half are due to error-prone labeling such as similar looking 

labels and labeling, poor package design, confusing instructions for use and 

confusing names. We investigate the causes and contributing factors of 

these errors and recommend revisions to the label, labeling and/or 

packaging of these products to avert further error. 

Our comprehensive Web site on medication errors is at 

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

Bar codes required on medicines 

Our regulation that calls for medicines to have a bar code became final in 

February 2004. It covers most prescription medicines and certain over-thecounter medicines commonly used in hospitals. The bar code rule aims to 

protect patients from preventable medication errors by helping ensure that 

health professionals give the right patient the right drug, at the appropriate 

dosages, 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 

scheduled to launch in 

fall 2005, 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 2004 Report to the Nation 

42 

Top 10 reasons for 

drug recalls in 

fiscal year 2004 

 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. 

Recent safetybased NME 

withdrawals 

Drug name

(FY received/ 

CY approved/ 

CY withdrawn) 

approved use/ 

reason withdrawn

 Azaribine

(1970/1975/1976) 

psoriasis treatment/ 

stroke 

 Ticrynafen

(1978/1979/1980) 

blood pressure reduction/

liver toxicity

 Benoxaprofen

(1980/1982/1982)

pain relief/liver toxicity

 Zomepirac

(1979/1980/1983) 

pain relief/ 

fatal allergic reaction

 Nomifensine

(1979/1984/1986) 

antidepressant/ 

hemolytic anemia

 Suprofen

(1979/1985/1987) 

pain relief/ 

flank pain syndrome

 Encainide

(1984/1986/1991) 

irregular heartbeat/ 

fatal arrhythmia

 Temafloxacin

(1990/1992/1992) 

antibiotic/kidney failure 

Drug recalls in 

fiscal year 2004 

 215 prescription 

drugs 

 71 over-the-counter 

drugs 

Drug Recalls

191 226 248 254 215

60

53 34

88

72 83

88

71

352 354

176

316

248

156

72

0

250

500

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Fiscal year

Prescription Over-the-counter
Improving Public Health Through Human Drugs 

43 

Safety-Based Drug Withdrawals 

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

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

Record of safety-based market withdrawals 

The rates of safety-based withdrawals of new molecular entities are similar 

for an earlier period before we collected user fees and for the period, 

beginning Oct. 1, 1992, when we collected user fees. 

Beginning with this report, our pre-PDUFA and PDUFA periods are based 

on when we received an application rather than when we approved it. The 

receipt date more accurately reflects whether we reviewed an application 

under user fee performance goals (page 33). Starting with Oct. 1, 2003, our 

chart includes our approvals of new therapeutic biologics. PDUFA-era 

applications exempt from user fees are also counted. 

One safety-based withdrawal in 2004 

In September, the manufacturer of rofecoxib voluntarily withdrew the 

COX-2 selective non-steroidal anti-inflammatory pain reliever because it 

was found to increase the risk of heart disease. 

Further analysis and a public meeting led us in 2005 to require boxed safety 

warnings on all prescription NSAIDs and the safety withdrawal of 

valdecoxib, a COX-2 selective NSAID, because of an increased risk of 

serious skin reactions. 

Discontinuations determined to be safety withdrawals 

We considered the 2003 marketing discontinuation of levomethadyl a 

safety-based withdrawal. The manufacturer of the treatment for managing 

opiate dependence discontinued its sale based on reports of cardiac 

arrhythmias and cardiac arrest and the availability of safer alternatives. 

We determined the 1999 marketing discontinuation of etretinate to be a 

safety withdrawal because it poses a greater risk of birth defects than 

acitretin, the active metabolite of etretinate used in its replacement product. 

 Flosequinan

(1991/1992/1993) 

congestive heart failure/

increased deaths 

 Fenfluramine

(1967/1973/1997) 

appetite suppression/

heart valve disease

 Terfenadine

(1983/1985/1998) 

antihistamine/ 

fatal arrhythmia

 Bromfenac

(1995/1997/1998) 

pain relief/ 

liver toxicity

 Mibefradil

(1996/1997/1998) 

blood pressure reduction/ 

fatal arrhythmia

 Grepafloxacin

(1997/1997/1999) 

antibiotic/fatal arrhythmia

 Astemizole

(1985/1988/1999) 

antihistamine/ 

fatal arrhythmia

 Cisapride

(1991/1993/2000) 

heartburn/fatal arrhythmia

 Troglitazone

(1996/1997/2000) 

diabetes/liver toxicity

Recent safetybased NME 

withdrawals (cont.)

Recent safetybased NME 

withdrawals (cont.)

 Alosetron

[Remarketed in 2002 with 

restricted distribution] 

(1999/2000/2000) 

irritable bowel syndrome/

ischemic colitis, severe 

constipation 

 Cerivastatin

(1996/1997/2001) 

cholesterol reduction/

muscle damage leading 

to kidney failure

 Rapacuronium

(1998/1999/2001) 

anesthetic/severe 

breathing difficulty 

 Etretinate

(1985/1986/1999) 

psoriasis/birth defects 

 Levomethadyl

(1993/1993/2003) 

opiate dependence/ 

fatal arrhythmia

 Rofecoxib

(1999/1999/2004 

pain relief/ 

heart attack, stroke 

 Valdecoxib

(2001/2001/2005) 

pain relief/skin disease

Safety-Based Withdrawals

NMEs approved Jan. 1, 1971, to June 30, 2005

BLAs approved Oct. 1, 2003, to June 30, 2005

2.9% 3.1%

0%

2%

4%

Pre-PDUFA (488/14) PDUFA (325/10)

Receipt periods (approvals/withdrawals)

Percentage
CDER 2004 Report to the Nation 

44 

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. 

Research on direct-to-consumer advertising 

We published the final report of our two national telephone patient surveys 

and one physician survey in November 2004 (http://www.fda.gov/cder/

ddmac/researchka.htm). Our main objective in the studies was to assess the 

variety of ways direct-to-consumer advertising could influence the doctorpatient relationship. The three surveys found both positive and negative 

effects: 

 Disease awareness increased. By and large, consumer ads seem to 

increase awareness of conditions and treatments, motivate questions to 

ask a healthcare provider and help patients ask better questions. 

 No increase in doctor visits. Our data provided no evidence of increased 

visits as a result of consumer advertising, and few patients reported that 

advertising motivated physician visits. On the contrary, most people 

reported that health reasons prompted their visits. 

It is clear, however, that direct-to-consumer advertising also has effects that 

may not be positive: 

 Physicians feel some pressure to prescribe. Although few physicians 

report excessive pressure to prescribe requested drugs from patients 

who have seen advertisements, nearly half report feeling at least a little 

pressure to prescribe. 

 Patients, physicians say efficacy overstated. Both patients and doctors 

indicate that consumer directed advertisements overstate drug efficacy 

and do not present a fair balance of benefit and risk information. 

 Patients rate brief summary modestly understandable. Patients gave 

only modest ratings to the understandability of the “brief summary” that 

is included in print advertisements. This is information meant to 

provide a more complete picture of the advertised product’s risks. 

 Patients find recent ads less useful than previously. Patients also 

expressed some negative opinions about direct-to-consumer advertising. 

Perhaps more importantly, fewer patients in the 2002 survey than in the 

survey conducted three years earlier indicated that advertising was 

useful in their interaction with their doctor and in their healthcare 

decision making. 

Studies of brief 

summary 

We are conducting 

three studies to help 

find the best way or 

ways to present 

information in the 

“brief summary”—the 

page of risk 

information in a print 

ad: 

 Purpose. The first 

study will concern the 

purpose of the brief 

summary—how do 

people use it and what 

topics do they find 

most useful. We hope 

to have data collected 

for this study by the 

end of summer 2005. 

 Content. The 

second study will 

address content 

issues in the brief 

summary, including 

the amount of 

common side effect 

information and the 

inclusion of numerical 

context. 

 Format. The third 

study will examine 

format issues, such as 

graphics, layout and 

font. 
Improving Public Health Through Human Drugs 

45 

811 total letters 

issued on drug 

promotion 

activities 

In 2004, we issued 

811 letters concerning 

drug promotion. These 

were: 

 56 letters citing 

violations of 

regulations for 

prescription drug 

promotion. 

 184 advisory letters 

concerning launch 

campaigns. 

 571 other types of 

advisory, closure or 

acknowledgement 

letters. 

Surveillance of drug promotion activities 

Drug advertising and promotion must be truthful, fair, balanced and not 

misleading. We issue letters to ensure compliance with our regulations 

when asked or as a result of our own surveillance. 

Regulatory letters citing violations. We issued 56 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 violative promotions include exhibit hall displays, oral 

representations, Internet sites, plus traditional materials such as journal 

advertisements, sales brochures and TV ads. 

Launch campaign advisory letters. When requested, we review 

advertisements and other promotional materials before drug companies 

launch marketing campaigns that introduce new drugs or campaigns that 

introduce new indications or dosages for approved drugs. In 2004, we 

issued 184 advisory letters to companies regarding their promotional 

materials for launch campaigns. 

Other advisory letters. We issued 423 other advisory letters to the industry 

regarding proposed promotional pieces, both professional and consumer 

directed. We also issued 148 other types of correspondence to the 

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

acknowledgement letters. 

Direct-to-consumer promotion 

We are reviewing and developing methods to increase our effectiveness in 

the oversight of direct-to-consumer advertising. Evidence from our own 

studies as well as those conducted by consumer groups and other entities 

consistently shows that direct-to-consumer 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. 

Letters Issued on Drug Promotion Compliance

129 220 245 237 171 117 105

417

558 539 399

350

276 178

773

515 597

37 42 56

186 185 184

465 510 571

0

700

1400

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

Regulatory letters citing violations Launch campaign advisory letters Other advisory letters

217 letters issued 

on direct-toconsumer 

advertising 

In 2004, 217 or 27 

percent of the 811 

letters we issued 

concerned direct-toconsumer promotion. 

We issued guidance 

on direct-to-consumer 

broadcast 

advertisements in 

1997. Since then, the 

number of letters 

addressing direct-toconsumer promotion 

and their percentage 

of the total of letters 

addressing promotion 

have been: 

 2004: 217 (27%) 

 2003: 254 (34%) 

 2002: 188 (27%) 

 2001: 190 (22%) 

 2000: 215 (24%) 

 1999: 247 (19%) 

 1998: 282 (44%) 

 1997: 240 (31%) 
CDER 2004 Report to the Nation 

46 

Compliance Oversight 

We provide comprehensive regulatory coverage of the production and 

distribution of drug products. We manage inspection programs designed to 

minimize consumer exposure to defective drug products. We have three 

basic strategies to meet this goal: 

 Evaluate the findings of inspections that examine the conditions and 

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

stored. 

 Monitor the quality of finished drug products in distribution, through 

sampling and analysis. 

 Monitor drug products to ensure that they comply with applicable 

approval and labeling requirements. 

We identify, evaluate and analyze inspection findings for trends in 

deficiencies. We publish guidances to assist drug manufacturers 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. 

Risk-based surveillance sampling of drugs 

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

and sampling of foreign and domestic finished dosage forms and bulk 

shipments of active ingredients. 

The drug products surveyed are selected according to a risk-based strategy 

that targets products with the greatest potential to harm the public health. 

FDA district offices conduct follow-up inspections to determine the cause 

of sample failures and to assure corrective action by the firms. 

Sampling criteria 

 Microbial/endotoxin concerns. 

 Stability concerns. 

 Sterility issues. 

 Dissolution issues. 

 Impurities/contaminants. 

 Product quality history. 

 Counterfeit drugs. 

 History of violations. 

Protection 

of federal funds 

Federal law prohibits 

the expenditure of 

federal funds for drug 

products determined to 

be less than effective 

for their labeled 

indications. 

Under an intra-agency 

agreement between 

the Centers for 

Medicare and 

Medicaid Services and 

FDA, we identify drugs 

that are not eligible for 

CMS’s Drug 

Reimbursement 

Program. 

These include dietary 

supplements and 

drugs still on the 

market that have been 

identified as less-thaneffective in Federal 

Register notices. 

This process has 

saved American 

taxpayers millions of 

dollars and has made 

those funds available 

for reimbursement of 

eligible drug products. 
Improving Public Health Through Human Drugs 

47 

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. 

1,375 preapproval 

inspections 

During fiscal year 

2004, FDA evaluated: 

 474 plants in 

support of new drug 

applications. 

 901 domestic firms 

in support of generic 

drug applications. 

1,825 good 

manufacturing 

practice 

inspections 

There were 1,825 

good manufacturing 

practice inspections in 

fiscal year 2004. 

 We approved 45 

field recommendations 

for regulatory action. 

These included 40 

warning letters, three 

injunctions and two 

seizures. 

 We reviewed 184 

foreign establishment 

inspection reports, 

resulting in one 

warning letter, one 

import alert and 

several regulatory 

meetings. 

Compounded drugs 

We generally defer to state authorities regarding the regulation of 

traditional pharmacy compounding—on-site compounding of reasonable 

quantities of drugs following a valid prescription for an individual patient 

from a licensed practitioner. 

Manufacturing disguised as compounding 

Some pharmacies manufacture and distribute compounded drugs in a way 

that goes beyond traditional pharmacy practice. Many of these pharmacies 

make large quantities of unapproved drugs in advance of receiving valid 

prescriptions. They also copy commercially available drugs when there is 

no medical need to do so. We hold pharmacies that manufacture drug 

products under the guise of pharmacy compounding to the same federal 

legal requirements as drug manufacturers. 

Furthermore, some pharmacies have compounded drugs that are 

contaminated, dangerously subpotent (weak) or superpotent (strong). In 

these situations, we take steps to protect the public from these products. 

These steps include issuing enforcement letters, referring complaints to 

state authorities, providing support when states ask, and pursuing 

enforcement actions, such as seizures of violative products. 

Medical gas 

inspections 

We reviewed 171 

medical gas 

inspections and 

approved issuing one 

warning letter. 

FDA Inspections of Manufacturing Plants

773 1,144 822 890 589 474

1,775 1,085 1,268 1,276

864 901

1,844

1,436 1,497 1,519

1,512 1,825

0

2,500

5,000

1999 2000 2001 2002 2003 2004

Fiscal year

New drug preapproval Generic preapproval Current good manufacturing practice
CDER 2004 Report to the Nation 

48 

Drugs sold without required applications 

We identify drugs that are marketed without an approved new or generic 

drug application. The marketing of products that lack required FDA approval may present safety risks and threatens to undermine the U.S. drug 

development and approval process, as well as the over-the-counter drug 

review process. 

We estimate that there are several thousand illegally marketed drug products in the United States, comprised of several hundred unique molecules. 

We issued a draft guidance in 2003 that describes how we intend to: 

 Encourage companies to sponsor unapproved drugs through the approval process. 

 Avoid unnecessarily restricting patient access to useful medicines. 

 Use risk-based criteria for enforcement action. 

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. They may use a 

fraudulent product for treating a serious disease in place of an approved, 

effective treatment, or they may delay the use of a proper treatment in favor 

of a fraudulent remedy. Fraudulent products may also contain toxic 

compounds or other hazardous substances that have the potential to cause 

serious illness, injury or even death. For these reasons, products that are 

mislabeled, fraudulent or make unproven claims may pose a significant 

health risk. 

Protecting consumers from misbranded or fraudulent drugs 

We protect consumers from mislabeled, fraudulent or hazardous products. 

We locate and identify these products on the Internet and other outlets, and 

we take steps to prevent their sale and to remove them from the market. 

These steps include issuing enforcement letters and pursuing enforcement 

actions, such as seizures of violative products and injunctions against firms 

and individuals. We also work with other federal agencies to coordinate 

enforcement action against firms and individuals who violate federal law. 

We may also take steps to warn the public about misbranded and fraudulent 

products. These steps include issuing press releases and MedWatch alerts 

to warn consumers about the potential health risks associated with these 

products. 

Drug importation 

International 

commerce in 

pharmaceuticals 

provides challenges, 

particularly in 

counterfeit drugs and 

counterterrorist 

activities. We work to: 

 Implement law. 

With FDA’s field force, 

we implement legal 

requirements 

establishing which 

drugs may be 

imported by 

manufacturers, 

distributors and 

consumers. 

 Block counterfeits.

We take steps to 

ensure that imported 

drugs are not 

counterfeit or 

mislabeled and that 

they meet applicable 

legal requirements 

relating to safety and 

effectiveness. 

 Improve 

technology. Along with 

the pharmaceutical 

and advanced 

technology industries, 

the states and other 

federal agencies, we 

are developing and 

implement anticounterfeiting 

technology that will 

trace a drug product 

through the U.S. drug 

distribution system. 

Regulation of OTC 

promotional 

statements 

Information that 

accompanies or is 

displayed with an 

over-the-counter drug 

is critical to its safe 

use. 

Approved drug 

applications and OTC 

drug monographs 

(page 27) define 

acceptable consumer 

labeling and 

promotional 

statements for drugs 

sold over-the-counter. 

We monitor the 

statements that 

accompany these 

products to make sure 

they comply with the 

appropriate application 

or monograph. 

We also monitor 

promotional materials 

associated with overthe-counter drugs 

marketed without an 

approved application 

or pursuant to a 

monograph, including 

fraudulent drugs, and 

take enforcement 

actions against these 

products. 
Improving Public Health Through Human Drugs 

49 

Drug Quality Surveillance Systems 

Our reporting tools help us rapidly identify significant health hazards and 

quality problems associated with the manufacturing and packaging of 

medicines. Problems that may affect a medicine’s safety, purity or potency 

may occur during manufacturing, processing, packing, labeling, storage or 

distribution. 

We evaluate reports and FDA field inspections to identify specific firms 

with manufacturing quality problems with the most potential impact on 

public health. We target these candidates for inspection and further product 

sampling and laboratory analysis. We recommend appropriate corrective 

actions based upon our analysis of the findings. We may take enforcement 

action in some cases. 

Types of reports 

 Drug Quality 

Reporting System. 

Through MedWatch 

(page 38), we receive 

reports from 

consumers and health 

care professionals of 

observed and 

suspected product 

quality defects. Our 

central reporting 

system assists us in 

evaluating and 

prioritizing these data 

to identify potential 

manufacturing quality 

problems and industry 

trends. 

 Field Alert Reports.

Firms are required to 

promptly notify FDA 

district offices about 

possible quality and 

labeling problems that 

may represent a safety 

hazard. Experts in 

FDA district offices 

evaluate the reports 

and conduct further 

investigations when 

needed. 

Types of reports

(cont.)

 Biological Product 

Deviation Reports.

Manufacturers are 

required to report any 

event associated with 

the manufacturing of a 

therapeutic biological 

that may affect its 

safety, purity or 

potency. 

Drug quality 

reports 

 374 field alerts 

 3,064 MedWatch 

reports 

Drug Quality Reports

2,020 2,125 2,469 2,800 2,846 3,064

296 281

299

413 447 374

0

2,000

4,000

1999 2000 2001 2002 2003 2004

Fiscal year

MedWatch drug quality reports Field alerts

Reported Drug Quality Defects

Potency, 3%

Volume, 4%

Mix-ups, 4%

Other, 6%

Container defect, 

7%

Dispenser 

malfunction, 8%

Tampering, 1%

Formulation 

questioned, 8%

Therapeutic effect 

lacking, 12%

Labeling defect, 

15%

Generic 

substitution 

questioned, 16%

Dosage form 

quality, 16%

Fiscal year 2004
CDER 2004 Report to the Nation 

50 

Product Quality Science 

Encouraging innovation, state-of-the-art manufacturing 

We have implemented an initiative to encourage manufacturers to be 

innovative and to apply state-of-the art quality assurance methodologies to 

their manufacturing processes. The Process Analytical Technologies 

Initiative is part of our efforts to ensure the continued availability of the 

highest quality pharmaceuticals to the American public. 

We developed the initiative—a key element in our Pharmaceutical cGMPs 

for the 21st Century (page 8)—with these essential precepts in mind: 

 Testing products after manufacturing is not sufficient to guarantee 

product quality. 

 Monitoring and controlling product quality during manufacturing 

provides a much higher degree of quality assurance. 

Process analytical technologies incorporate assessment of a product’s 

characteristics in real-time and feed that information back into process 

control systems that maintain the desired state of product quality 

throughout manufacturing. 

Final guidance establishes scientific tools, regulatory scheme 

Our final guidance on process analytical technologies, issued in 2004, 

includes biotechnology products and establishes a framework that both 

facilitates innovation and enables risk-based regulatory decisions. The 

framework has two components: 

 A set of scientific principles and tools supporting innovation. 

 A strategy for regulatory implementation that will accommodate 

innovation. 

The regulatory implementation strategy includes creation of a process 

analytical technologies team approach to our review of the chemistry 

manufacturing and controls section of an application and to inspections of 

current good manufacturing practices. It includes specialized, joint training 

and certification of reviewers and inspectors.

To review applications using these new technologies, we bring together the 

appropriate experts in analytical and physical chemistry, pharmaceutical 

science, regulatory compliance and chemical engineering to provide a 

comprehensive assessment of the manufacturing process. 

Process analytical technologies Web site 

Our effort to facilitate the introduction of new technologies to the 

manufacturing sector of the pharmaceutical industry 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 53).

We have a new 

program to advance 

rapid microbiology test 

methods. 
Improving Public Health Through Human Drugs 

51 

3-drug regimen 

eligible for 

purchase under 

president’s plan 

In January 2005, 

within two weeks of 

receiving a complete 

application, we 

tentatively approved a 

complete three-drug 

product. It consisted of 

co-packaged 

lamivudine/zidovudine 

fixed-dose 

combination tablets 

and nevirapine tablets. 

Generic drugs 

eligible for 

purchase under 

president’s plan 

As of July 22, 2005, 

we had tentatively 

approved these 

generic drugs: 

 Efavirenz 

 Lamivudine 

 Nevirapine 

 Stavudine 

 Zidovudine 

3 

INTERNATIONAL

ACTIVITIES

President’s Emergency Plan for AIDS Relief 

The president’s $15 billion plan for AIDS relief around the world was 

announced in 2003 and has a special focus on 15 countries hardest hit by 

the HIV epidemic. It targets three specific areas related to HIV/AIDS: 

 Prevention of HIV transmission. 

 Treatment of AIDS and associated conditions. 

 Care, including palliative care, for HIV infected-individuals and care 

for orphans and vulnerable children. 

In May 2004, we announced we would implement a new, expedited review 

process to ensure that the United States could provide safe, effective drugs 

to developing countries. That same month, we published a draft guidance 

encouraging manufacturers to submit applications for fixed-dose 

combination and co-packaged versions of previously approved 

antiretroviral therapies. In June 2004, we traveled to South Africa and India 

to discuss the new guidance with generic drug manufacturers. 

Through our commitment to expedited review, we hope to make safe, 

effective and affordable quality drugs available quickly for patients with 

HIV or AIDS in the undeveloped world. Tentative approval—whether for a 

new drug application or a generic drug application—will be the regulatory 

mechanism by which low-cost versions of innovator drugs sold in the 

developed world will become eligible for purchase under the emergency 

plan. Our tentative approval (page 29) means that existing patents or 

exclusivity prevent the product from being sold in the United States. 

We are committed to ensuring that only quality drug products reach the 

affected nations as quickly as possible. Because we lack information about 

most clinical laboratories and manufacturing sites associated with the 

products seeking approval under the emergency plan, our involvement also 

includes: 

 Outreach activities. 

 Expedited application review and manufacturer assistance. 

 Inspections. 

 Post-marketing monitoring. 
CDER 2004 Report to the Nation 

52 

Internet resources 

More information 

about our international 

activities, including 

Spanish language 

materials, is at http://

www.fda.gov/cder/

audiences/iact/

iachome.htm.

Information-Sharing Agreements 

Because of enhanced cooperation among regulators around the world, FDA 

has entered new international agreements in which we play a critical 

implementation role. 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. 

Japan and Australia 

We routinely exchange recall information about products of interest to 

Japan and Australia and communicate emerging enforcement activities of 

mutual interest. We continue to collaborate with our counterparts regarding 

site inspection information. With limited inspection resources of our own, 

we increasingly depend on foreign regulatory inspections and incorporate 

their 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 agency primarily responsible for approving drugs. It 

permits our review and compliance staff to share important information 

about pending approvals, post-marketing surveillance and enforcement 

actions concerning products and facilities under the European agency’s 

oversight. Implementation, to be phased in, includes activities to build 

understanding and mutual confidence in one another’s systems. 

Mexico and Canada 

FDA is working jointly with our North American neighbors to develop 

information exchange arrangements about drug manufacturing facilities in 

each of our countries and to share information about product recalls that 

may impact our consumers. Our recent contributions to this long-standing 

effort have been vital in moving this relationship in mutually beneficial 

direction. An agreement with Canada provides for the exchange of 

information about pending approvals, post-marketing surveillance and 

enforcement actions. Exchanges of emerging compliance issues and sitespecific information have already begun. 

Switzerland 

The working arrangement with Switzerland began several years ago and 

important progress has been made in the past year. The present agreement 

addresses the need for protection of confidential information and provides 

for the exchange of information about marketing approval decisions, postmarket surveillance, policy developments and compliance or enforcement 

activities of mutual interest. Progress in implementing this arrangement 

includes the exchange of technical staff and training opportunities. 

Successful joint inspections have helped foster mutual confidence and 

improve communications. 

Pharmaceutical 

Inspection 

Cooperation 

Scheme 

As part or our initiative 

to improve 

manufacturing 

practices (page 8), 

FDA announced it 

would seek 

membership in the 

Pharmaceutical 

Inspection 

Cooperation Scheme. 

This is an international 

organization dedicated 

to drug regulatory 

harmonization and 

collaboration in the 

area of good 

manufacturing 

practices. 

Membership would 

formalize a working 

relationship that has 

been in effect for many 

years and that will 

offer greater 

opportunities for 

expanding 

international 

cooperation in drug 

quality regulation. 
Improving Public Health Through Human Drugs 

53 

Module 1 

Administrative 

and prescribing 

information 

(not harmonized) 

Module 2 

Nonclinical 

overview 

Nonclinical 

summary 

Clinical 

overview 

Modular Structure of Common Technical Document 

Clinical 

summary 

Module 4 

Nonclinical 

study reports 

Module 3 

Quality 

data 

Module 5 

Clinical 

study reports 

Quality 

overall 

summary 

Harmonization 

guidances 

We publish 

International 

Conference on 

Harmonization 

documents as 

guidances to industry 

on our Web site at 

http://www.fda.gov/

cder/guidance/

index.htm. 

As of June 8, 2005, we 

had: 

49 final guidances 

 13 safety 

 3 joint safety/

efficacy 

 15 efficacy 

 18 quality 

8 draft guidances 

 2 safety 

 1 joint safety/

efficacy 

 3 efficacy 

 2 quality 

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 in the three regions. 

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. 

Electronic 

Common 

Technical 

Document 

Electronic submissions 

using the eCTD can 

be used to submit all 

applications and 

related submissions 

(page 32) such as 

promotional materials 

and adverse events. 

Among other things, 

the eCTD allows 

reviewers to: 

 Create an up-todate, cumulative table 

of contents for the 

entire application at 

any time. 

 Access any 

electronic submission 

from a single screen. 

 Download files so 

submissions can be 

used even when the 

reviewer is off the 

network. 
CDER 2004 Report to the Nation 

54 

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 

 4,491 

Export Certificates Issued

4,762 5,509

4,544 4,491 4,197 3,973 4,499 4,378 4,382

1,747

0

3,000

6,000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Fiscal year
Improving Public Health Through Human Drugs 

55 

4 

COMMUNICATIONS

In 2004, we met 29 times with outside expert advisors in public discussions 

of difficult scientific and public health issues. We received more than 12 

million visits and more than 205 million hits on our Internet information 

site, which has nearly 100,000 pages and documents, seven databases and 

400,000 hyperlinks. Drugs@FDA (page 20) is the most visited content 

page on the FDA Web site. 

Public participation 

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

public health in meetings open to the public. 

 We assure that patient representatives are included on advisory 

committees considering medicines for HIV, AIDS, cancer and other 

serious disorders. 

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

receive comments on our guidances to industry. 

We held public meetings and workshops to both present information and 

gather a wide variety of viewpoints on major scientific and regulatory 

issues, including: 

 Radioactive drugs for certain research uses. 

 Developing follow-on protein products. 

 Targeting safe and effective diabetes prevention and treatment, a joint 

symposium with the National Institutes of Health. 

 Structured product labeling. 

 Electronic Common Technical Document. 

Transparency of policies, decisions 

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

comment on another four proposed regulations. 

 Guidances. We published 25 guidances for industry that explain our 

position on best practices in scientific and technical areas. We 

published another 25 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 22 documents last year. 

 Freedom of Information requests. We responded to 6,807 requests 

under the Freedom of Information Act. 

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 
CDER 2004 Report to the Nation 

56 

Internet updates 

We have more than 

25,000 subscribers to 

our service that 

provides daily e-mail 

updates of new 

content on our Web 

site and more than 

24,000 subscribers to 

our weekly e-mail 

updates. 

To subscribe, visit 

http://www.fda.gov/

cder/cdernew/

listserv.html.

Public education 

programs 

Our programs educate 

and empower 

consumers to make 

wise choices about 

their medications. Our 

messages, which 

reached 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 

 Using medicines 

safely in children 

 Counterfeit drugs 

 Generic drug 

quality 

 Medicines and the 

elderly 

 Misuse of 

prescription pain 

relievers 

 Over-the-counter 

medicine labels 

 Sedating medicines 

and driving 

These are available on 

the Internet at http://

www.fda.gov/cder/

consumerinfo/

DPAdefault.htm. 

Average Monthly Use of CDER Internet Site

0.03 0.1 0.8 1.0 1.4 0.2 0.2 0.4 0.5

24

0.5 1 3 3

7

9

14

17

0.0

1.0

2.0

1996 1997 1998 1999 2000 2001 2002 2003 2004

Calendar year

Visitors (millions)

0

15

30

Hits (millions)

Visitors (millions) Hits (millions)

Consumer, industry outreach 

 Trade press. We responded to about 2,500 telephone and e-mail 

requests from the specialized press covering the pharmaceutical 

industry. 

 Exhibits. We exhibited at 30 conferences, reaching an estimated 

audience of more than 100,000 consumers, educators and health care 

professionals. 

 Videoconferencing. We held about 150 domestic and foreign 

videoconferences for academia, industry and associations. 

 General information requests. We answered more than 32,000 

telephone inquiries, 31,000 e-mails and 1,700 letters from consumers, 

health professionals and industry. We respond to phone calls and e-mail 

within 48 hours and letters within 30 days. 

 CDER Live! We produced one satellite television broadcast 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. 
Improving Public Health Through Human Drugs 

57 

Jurisdictional 

issues 

Many times it is not 

readily apparent where 

a proposed product 

will be reviewed and 

regulated either within 

the center or between 

FDA centers. 

Our ombudsman is our 

jurisdiction officer and 

a member of the 

steering committee 

that advises FDA’s 

Office of Combination 

Products, which 

coordinates intracenter 

jurisdictional issues. 

Our ombudsman 

responded to more 

than 200 informal 

jurisdiction questions 

that helped guide 

product development. 

When regulatory 

assignment is not 

readily apparent, a 

sponsor may submit a 

formal request for 

designation. 

FDA received 67 of 

these requests in 

2004, a majority of 

which were 

combinations of drugs 

and devices. 

Ombudsman's 

2004 hot topics 

 Enforcement 

against importing 

prescription medicines 

from Canada. 

 Our non-approval 

letter for over-thecounter sales of 

emergency 

contraception. 

 Drug safety 

monitoring and related 

testimony before 

Congress. 

Of the approximately 

1,950 people who 

contacted us, more 

than half were by 

e-mail. Approximately 

250 of these were 

forwarded to our 

“druginfo” account 

(page 58). We 

received 

approximately 800 

specific issue contacts 

by telephone. 

E-mail contact 

ombudsman@cder. 

fda.gov 

Dispute resolution 

Our ombudsman is the initial contact for dispute resolution under our pilot 

program, that gives our reviewers a forum to discuss and resolve differing 

professional opinions (http://www.fda.gov/cder/mapp/4151.2.pdf).

Sponsors and investigators can contact the ombudsman for informal dispute 

resolution on procedural issues regarding our reviews at any stage of a 

product’s development. 

Outreach 

We conducted outreach to explain the ombudsman’s functions including 

product jurisdiction and dispute resolution at several venues. Our 

ombudsman is a member of the Coalition of Federal Ombudsmen and the 

American Association of Ombudsmen. 

Ombudsman’s Activities 

Our ombudsman serves as a portal for consumers, regulated industry and 

small business to, among other things: 

 Comment on our programs and actions. 

 Obtain formal and informal dispute resolution. 

 Seek general information on product development and regulation. 

 Report adverse drug experiences. 

Several people reported irregularities and possible fraud in conducting and 

reporting clinical trials, misleading or false promotional activities and 

violations in pharmaceutical manufacturing. 

Several hundred people contacted the office to express their opinions on 

advisory committee members, direct-to-consumer prescription drug 

advertising, pending decisions on specific therapies and unwanted e-mail 

promotion by on-line pharmacies. 

Further, numerous consumers have commented on the association of 

certain antidepressants with suicide, suicidal ideation and addiction. 

Examples of cases and allegations our ombudsman handles include: 

 Review and drug development delay. 

 Unfair handling of an issue. 

 Freedom of Information request backlog. 

 Docket posting dispute. 

 User-fee dispute. 
CDER 2004 Report to the Nation 

58 

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 of Drug Information 

HFD-240, Room 12B-05 

5600 Fishers Lane 

Rockville, MD 20857 

E-mail notification from us 

At http://www.fda.gov/cder/cdernew/listserv.html, you can sign up for 

these updates from the Center for Drug Evaluation and Research: 

 Website updates. Daily and weekly lists of new postings. 

 MedWatch. Medical safety alerts 

 Drug shortages. New, medically important drug shortages. 

 Consumer news. New education materials. 

 Small business. Information for small pharmaceutical companies. 
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 Medical Informatics 

 Associate Director for Policy 

Office of Executive Programs 

 Executive Operations Staff 

 Quality Assurance Staff 

 Advisors & Consultants Staff 

 International Programs 

 Ombudsman 

 Organizational Development & Strategic 

Planning 

Office of New Drugs 

 Pharmacology/Toxicology Staff 

 Program Management Team 

 Study Endpoints & Labeling Team 

 Pregnancy & Lactation Team 

 Guidance Policy Team 

 Regulatory Affairs Team 

Office of Pharmacoepidemiology 

& Statistical Science 

Office of Pharmaceutical Science 

 Informatics & Computational Safety 

Analysis Staff 

 Process Analytical Technologies 

 Quality Implementation Staff 

 New Drug Microbiology Team 

Office of Drug Evaluation I 

 Div. of Neurology Products 

 Div. of Psychiatry Products 

 Div. of Cardio-Renal Drug 

Products 

 Botanicals Review Team 

Office of Drug Evaluation II 

 Div. of Pulmonary Drug Products 

 Div. of Anesthesia, Analgesia & 

Rheumatology Products 

 Div. of Metabolic & Endocrine 

Drug Products 

Office of Drug Evaluation III 

 Div. of GastroIntestinal 

& Coagulation Drug Products 

 Div. of Reproductive & Urologic 

Drug Products 

 Div. of Dermatologic & Dental 

Drug Products 

Office of Nonprescription 

Products 

Office of Drug Safety 

 Div. of Surveillance, Research 

& Comm. Support 

 Div. of Medication Errors 

& Tech. Support 

 Div. of Drug Risk Evaluation 

Office of Biostatistics 

 Quantitative Methods 

& Research Staff 

 Div. of Biometrics I 

 Div. of Biometrics II 

 Div. of Biometrics III 

 Biologic Therapeutics Statistical 

Staff 

Office of Information 

Management 

 Business Information Staff 

 Review Technology Staff 

 Div. of Records Management 

Office of Regulatory Policy 

 Div. of Regulatory Policy I 

 Div. of Regulatory Policy II 

 Div. of Information Disclosure 

Policy 

Office of Management 

 Div. of Management & Budget 

 Div. of Management Services 

Office of Training 

& Communications 

 Div. of Training & Development 

 Div. of Drug Information 

 Div. of Library & Info. Services 

 Div. of Public Affairs 

Office of Compliance 

 Div. of New Drugs & Labeling 

Compliance 

 Div. of Manufacturing & Product 

Quality 

 Div. of Compliance Risk Mgmt. 

& Surveillance 

Office of Testing & Research 

 Laboratory of Clinical Pharmacology 

 Div. of Applied Pharmacology 

Research 

 Div. of Pharmaceutical Analysis 

 Div. of Product Quality Research 

Office of New Drug Chemistry 

 Div. of New Drug Chemistry I 

 Div. of New Drug Chemistry II 

 Div. of New Drug Chemistry III 

Office of Clinical 

Pharmacology 

& Biopharmaceutics 

 Div. of Pharmaceutical 

Evaluation I 

 Div. of Pharmaceutical 

Evaluation II 

 Div. of Pharmaceutical 

Evaluation III 

Office of Generic Drugs 

 Div. of Bioequivalence 

 Div. of Chemistry I 

 Div. of Chemistry II 

 Div. of Chemistry III 

 Div. of Labeling & Program Support 

1-888-INFO FDA 

8/10/2005 

American Consumers 

Office of Drug Evaluation IV 

 Div. of Anti-Infective & 

Ophthalmologic Products 

 Div. of Anti-Viral Drug Products 

 Div. of Special Pathogen & 

Immunologic Drug Products 

Office of Biotechnology 

Products 

 Div. of Monoclonal Antibodies 

 Div. of Therapeutic Proteins 

Office of Drug Evaluation VI 

 Div. of Review Management & 

Policy 

 Div. of Therapeutic Biological 

Internal Medicine Products 

Office of Information 

Technology 

 Quality Assurance Staff 

 Technology Support Services 

Staff 

 Div. of Applications Development Services 

Office of Medical Policy 

 Div. of Scientific Investigations 

 Div. of Drug Marketing, 

Advertising 

& Communication 

Office of Counter-Terrorism & 

Pediatric Drug Development 

 Div. of Pediatric Drug Dev. 

 Div. of Counter-Terrorism 

Drug Safety Oversight Board 

Office of Oncology Drug 

Products 

 Div. of Biological Oncology 

Products 

 Div. of Oncology Drug Products 

 Div. of Medical Imaging Drug 

Products 
U.S. Department of Health and Human Services

Food and Drug Administration 

Center for Drug Evaluation and Research