Statistics 

Drug Safety 

Drug Quality 

Adverse Events 

MedWatch 

Withdrawals 

New Drugs 

New Therapeutic Biologics 

Generic Drugs 

Over-the-Counter Drugs 

International Activities 

Communications 

Center for Drug Evaluation and Research 

Improving Public 

Health 

Through 

Human 

Drugs 

REPORT

TO THE

NATION

2005

U.S. Department of 

Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation 

and Research 
U.S. Department of 

Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation 

and Research 
Center for Drug Evaluation and Research 2005

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 2005 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/2005/rtn2005.pdf.

 HTML: http://www.fda.gov/cder/reports/rtn/2005/rtn2005.htm.

 Slides: http://www.fda.gov/cder/reports/rtn/2005/rtn2005.ppt.

Suggested citation: U.S. Food and Drug Administration. CDER 2005 

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 ....................................7 

 Counterterrorism..................................................................8 

 Scientific Research ............................................................10 

1 DRUG REVIEW.......................................................................12 

 New Drug and Biologic Review........................................13 

 New or Expanded Use Review..........................................20 

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

 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 

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

 Medication Error Prevention .............................................40 

 Public Health Advisories in 2005......................................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 2005 Report to the Nation 

ii 

Graphs and Charts 

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.................................20 

Standard New or Expanded Use Approvals...............................21 

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

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

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

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

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

More Generic Competition Lowers Drug Prices........................30 

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

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

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

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

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

Drug Promotion Letters Citing Violations .................................45 

Advisory Drug Promotion Letters .............................................45 

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

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

Export Certificates Issued ..........................................................53 

Modular Structure of Common Technical Document................54 

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

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

iii 

Director’s Message 

I am pleased to provide our 2005 Report to the Nation from the Center for Drug Evaluation and Research. 

In this report, we outline our initiatives and document our performance across our program areas during 

2005. I am very proud to report that we have made substantial advances in identifying, managing and 

communicating safety-related issues. We have also made major advances in our efforts to improve the 

science of drug manufacturing. 

As an organization, our Center is becoming more transparent, flexible, results-oriented and highperforming. These improvements are helping us maintain our place as the world leader in the review of 

the safety and efficacy of pharmaceutical products and in responding to the challenges of emerging public 

health threats. Through our participation in the FDA’s Critical Path Initiative, we are playing a key role in 

helping to enhance the efficiency of drug development. Although, we play an important role in many 

areas, I would like to focus on just a few key efforts to give you an idea of what we are doing to ensure 

the success of our mission. 

Addressing public concerns about drug safety 

All medicines have benefits and risks. We have continued to focus on the importance of minimizing these 

risks and improving the way medicines are used. For example, during 2005, we issued 16 public health 

advisories about important drug safety issues. To sustain a multi-disciplinary, cross-Center approach to 

drug safety, we elevated the Office of Surveillance and Epidemiology (formerly the Office of Drug 

Safety) to report directly to the Center Director, and we appointed an Associate Center Director for 

Safety, Policy and Communication to focus on broad drug-safety policy and communication, including 

overseeing MedWatch and the Drug Safety Oversight Board staff. We anticipate that this reorganization 

will help us successfully promote the efficient assessment of and response to emerging safety issues. 

In addition, the creation last year of the Drug Safety Oversight Board continues to foster a culture of 

openness and enhanced oversight around safety issues within the Center. In 2005, the board, under chair 

Douglas Throckmorton, M.D., the Center’s Deputy Director, met five times and discussed critical safety 

issues including: long-acting beta agonists associated with more severe asthma episodes; Clostridium 

sordellii infections in patients taking mifepristone; antidepressants and suicidality; and the concerns with 

misuse of fentanyl transdermal patches. The board continues to work to help us improve how we identify 

and manage emerging drug safety issues and how we provide emerging information to health-care 

professionals and patients about the risks and benefits of medicines. 

Improving our analytic and predictive tools to enhance drug development 

One of the organizational changes announced in 2005 is a response to FDA’s efforts to improve the 

science of medical product development, the Critical Path Initiative. To support this priority activity and 

to speed the movement of innovative therapies to patients, we created an Office of Translational Sciences, 

which includes the Office of Clinical Pharmacology and the Office of Biostatistics. The Office of 

Translation Sciences will support cross-cutting science programs such as the Regulatory Science and 

Review Enhancement Committee, the Research Involving Human Subjects Committee and the Critical 

Path Initiative. This office also has the important task of coordinating our collaborations with outside 

groups to help identify and resolve issues that are standing in the way of efficient drug development. We 

anticipate that, by putting these functions together into one office, we will be better able to promote these 

many scientific activities. 
CDER 2005 Report to the Nation 

iv 

Improving our scientific tools to ensure product quality 

We are continuing our work on the transformation of product manufacturing and how it is regulated, by 

extending the work done in the Agencywide Pharmaceutical cGMPs for the 21st Century initiative. 

Activities have included: 

 Incorporating the fundamentals of quality systems into CDER operations. 

 Restructuring the chemistry, manufacturing and controls review staff in the Office of New Drug Quality 

Assessment to provide for better efficiency. 

 Rolling out concepts and philosophy of the changes to industry. 

 Training chemistry, manufacturing and controls reviewers 

 Introducing a pilot program for new drugs through which industry can submit applications using a 

quality-by-design framework to help expand the Agency’s knowledge in this area. 

All of these activities have helped strengthen the overall scientific focus for chemistry, manufacturing and 

controls review as well as reduce some of the regulatory burden for both the Agency and the industry. 

Improving efficiency and consistency of cancer product reviews 

Our efforts to improve the timely development of new drugs for the treatment of cancer have continued. To 

enable this, we made significant changes to our organizational structure to provide a stronger and more 

consistent approach to the review process for drugs and therapeutic biologics used to diagnose, treat and 

prevent cancer. We created a new oncology office, called the Office of Oncology Drug Products. This new 

office is a consolidation of three pre-existing areas within the Center: Drug Oncology Products, Biologic 

Oncology Products and Medical Imaging and Hematology Products. Creation of this new office will 

improve consistency of review and policy for oncology products and bring together a critical mass of 

oncologists who can help during the development of new cancer therapies. This office will also provide 

technical consultation to other FDA components. 

Speeding the development of medical countermeasures 

We recognize the need to facilitate the development of countermeasures to protect Americans from 

biological, chemical, nuclear and radiological agents of terrorism. Many parts of the Center contribute to 

this effort, focused through the Office of Counter-Terrorism and Emergency Coordination, an office we 

formed in 2006. One important goal we have identified is to foster the development of medical 

countermeasures for vulnerable populations. For example, in 2005, following an expedited review, we 

approved ThyroShield, a ready-to-use, liquid medicine to block the uptake of radioactive iodine in 

vulnerable populations. Unlike already approved tablets, which are not ideally suited for young children, 

this black raspberry flavored solution is dosed using an eyedropper to enable easy treatment of young 

children and newborns. 

We are extremely proud of the work outlined in this report and look forward to another year of important 

strides in approving therapies to improve the health of Americans. 

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, healthcare 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 2005 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. To 

ensure a safe and effective drug supply, we enforce federal requirements 

for drug approval, manufacturing and labeling. When necessary, we take 

legal action to stop distribution of products in violation of these 

requirements. As the pharmaceutical industry has become increasingly 

global, we are involved in international negotiations with other nations to 

harmonize standards for drug quality and the data needed to approve a new 

drug. This harmonization will go a long way toward reducing the number 

of redundant tests manufacturers do and help ensure drug quality for 

consumers at home and abroad. 

Why we do it 

Our 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, often at 

much lower cost. 

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 10th performance report. Our work in 2005 

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 ways to improve the science of drug development. 

 Improving manufacturing practices. 

 Protecting the homeland with improved medical countermeasures to be 

used in the 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 80 new medicines, including 20 truly new 

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

country. We approved 141 new or expanded uses for already approved 

medicines. We approved 344 generic versions of existing drugs. 

 User-fee performance. We met almost all of our goals for review 

performance in fiscal year 2005. 

 Drug safety surveillance. We processed and evaluated more than 

460,000 reports of adverse drug events, including more than 25,000 

submitted directly from individual health-care providers and patients. 

 Drug promotion and advertising. We issued 60 letters on violations in 

drug promotion and more than 800 letters to help ensure manufacturers 

comply with regulations concerning drug promotion. 

 Public database of electronic labels. We required manufacturers to 

begin submitting drug labeling information electronically so that it can 

be made publicly available rapidly. 

 Public health advisories. We issued alerts on non-steroidal antiinflammatory pain medicines and 15 other safety concerns. 

 Manufacturing compliance. We acted to halt distribution of drugs that 

were unapproved, poorly manufactured or improperly labeled. 
CDER 2005 Report to the Nation 

4 

Drug Safety Initiative 

Our highest priority is assuring that safe and effective medicines are 

available to the American public. Safe medicines, where the benefits 

outweigh the risks, were the focus of a number of high-profile initiatives in 

2005. We worked to ensure that our systems for assessing and evaluating 

safety continue to be robust and that we communicate new information for 

health-care providers and patients in a timely and clear manner. Our efforts 

included: 

 Establishing the Drug Safety Oversight Board. 

 Sharing drug safety information sooner and more broadly. 

 Laying the foundations of an electronic information infrastructure that 

will give patients, health-care professionals and consumers quick and 

easy access to the most up-to-date and accurate information on 

medicines. 

 Obtaining public input on our drug risk communications strategies. 

Drug Safety Oversight Board 

The 15-member board provides drug safety oversight and recommendations 

to the Center Director on drug safety issues. The board held five meetings 

in 2005. In its initial meetings, members explored the methods we use in 

risk assessment of marketed drugs, including: 

 Review and analysis of spontaneous reports of adverse events. 

 Drug use data. 

 Health-care administrative data. 

 Epidemiologic and observational studies. 

 Clinical trials. 

 Active surveillance systems. 

In later meetings, members discussed pre- and post-decisional risk 

management examples to further clarify and define their oversight and 

advisory responsibilities including their role in helping establish policies 

and managing the communication of important drug safety issues to 

stakeholders. Members include representatives from each of our offices 

with responsibility for drug safety, a representative from each of the two 

other FDA centers dealing with human medical products, a representative 

the Veterans Administration and a representative the National Institutes of 

Health. 

More information about the board is at http://www.fda.gov/cder/

drugSafety.htm. Public summaries of board meetings are at http://

www.fda.gov/cder/drug/DrugSafety/DSOBmeetings/default.htm. 

Institute of 

Medicine study 

We contracted with the 

Institute of Medicine to 

study the effectiveness 

of the nation’s drug 

safety system. The 

study will emphasize 

the post-market phase 

and assess what 

additional steps could 

be taken to learn more 

about the side effects 

of drugs as they are 

actually used. 

The institute, a 

component of the 

National Academy of 

Sciences, is the 

nation’s foremost body 

for science-based 

advice on matters of 

biomedical science, 

medicine and health. 

More information 

about their study and 

transcripts of the 

public meetings are 

available at http://

www.iom.edu/

CMS/3793/26341. 

aspx.

Comprehensive 

oversight of drug 

safety 

Our professional staff 

spends about one-half 

their time addressing 

safety issues, 

including: 

 Watching for 

problems once we 

approve a drug. 

 Overseeing clinical 

trials. 

 Evaluating new 

therapies and new or 

expanded uses for 

existing therapies to 

balance risks against 

expected benefits. 

 Overseeing 

manufacturing, 

distribution and 

promotional activities. 

 Preventing 

medication errors by 

evaluating proposed 

proprietary names, 

labeling and 

packaging. 

 Developing 

proactive risk 

management 

strategies both before 

and after approval. 
Improving Public Health Through Human Drugs 

5 

Drug safety communication channels 

We began sharing “emerging” drug safety information broadly through 

public health advisories and through specific drug safety information sheets 

that are tailored to the needs of health-care professionals and patients. In 

some cases, we are sharing safety information even before we have reached 

conclusions that would prompt a regulatory action. Our communications in 

2005 included: 

 Public Health Advisories. We issued 16 advisories to alert health-care 

providers and consumers to safety concerns about drugs (page 41).

 Health-care professional information sheets. We published sheets on 44 

drugs with detailed information about emerging important drug safety 

concerns, including a description of the concern along with 

recommendations and considerations about the concern for the 

prescriber. 

 Patient information sheets. We published 41 information sheets 

containing new information about emerging drug safety concerns for 

approved drugs and provided in a consumer-friendly format. 

More about drug safety communication is at http://www.fda.gov/cder/

drugSafety.htm. 

Prescription drug information infrastructure 

Accurate, up-to-date information about a prescription drug is critical for its 

safe and effective use. Too frequently, information about a prescription 

drug reads more like a legal disclaimer than useful or actionable health 

information. We worked hard in 2005 to bring to fruition several 

interconnected regulatory actions, including: 

 Electronic submission of drug labeling. We issued final guidance to 

assist manufacturers in submitting prescription drug label information 

to us in a new electronic format (page 32).

 Launching the DailyMed public database of drug information. This 

multi-agency effort to improve patient safety is enabling us—through 

the National Library of Medicine—to provide an up-to-date 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. 

 Working to bring out our final requirement for revised prescription 

drug labeling. Our final regulation, issued in January 2006, amends the 

content and format of information in prescription drug labeling, 

commonly called the package insert. The new label will provide the 

most important information about new and recently approved 

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

more easily accessible and more memorable for physicians. 

Public hearing on 

communication of 

drug safety 

information 

Making us a reliable 

“trusted source” of 

health-care provider 

and consumer 

information about 

medicines emerged as 

the key theme at a 

two-day public hearing 

in 2005 on our risk 

communications. We 

were urged to engage 

health-care 

professional 

organizations, simplify 

our risk 

communications, 

improve provider and 

consumer access to 

our Internet site, 

develop consistent 

communication 

approaches and 

address those with 

limited health literacy 

and English skills. 
CDER 2005 Report to the Nation 

6 

Critical Path Initiative 

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

a national effort to modernize the scientific processes through which a 

potential human drug or therapeutic biologic is transformed from a 

discovery or “proof of concept” into a medical product. 

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, an FDA report in 2004 described an urgent need to modernize 

the medical product development process—the Critical Path—to make 

product development more predictable and efficient. Because of our unique 

vantage point, we can work with companies, patient groups, academic 

researchers and other stakeholders to coordinate, develop and help 

disseminate solutions to scientific hurdles that are impairing the efficiency 

of medical product development. 

Critical Path Opportunities List 

During 2005, we helped the Agency describe and provide examples of how 

new scientific discoveries—in fields such as genomics, proteomics, imaging 

and bioinformatics—could be applied to improve the accuracy of the tests 

we use to predict the safety and efficacy of investigational medical products. 

The list was released in early 2006. 

The list provides a concrete focus for public and private efforts and 

investments in new tools that could revolutionize product development. The 

goal is to encourage others to undertake such work in their areas of interest. 

It was developed based on feedback from stakeholders and the special 

insights of FDA’s product reviewers. 

The list’s 76 scientific projects mark a starting point in identifying the 

essential development priorities. These are highly-targeted research projects 

divided into six key areas: 

 Better evaluation tools—biomarkers and disease models. 

 Streamlining clinical trials. 

 Harnessing bioinformatics. 

 Moving manufacturing into the 21st century. 

 Products to address urgent public health needs. 

 At-risk populations. 

The comprehensive Web site on the Critical Path is at http://www.fda.gov/

oc/initiatives/criticalpath/. 

Personalized 

medicine 

The Critical Path 

recognizes 

“pharmacogenomics” 

and encourages its 

use in drug 

development. 

Pharmacogenomics 

allows health-care 

providers to identify 

differences in people’s 

drug risk response 

profiles and predict the 

best possible 

treatment options for 

them. 

In 2005, we helped lay 

the regulatory 

groundwork for 

pharmacogenomics in 

the Critical Path by 

issuing: 

 A final guidance on 

voluntary submissions 

of pharmacogenomic 

data 

 A draft concept 

paper on how to codevelop a drug or 

biological therapy 

along with a device 

test in a scientifically 

robust and efficient 

way. 

We received 15 

voluntary genomic 

data submissions from 

industry in 2005. 

More information is 

available at 

www.fda.gov/cder/

genomics.

Pharmacogenomics 

workshop 

In 2005, we held the 

third in a series of 

scientific workshops 

on how pharmacogenomics could 

enable efficient and 

successful drug 

development in such 

areas as: 

 The efficiency and 

informativeness in 

clinical trials. 

 Clinical trials for 

cancer therapy. 

 International 

harmonization of 

pharmacogenomics 

guidances. 

 Strategies to bridge 

pharmacogenomics 

information from drug 

development research 

to clinical practice. 

 Clinical qualification 

of genomic biomarkers 

for decision making. 

 Creation of 

diagnostic tests for 

clinical practice. 
Improving Public Health Through Human Drugs 

7 

21st Century Drug Quality System 

Our overhaul of the regulatory and quality control systems for 

pharmaceutical products encourages manufacturers to modernize their 

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

production inefficiencies and undue risks for consumers. Our initiative 

implements improved policies that are making better use of our limited 

resources through more targeted and effective inspections. 

We are improving both our external polices, known as “current good 

manufacturing practices” or cGMPs as well as our internal programs for the 

review of an application’s chemistry, manufacturing and controls sections. 

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

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

www.fda.gov/cder/gmp/. 

New drug quality assessment 

Our chemists reorganized during 2005 to transform drug quality assessment 

from a checklist review to a scientifically sound, risk-based process. The 

mission of our new Office of New Drug Quality Assessment is to: 

 Assess the critical quality attributes and manufacturing processes of 

new drugs. 

 Establish quality standards to assure safety and efficacy 

 Facilitate new drug development. 

Our chemists are now focusing on critical pharmaceutical quality attributes 

and their relevance to safety and efficacy. These include chemistry, 

pharmaceutical formulation, stability, manufacturing processes, 

bioavailability and product performance. Our long-term goal is to: 

 Emphasize quality by design in the evaluation of critical aspects of 

pharmaceutical quality. 

 Have a strong focus on manufacturing science. 

 Integrate review and inspection functions. 

 Use modern statistical methodologies. 

Our vision for “desired state” in manufacturing 

 Product quality and performance assured by effective and efficient 

manufacturing processes. 

 Product attributes based on mechanistic understanding of how 

formulation and process impact performance. 

 Continuous improvement and continuous real-time assurance of quality 

enabled. 

 Regulatory policies recognize level of product and process knowledge. 

Workshop 

explores drug 

quality system 

We held a three-day 

scientific workshop for 

industry to explore 

how we can achieve 

the new drug quality 

system. We worked 

with industry scientists 

to: 

 Identify scientific 

training gaps that must 

be filled for the 

successful 

implementation of the 

new system. 

 Obtain industry 

input on building a 

scientific, risk-based 

regulatory system that 

maintains high quality 

and facilitates 

continuous 

improvement. 

 Help determine 

how to best use 

information from the 

pharmaceutical 

development phase in 

the industrialization 

phase. 

 Identify the roles 

and responsibilities for 

industry and us in the 

new system. 

 Propose ways to 

reduce the number of 

post-marketing 

supplements. 

Chemistry, 

manufacturing, 

controls pilot 

program 

We launched a formal 

pilot program in July 

2005 under which 

pharmaceutical 

companies can 

voluntarily submit new 

drug applications that 

apply quality-bydesign principles and 

demonstrate their 

product knowledge 

and process 

understanding. 

This scientific 

information—more 

relevant than found in 

a traditional 

submission—-will 

enable us to: 

 Perform a riskbased assessment of 

product quality and 

process performance. 

 Consider an 

applicant’s proposal 

for regulatory flexibility 

in setting product 

specifications and 

post-approval 

changes. 
CDER 2005 Report to the Nation 

8 

Counterterrorism, Emergency Response 

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

helping to prepare the nation for terrorist events, emerging health threats 

and emergency response to natural and man-made crises, including: 

 Assuring the availability of medicines during a crisis. 

 Addressing issues on procurement, packaging, labeling, use and shelflife extension of products in the Strategic National Stockpile. 

 Utilizing regulatory mechanisms to provide emergency access to new 

therapies and to approved therapies used in novel ways. 

 Assuring alternative manufacturing sites for critical medicines. 

 Protecting the nation’s drug supply from attack or deliberate 

contamination. 

 Leveraging with other federal agencies to answer scientific questions 

about treatments for emerging health threats and terrorist events. 

 Preparing ourselves to continue operations during a crisis. 

Interagency collaborations 

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

centers and the Centers for Disease Control and Prevention, 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 

counterterrorism working groups that have contributed to gap analyses 

in medical countermeasures and authored many of the requirements 

documents that will be used to prioritize products for development and 

eventual procurement under BioShield. 

Counterterrorism guidances published in 2005 

 Draft Guidance for Industry: Internal Radioactive ContaminationDevelopment of Decorporation Agents. 

 We participated in developing FDA’s Draft Guidance: Emergency Use 

Authorization of Medical Products.

Hurricane 

response 

We assisted in the 

response to hurricanes 

Katrina, Rita and 

Wilma by coordinating 

the Internet posting of 

information about: 

 The safety of 

medications potentially 

damaged by flooding 

or high temperature. 

 Insulin use. 

 Safety of using 

combination 

sunscreen and insect 

repellent in children. 

 Reporting 

prescription drug 

sample losses. 

 Assisting 

investigators 

conducting clinical 

trials in hurricaneaffected areas. 

 Facilitating 

donation of drugs. 

 Coordinating 

volunteer responses 

for relief efforts. 

About 150 Public 

Health Service 

Commissioned Corps 

officers—one-half the 

total assigned to our 

center—were 

deployed to provide 

medical and pharmacy 

services in areas 

affected by the 

hurricane. 

Pandemic flu 

preparedness 

We are preparing for 

an influenza pandemic 

by: 

 Participating in the 

FDA Pandemic 

Influenza 

Preparedness Task 

Force, as well as in 

the Antiviral Subgroup 

and the Emergency 

Preparedness, 

Response and 

Communications 

Subgroup. 

 Helping to develop 

FDA’s Pandemic 

Influenza 

Preparedness 

Strategic Plan and our 

center’s portion of 

FDA’s Pandemic 

Influenza Continuity of 

Operations Plan. 

 Providing input on 

the HHS Pandemic 

Influenza Plan from 

the Department of 

Health and Human 

Services. 
Improving Public Health Through Human Drugs 

9 

Medical countermeasure approvals 

 Potassium iodide oral solution (ThyroShield). This oral solution of a 

thyroid blocking agent for use in radiation emergencies is appropriate 

for children or adults who cannot swallow tablets. We advised the 

Department of Health and Human Services in a BioShield procurement 

of the product, which was approved as a generic drug. 

 Generic ciprofloxacin. We approved four additional new generic 

ciprofloxacin drug products, all with approved labeling for the 

management of inhalational anthrax (post-exposure). 

 Revised labeling for ciprofloxacin (Cipro). We approved revisions for 

the sections of the package insert concerning Indications and Usage, 

Adverse Reactions and Inhalational Anthrax—Additional Information. 

These changes for the tablets, intravenous solution and oral suspension 

were based on information obtained by the Centers for Disease Control 

and Prevention during the 2001 anthrax attacks. Because of these data, 

we released the manufacturer from its accelerated approval commitment 

to report data from confirmatory anthrax studies. 

Facilitating medical countermeasure development 

 Plague. The Centers for Disease Control and Prevention continued to 

enroll patients in the second year of an FDA-funded clinical trial to 

assess the efficacy of the antibiotic gentamicin for endemic plague in 

Madagascar, where antimicrobial options for plague are extremely 

limited. We contributed to protocol design and the formation of a data 

safety monitoring board to oversee the safe conduct of the study. We 

are continuing our collaboration with FDA’s 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—in a non-human primate 

model of pneumonic plague. 

 Inhalational Anthrax. We continued our collaboration with both 

institutes to establish a non-human primate natural history model for 

inhalational anthrax. 

 Radiological and nuclear threats. We continued to collaborate with the 

National Institute of Allergy and Infectious Diseases to identify 

promising new products for use against radiological and nuclear threats. 

We discussed scientific and regulatory issues with manufacturers of 

such products and informed them about possible funding sources, both 

for early development and for procurement by the federal government.

Internet resources 

We provide the most 

current information on 

medical countermeasures and 

vaccines, plus advice 

on purchasing and 

taking medication, at 

http://www.fda.gov/

cder/drugprepare/

default.htm.

Emergency 

preparedness 

We provided rapid 

responses to requests 

for information on 

medical countermeasures during a 

five-day 

interdepartmental 

exercise, known as 

TOPOFF 3 (“Top 

Officials”). The 

exercise simulated 

simultaneous terrorist 

attacks using multiple 

threat agents—both 

pneumonic plague in 

New Jersey as well as 

the release of mustard 

gas and a high-yield 

explosive in 

Connecticut. 

Emergency use 

authorization 

We worked with the 

Centers for Disease 

Control and 

Prevention to identify 

potential medical 

countermeasures in 

the Strategic National 

Stockpile as 

candidates for 

Emergency Use 

Authorization for an 

unapproved use under 

the Project BioShield 

Act of 2004. 

We also began to 

outline the internal 

processes and 

procedures we need to 

handle emergency use 

requests. 

Flu prevention 

for children 

In December, we 

approved oseltamivir 

(Tamiflu) for 

prevention 

(prophylaxis) of 

influenza in children 1 

to 12 years of age. 

This gives health-care 

providers an option for 

preventing influenza in 

children following 

close contact with an 

infected individual. 

Our approval followed 

presentation of an 

adverse event safety 

update on the drug to 

the Pediatric Advisory 

Committee. The 

meeting provided a 

public forum to discuss 

the safety of the drug’s 

use in children as part 

of a routine drug 

safety update required 

by the Best 

Pharmaceuticals for 

Children Act. 
CDER 2005 Report to the Nation 

10 

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. 

 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. 

Counterterrorism 

biotechnology 

research 

We have used 

congressionally 

mandated special 

funding to initiate 

research in several 

areas relevant to 

counterterrorism. Our 

scientists are studying: 

 Microarray 

technologies, which 

could assist in 

identifying infectious 

biowarfare agents. 

 Non-specific 

immune boosters, 

which could provide 

transient protection 

against such agents. 

 Monoclonal 

antibodies as 

neutralizers of 

biological toxins. 

 Various strategies 

to defend against 

anthrax. 

 Development of 

Anthrax Toxin assays 

for assessment of 

potential therapies. 

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. 

Evaluation of new 

technologies 

We conduct targeted 

research to 

understand how new 

technologies will affect 

future regulatory 

decision making. 

For example, we are 

evaluating how 

microarrays that can 

identify thousands of 

genes or proteins 

rapidly and at the 

same time could 

improve the interface 

between drug 

development and 

regulatory practice. 
Improving Public Health Through Human Drugs 

11 

Biotechnology research 

Our Office of Biotechnology Products 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 

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. 
CDER 2005 Report to the Nation 

12 

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 2005 include: 

 80 new medicines. We approved 78 drugs and two biologics (22 priority 

and 58 standard reviews). 

 20 truly new medicines. We approved 18 drugs and two new biologics 

that had never been marketed before in any form in this country (15 

priority and 5 standard reviews). 

 141 new treatment options. We approved new or expanded uses for 126 

already approved drugs and 15 already approved biologics (36 priority 

and 105 standard reviews). 

 5 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. 

 10 “orphan” medicines. Our approvals included nine drugs and one 

biologic for patient populations of 200,000 or fewer. 

 344 generic drugs. We gave final approval to 344 generic versions of 

existing drugs and tentative approval to another 108. We received 777 

marketing applications for generic drugs. 

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

year 2004 receipt cohort, the latest year for which we have full 

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

goals for the fiscal year 2005 cohort. 

 652 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. 

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.” 

Approval totals 

 80 drugs and 

biologics 

 78 drugs 

 2 biologics 

 20 truly new 

medicines 

 18 drug NMEs 

 2 new biologic 

NMEs 

 14 orphan 

approvals 

 9 NDAs (includes 

6 NMEs) 

 1 new biologic 

 4 approvals for 3 

new or expanded uses 
Improving Public Health Through Human Drugs 

13 

Additional 

statistics 

More review statistics 

are available at http://

www.fda.gov/cder/

rdmt/default.htm. 

Data updates 

You should be aware 

that these data may 

differ from those in 

previous issues of this 

report. We have 

revised data from 

previous years. 

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. 

 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. 

 Median times. Our charts show review and approval times as 

“medians.” The value for the median time is the number that falls in the 

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

truer picture of our performance than average time, which can be 

unduly influenced by a few very long or short times. Our guide to 

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

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

New 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. 

Biologic license 

applications 

BLAs are the formal 

submissions of data 

that sponsors send us 

when they are seeking 

approval to market a 

biologic in the United 

States. A “new BLA” is 

an application for a 

biologic that has never 

been approved for 

marketing in the 

United States. 
CDER 2005 Report to the Nation 

14 

Notable 2005 New Approvals 

Last year’s approvals benefited children, people with HIV infection, 

cancer, diabetes and other disorders. 

Children 

Emtricitabine (Emtriva) is an oral solution of an antiretroviral medicine 

that can be used in combination with other antiretroviral agents for the 

treatment of HIV infection in children 3 months old and older. The drug, 

first approved as a capsule for adults in 2003, is an HIV nucleoside reverse 

transcriptase inhibitor that helps to block an enzyme needed for HIV to 

multiply. Related to Best Pharmaceuticals for Children Act. (priority)

Mecasermin [rDNA origin] (Increlex) and Mecasermin rinfabate [rDNA 

origin] (Iplex) are for the long-term treatment of children who are very 

short for their age because their bodies do not make enough insulin-like 

growth factor-1. Both drugs contain human insulin-like growth factor-1 

from genetically engineered bacteria, but mecasermin rinfabate also 

contains insulin-like growth factor binding protein-3 from genetically 

engineered bacteria. (2 NMEs, priorities, orphans)

Priority new drugs 

and biologics 

 22 approvals 

 20 drugs 

 2 biologics 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 29 filings 

 36 actions 

 9 orphan 

approvals

 8 drugs (6 NMEs) 

 1 new biologic 

Priority NDA & BLA Approvals

Median times, approvals

7.97.97.87.86.26.46.26.46.16.16.06.06.06.013.819.17.77.76.06.06.06.0

29 29

22

11

20 28

10

14

20

16

25

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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 18 32 44 35 46 43 41 27 18 26 26 21 32 27 31 7 19 31 29 42 36

61%

69%

50% 66% 54%

65%

49%

37%

61% 54%

57%

0

25

50

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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 

People with HIV infection

Lopinavir/ritonavir (Kaletra) is a new formulation in a tablet form that may 

be prescribed for once-daily use in combination with other anti-HIV 

medicines for some patients who have not taken anti-HIV medications in 

the past. (priority) 

Tipranavir (Aptivus) is a protease inhibitor taken with 200 mg of ritonavir 

and two other anti-HIV medicines to treat adults with HIV infection. The 

drug blocks HIV protease, an enzyme needed for HIV to make more virus. 

Tipranavir helps reduce the amount of HIV in the blood and keep the 

immune system healthy so it can help fight infection. (NME, priority) 

Lamivudine/zidovudine/nevirapine is the first three-drug HIV regimen in 

one package approved for purchase under the President’s Emergency Plan 

for AIDS Relief (page 51). We gave it “tentative approval” in less than two 

weeks because patent or exclusivity provisions prevent its sale in the 

United States. It can also serve as a reference product for generic versions. 

(priority)

Priority new 

molecular entities 

and new biologics 

 15 approvals 

 13 NMEs 

 2 new BLAs 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 17 filings 

Priority NME & New BLA Approvals

Median times, approvals

7.97.97.79.66.46.76.26.26.36.96.06.06.06.013.816.36.76.76.06.06.06.0

15

18

9

16

19

9 7

7

9

21

10

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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 17

10

5

15 14 14 16 16 16

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

Calendar year

*Includes therapeutic BLAs

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

Number
CDER 2005 Report to the Nation 

16 

Standard drugs 

and biologics 

 58 approvals 

 58 drugs 

 Median review 

time: 11.8 months 

 Median approval 

time: 13.1 months 

 82 filings 

 107 actions 

 1 orphan approval 

People with cancer

Nelarabine (Arranon) is a chemotherapy drug for the treatment of patients 

with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic 

lymphoma whose disease has not responded to or has relapsed following 

treatment with at least two chemotherapy regimens. (NME, priority, 

orphan) 

Sorafenib tosylate (Nexavar) is a chemotherapy agent indicated for the 

treatment of patients with advanced cancer of the kidney cells. (NME, 

priority, orphan) 

People with infections

Entecavir (Baraclude), in tablets and oral solution, treats chronic infection 

with hepatitis B virus in adults who also have active liver damage. 

Entecavir, a nucleoside analogue, competes with a natural substance 

needed for viral replication. The tablet form was counted as an NME. We 

also provided priority approval to a separate application for the oral 

solution. (1 NME, both priorities) 

Notable 2005 new drug approvals (continued)

Standard NDA & BLA Approvals

Median times, approvals

16.218.715.117.814.715.012.012.012.013.812.012.012.014.012.715.311.915.411.912.911.813.1

90

58

67

102 101

65 55

78

56

67

58

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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

92185902259220087153101147871978814379154891397516282107

54% 56%

51%

44% 42%

37% 40% 39%

42% 45%

36%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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 

 5 approvals 

 5 NMEs 

 Median review 

time: 15.8 months 

 Median approval 

time: 23.0 months 

 19 filings 

Micafungin sodium (Mycamine) is used to prevent fungal infections caused 

by Candida in patients who are undergoing a stem-cell transplantation. 

Micafungin inhibits synthesis of a component of the fungal cell wall.

(NME, priority)

Tigecycline (Tygacil) treats adults who have complicated skin or intraabdominal infections caused by certain strains of bacteria. It belongs to the 

glycylcycline class of antibiotics. (NME, priority) 

People with eye disease

Fluocinolone acetonide intravitreal implant (Retisert) treats chronic noninfectious inflammation of the tissue in the rear of the eye. The drug 

product is surgically implanted into the affected eye and slowly releases an 

inflammation-controlling steroid over approximately the next 30 months. 

(orphan) 

Nepafenac (Nevanac) treats the pain and inflammation associated with 

cataract surgery. Nepafenac is a nonsteroidal anti-inflammatory and 

analgesic prodrug. After topical ocular dosing, nepafenac penetrates the 

cornea and is converted by eye tissue to amfenac, a nonsteroidal antiinflammatory drug. (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. 

Standard NME & New BLA Approvals

Median times, approvals

15.917.814.615.114.415.012.313.414.016.315.419.915.719.012.515.913.823.116.024.715.823.0

14 16 12

35

19

30

18 17 10 15 5

0

15

30

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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 19

13 12

25

12

22 28 25 29 34

0

20

40

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

Calendar year

 *Includes therapeutic BLAs

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

Number
CDER 2005 Report to the Nation 

18 

Notable 2005 new drug approvals (continued)

People with arthritis 

Abatacept (Orencia) treats adults with moderate to severe rheumatoid 

arthritis who have not been helped by other medicines. Abatacept may be 

used alone or with other arthritis medicines except those known as TNF 

antagonists. Abatacept modulates parts of the immune system implicated in 

causing rheumatoid arthritis. (biologic, priority) 

People with other rare disorders

Deferasirox (Exjade) is an iron chelating agent for the treatment of chronic 

iron overload due to blood transfusions in patients 2 years of age and older. 

(NME, priority, orphan)

Galsulfase (Naglazyme) is an enzyme replacement therapy for patients with 

mucopolysaccharidosis VI. Also known as MPS VI or Maroteaux-Lamy 

syndrome, the inherited condition results when the body fails to make 

sufficient enzymes to break down certain complex carbohydrates that then 

accumulate and cause widespread cellular, tissue and organ dysfunction. 

The biotechnology product provides an injectable enzyme that helps the 

body break down the appropriate proteins. (biologic, priority, orphan) 

Lenalidomide (Revlimid) treats people with transfusion-dependent anemia 

due to low or intermediate-1 risk myelodysplastic syndromes that are 

associated with a specific genetic abnormality. The syndromes result when 

the bone marrow does not make enough normal blood cells. Patients may 

need blood and platelet transfusions and antibiotic therapy for infections. In 

clinical trials, most patients treated with the drug became independent of 

transfusions by three months, and the transfusion-free period lasted for an 

average of 44 weeks. Because the drug is structurally similar to 

thalidomide, which is known to cause severe birth defects, it is sold under a 

risk management plan designed to prevent fetal exposure. (NME, priority, 

orphan) 

Hospitalized people with dangerously low sodium

Conivaptan hydrochloride (Vaprisol) is an injectable medicine and the first 

indicated to treat hospitalized patients with a potentially life-threatening 

condition that occurs when the body’s blood sodium level falls significantly 

below normal. Known as euvolemic hyponatremia, the condition is the 

most common electrolyte disorder in clinical medicine and one of the most 

difficult to treat. It often results from elevated levels of antidiuretic 

hormone, a hormone that regulates water and salt balance in the body. The 

drug blocks the activity of this hormone, resulting in increased urine output 

without loss of valuable electrolytes such as sodium and potassium. (NME) 

NMEs 

(P=priority, 

S=standard, 

O=orphan) 

 Conivaptan 

hydrochloride (S) 

 Deferasirox (P, O) 

 Entecavir (P) 

 Exenatide (S) 

 Hyaluronidase (P) 

 Hyaluronidase 

human (P) 

 Insulin detemir (S) 

 Lenalidomide (P, 

O) 

 Mecasermin [rDNA 

origin] (P, O) 

 Mecasermin 

rinfabate [rDNA origin] 

(P, O) 

 Micafungin sodium 

(P) 

 Nelarabine (P, O) 

 Nepafenac (P) 

 Pramlintide acetate 

(S) 

 Ramelteon (S) 

 Sorafenib tosylate 

(P, O) 

 Tigecycline (P) 

 Tipranavir (P) 

New BLAs 

 Abatacept (P) 

 Galsulfase (P, O) 

Other NDA 

priority approvals 

(T=tentative)

 Emtricitabine (new 

formulation) 

 Entecavir (new 

formulation) 

 Fluocinolone 

acetonide (new 

formulation, O) 

 Lamivudine; 

zidovudine; nevirapine 

(new combination, T) 

 Lopinavir; ritonavir 

(new formulation) 

 Sildenafil citrate 

(new formulation) 

 Sodium benzoate; 

sodium phenylacetate 

(new formulation, O) 
Improving Public Health Through Human Drugs 

19 

People with pulmonary hypertension 

Sildenafil citrate (Revatio) treats pulmonary arterial hypertension to 

improve exercise ability. This serious condition, which can lead to fatal 

heart failure, is caused by continuous high blood pressure in the artery 

carrying blood from the heart to the lung. (priority) 

People with diabetes

Pramlintide acetate (Symlin) is an injectable medicine for adult patients 

with either type 1 or type 2 diabetes. It slows down the movement of food 

through the stomach. This affects how fast sugar enters the blood after 

eating. It is always used with insulin to help lower blood sugar during the 

three hours after meals. The synthetic drug is similar to a naturally 

occurring human hormone that contributes to blood sugar control after 

eating a meal. (NME) 

Exenatide (Byetta) is used to help improve blood sugar control in patients 

with type 2 diabetes who have not achieved adequate control on metformin, 

a sulfonylurea or a combination of metformin and a sulfonylurea. The drug, 

chemically different from other diabetes treatments, enhances insulin 

secretion, suppresses inappropriately elevated secretion of a hormone that 

raises blood sugar and slows emptying of the stomach. (NME) 

Insulin detemir [recombinant DNA origin] (Levemir) can be injected once 

or twice a day under the skin by patients with type 1 or type 2 diabetes who 

require a long-acting insulin for the control of high levels of blood sugar. 

Because the medicine, made by recombinant DNA technology, differs 

slightly from human insulin, it is released more slowly to target tissues. 

(NME)

People with insomnia

Ramelteon (Rozerem) treats insomnia in adults where the problem is 

trouble falling asleep. The drug is active at the body’s melatonin receptors, 

which are thought to be involved in the maintenance of the circadian 

rhythm underlying the normal sleep-wake cycle. (NME) 

Other priority approval 

Sodium benzoate/sodium phenylacetate (Ammonul) was approved to be 

manufactured by a different company. The drug, first approved in 1987 and 

discontinued by its original manufacturer, helps treat acutely elevated 

levels of ammonia and associated brain swelling in patients with 

deficiencies in enzymes of the urea cycle. (priority, orphan) 

Notable 2005 new drug approvals (continued)

New drug review 

consolidated at 

White Oak campus 

Most of our review 

operations were 

successfully 

consolidated in a new 

facility in White Oak, 

Md. We took 

advantage of the move 

to reorganize the 

Office of New Drugs in 

a way that created 

logical groupings in 

the same divisions, 

created divisions with 

better balanced 

workloads and 

resource allocation 

and completed the 

integration of biologics 

reviewers and 

indications within our 

review divisions. 

Within OND, we 

renamed two offices—

the Office of Oncology 

Drug Products and the 

Office of Antimicrobial 

Products. We created 

a new Office of 

Nonprescription 

Products with two 

divisions (page 27). 

Review of psychiatric 

and neurological 

products was 

separated into two 

divisions. 

More information is at 

http://www.fda.gov/

cder/cderorg/

ond_reorg.htm.

Treatment and 

diagnostic aids

Hyaluronidase 

(Hydase) and 

Hyaluronidase human 

(Hylenex recombinant) 

help increase the 

absorption and 

dispersion of other 

injected drugs and 

improve resorption of 

X-ray contrast agents. 

The first drug is a 

purified enzyme 

derived from cow 

tissue, and the second 

is a purified 

preparation of the 

human enzyme 

hyaluronidase 

produced by 

genetically engineered 

hamster cells. 

(2 NMEs, priorities)
CDER 2005 Report to the Nation 

20 

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. 

People infected with both hepatitis and HIV 

Peginterferon alfa-2a (Pegasys), when used alone or in combination with 

Ribavirin, had its indication expanded to include treatment of adult chronic 

hepatitis C patients co-infected with HIV, who have clinically stable HIV 

disease. (priority, biologic)

Ribavirin (Copegus), when used in combination with peginterferon alfa-2a, 

can now be used to treat chronic hepatitis C in adult patients co-infected 

with HIV. (priority)

Priority new or 

expanded uses 

(efficacy 

supplements)

 36 approvals

 34 drugs 

 2 biologics 

 Median review 

time: 6.0 months 

 Median approval 

time: 6.0 months 

 52 actions 

 4 orphan approvals 

for 3 new or expanded 

uses 

Pediatric new 

or expanded uses 

See page 24 for the 

drugs with new or 

expanded uses in 

children approved 

under priority review 

required by the Best 

Pharmaceuticals for 

Children Act. 

Priority New or Expanded Use Approvals

Median times, approvals

6.06.06.06.04.44.46.06.06.06.06.06.06.06.06.06.06.06.06.06.06.06.0

36

48

21 19

6

18

7 9 13

4 4

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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

52

5 9 7 13 19 23

10

36

69%

78% 100%

47%

78%

57%

80%

60%

53%

64%

75%

0

40

80

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

Calendar year

*Includes BLAs for therapeutic biologics

Actions

0%

50%

100% Percent

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

21 

Standard new or 

expanded uses 

(efficacy 

supplements)

 105 approvals

 92 drugs 

 13 biologics 

 Median review 

time: 10.0 months 

 Median approval 

time: 10.0 months 

 171 actions 

Standard New or Expanded Use Approvals

Median times, approvals

16.717.812.614.811.912.011.912.011.011.310.010.010.711.310.010.010.010.010.010.010.010.0

99 105 110

133

85

116

88

111 111 104 65

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

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

178 161 171

237 203 182 160 165 180 187 182

62% 61% 61%

56%

42%

36% 57% 64%

53%

69%

59%

0

150

300

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*

Calendar year

*Includes BLAs for therapeutic biologics

Actions

0%

50%

100% Percent

Actions Percentage of actions that are approvals

Approval totals 

 141 drugs and 

biologics 

 126 drugs 

 15 biologics 

Notable 2005 new or expanded uses 

People with cancer 

Bortezomib (Velcade) can be used to treat multiple myeloma patients who 

have received as least one prior therapy instead of the two prior therapies 

indicated in the 2003 approval. (priority)

Erlotinib hydrochloride (Tarceva), a non-small-cell lung cancer treatment, 

can be used in combination with gemcitabine for the first-line treatment of 

patients with locally advanced pancreatic cancer that cannot be removed 

surgically or that has spread. (priority)

Temozolomide (Temodar) can be used along with radiotherapy to treat 

patients with newly diagnosed high grade brain tumors and then as 

maintenance treatment. (priority)
CDER 2005 Report to the Nation 

22 

Antimicrobial Resistance 

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

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. 

Notable 2005 new or expanded uses (continued)

Letrozole (Femara) can be used to help treat postmenopausal women with 

hormone-receptor-positive early breast cancer. The drug, an inhibitor of 

estrogen synthesis, was originally approved for treating the late stage of the 

disease. (priority)

People with heart disease 

Candesartan cilexetil (Atacand), a high-blood pressure treatment first 

approved in 1998, received two new indications. It can be used to treat 

heart failure in patients with left ventricular systolic dysfunction to reduce 

cardiovascular death and to reduce hospitalizations for heart failure and to 

treat heart failure to reduce the risk of death from cardiovascular causes and 

to reduce hospitalizations for heart failure. (priority)

Perindopril erbumine (Aceon), a high-blood pressure treatment, can be 

used in patients with stable coronary artery disease to reduce the risk of 

cardiovascular mortality or non-fatal myocardial infarction. (priority)

People with other conditions 

Fluocinolone acetonide (Derma-Smoothe/FS) ear drops can be used to treat 

chronic eczematous external inflammation of the ear. (priority)

Infliximab (Remicade), a treatment for the inflammation of the 

gastrointestinal tract known as Crohn’s disease, has a new indication for the 

treatment of patients who have moderately to severely active ulcerative 

inflammation of the colon and who have had an inadequate response to 

conventional therapy. (priority, biologic)

Ropinirole hydrochloride (Requip), a Parkinson’s disease therapy, can be 

used for restless legs syndrome, which is characterized by an urge to move 

the legs usually accompanied or caused by uncomfortable and unpleasant 

leg sensations. (priority)
Improving Public Health Through Human Drugs 

23 

Pediatric Drug Development 

The Best Pharmaceuticals for Children Act of 2002 (BPCA) 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 2005, we approved 25 pediatric labeling 

changes as a result of studies conducted under the exclusivity provision. 

Pediatric exclusivity. As of April 30, 2006, we had received 467 proposed 

pediatric study requests from manufacturers, issued 320 written requests, 

made 130 exclusivity determinations, granted exclusivity to 118 drugs and 

added new pediatric information to 109 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. The failure to produce drugs in dosage 

forms that can be taken by young children—such as liquids or chewable 

tablets—can deny them access to important medications. As a result of 

pediatric testing we now have 12 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. 

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 have published five lists of offpatent drugs for which additional pediatric studies are needed. To date, we 

have issued 17 written requests—five in 2005—for these off-patent drugs. 

We also have forwarded eight written requests – two in 2005-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. As 

of April 30, 2006, we have posted 60 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. The reviews of the reports are then presented to the Pediatric 

Advisory Committee. As of April 2006, reports for 54 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 

In September 2005, 

we published a draft 

guidance on how to 

comply with the law. 

The 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. 
CDER 2005 Report to the Nation 

24 

Notable 2005 pediatric new or expanded uses 

The Best Pharmaceuticals for Children Act requires us to give priority 

status to pediatric supplements for drug studies submitted in response to a 

written request. An efficacy supplement may change labeling to reflect new 

information about pediatric use, even if there are no new or expanded uses. 

The review of these pediatric supplements resulted in labeling that 

describes new and expanded uses of these medications in children: 

Ertapenem sodium (Invanz), an injectable antibiotic, had its labeling 

expanded to include the treatment of susceptible moderate to severe 

infections in children 3 months of age and older. Clinical pharmacokinetic 

studies proved that ertapenem is not recommended in the treatment of 

meningitis in the pediatric population due to lack of sufficient CSF 

penetration. 

Ethinyl estradiol and norgestimate (Ortho Tri-Cyclen), an oral hormone 

combination, had its labeling revised to indicate that there was no 

significant difference between treatment and placebo in bone mineral 

density in 123 adolescent females with anorexia nervosa in a one-year 

clinical trial. 

Insulin aspart (NovoLog), a rapid-acting injectable human insulin analog, 

labeling was expanded to include treatment of patients 6 to 18 years old 

with type 1 diabetes. 

Levetiracetam (Keppra), available as tablets and oral solution, labeling was 

expanded to include use as adjunctive therapy in the treatment of partial 

onset seizures in pediatric patients 4 years and older with epilepsy. 

Meloxicam (Mobic), a nonsteroidal anti-inflammatory drug available as 

tablets and oral suspension, labeling was expanded to include treatment of 

certain types of juvenile rheumatoid arthritis in patients 2 years of age and 

older. 

2005 new approvals with pediatric indications 

 New molecular entities. Two orphan treatments for children who are 

very short for their age (page 14) and an iron chelating agent indicated 

for patients 2 and older. (page 18).

 Biologics. An enzyme replacement therapy for a rare inherited 

condition that can affect children (page 18).

 New drugs. An oral solution of an antiretroviral medicine (page 14) and 

four over-the-counter drugs (page 27).

Safety issues for 

children’s uses 

We issued Public 

Health Advisories 

(page 41) about 

pediatric safety issues 

including: 

 A boxed warning 

about using the 

eczema therapies 

pimecrolimus and 

tacrolimus only as 

directed and not at all 

in children younger 

than 2 years of age. 

 Suicidal thinking in 

children and 

adolescents treated 

with atomoxetine for 

attention deficit 

hyperactivity disorder. 

We added a black box 

warning about 

suicidality in children 

and adolescents to the 

labeling for 

antidepressants. Full 

information and a list 

of the drugs is at http://

www.fda.gov/cder/

drug/antidepressants/

default.htm. 
Improving Public Health Through Human Drugs 

25 

Internet resources 

Our Web site for up-todate pediatric labeling 

changes for drugs 

studied under the 

pediatric exclusivity 

process is at http://

www.fda.gov/cder/

pediatric/index.htm.

2005 pediatric drug 

statistics 

 10 written requests 

issued 

 25 pediatric 

exclusivity labeling 

changes granted 

 15 exclusivity 

determinations made 

Pediatric Drug Development

12 17 23 20 23 17 15

11 12 19 15 25 25

98

45

69

21 24 19 10

4

2 3

31

0

60

120

1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Pediatric exclusivity determinations Pediatric exclusivity labeling changes

Written requests issued

Notable 2005 pediatric new or expanded uses (cont.)

Mixed salts of a single entity amphetamine (Adderall XR), a once or twice 

daily extended-release central nervous system stimulant, labeling expanded 

to include treatment of attention deficit hyperactivity disorder in patients 13 

to 17 years of age. Previously approved for use in children 6 to 12 years 

old. 

Ondansetron (Zofran), an antiemetic available as tablets and an injectable, 

labeling expanded to include dosing in children down to 6 months of age 

for the prevention of chemotherapy-induced nausea and vomiting, as well 

as dosing in children down to 1 month of age for the prevention of 

postoperative-induced nausea and vomiting. Labeling previously provided 

dosing down to 4 years of age for the prevention of chemotherapy-induced 

nausea and vomiting and dosing down to 2 years of age for the prevention 

of postoperative-induced nausea and vomiting. 

Oxcarbazepine (Trileptal), an anticonvulsant available as tablets and oral 

suspension, labeling expanded to include treatment as adjunctive therapy in 

children aged 2 years and above with epilepsy. Previously approved for 

children 4 years and older. In clinical studies, it was observed that children 

2 to <4 years of age may require up to twice the dose per body weight 

compared to adults. 

Sibutramine (Meridia), a weight loss aid, labeling modified to reflect that 

data from a clinical study in obese adolescents are inadequate to 

recommend the use of sibutramine for the treatment of obesity in pediatric 

patients. In addition, important safety information was added. 

Notable non-BPCA pediatric new or expanded use 

Nitazoxanide (Alinia) can be used to treat diarrhea caused by 

Cryptosporidium parvum in non-HIV infected patients 12 years of age and 

older. 

Priority pediatric 

labeling changes 

[number of approvals]

Our priority review of 

these pediatric 

supplements was 

consistent with the 

BPCA unless noted: 

 Alendronate 

sodium 

 Amphetamines, 

Mixed salts 

 Ertapenem 

 Gemcitabine 

hydrochloride 

 Glimepiride 

 Insulin aspart 

recombinant 

 Levetiracetam [2] 

 Linezolid [3] 

 Meloxicam [3]

 Nefazodone 

 Nitazoxanide [2]

(unrelated to BPCA) 

 Ethinyl estradiol 

and norgestimate 

 Ondansetron 

 Oxcarbazepine [2] 

 Ritonavir [2] 

 Rosiglitazone 

 Sibutramine 

 Sirolimus [2] 
CDER 2005 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 

on drug use 

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 new drug applications for first-time over-the-counter 

sale. There were no prescription-to-OTC switches or new uses approved in 

2005. Our OTC approvals were: 

 Ibuprofen and diphenhydramine hydrochloride (Advil PM Liquigels and 

Caplets) for relief of occasional sleeplessness associated with pain in 

adults. 

 Loratadine (Loratadine Oral Suspension) for the temporary relief of 

these symptoms due to hay fever or other upper respiratory allergies: 

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

adults and children 2 years of age and older. 

 Chlorhexidine gluconate (2% Chlorhexidine Gluconate Cloth) for use 

as a patient preoperative skin preparation in adults and children 2 

months of age and older. 

 Loperamide (Loperamide HCl soft gelatin capsules) to control 

symptoms of diarrhea, including traveler’s diarrhea in adults and 

children 6 years of age and older. 

 Chlorhexidine gluconate and isopropyl alcohol (Chlorascrub Swab, 

Chlorascrub Swabstick and Chlorascrub Maxi Swabstick) for use as a 

patient pre-injection preparation and as a patient preoperative skin 

preparation (Chlorascrub Swabstick and Chlorascrub Maxi Swabstick)

in adults and children 2 months of age and older. 

Office of Nonprescription Products created 

We created an Office of Nonprescription Products in our reorganization of 

the Office of New Drugs. Within the office, the Division of 

Nonprescription Clinical Evaluation focuses mainly on the review of 

investigational new drugs and new drug applications. The Division of 

Nonprescription Regulation Development focuses mainly on the 

development of OTC drug monographs. 

Over-the-counter 

drug statistics 

 5 approvals for 

first-time OTC sale 

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 5

1 1

1

2

13 3

9 9 8

20

8

3

3

1

7

0

12

24

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

New approvals or Rx-to-OTC switches New uses
CDER 2005 Report to the Nation 

28 

Notable 2005 generic drug approvals 

Examples of first-time generic drug approvals are: 

 Azithromycin. An antibiotic used for the treatment of mild to moderate 

infections of various types. 

 Fentanyl transdermal system. Used for managing chronic pain. 

 Fexofenadine. Used to relieve seasonal allergic rhinitis symptoms. 

 Levofloxacin. A broad spectrum antibiotic used for various conditions 

such as pneumonia, bronchitis and sinusitis. 

 Ramipril. Used to treat high blood pressure, heart failure after a heart 

attack and risk reduction for certain cardiac events. 

 Zidovudine. Used in combination with other antiretroviral agents for the 

treatment of HIV infection. 

Our approval of generic versions of these drugs can 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 

over the same time 

period as the brandname 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 Review 

We approved 344 generic drug products in 2005, 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 16.4 

months. 

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

months for six years. We have made several changes to improve the 

efficiency of our generic drug review process in order to try to keep up with 

the dramatic increase in applications. These efforts will continue. 

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 in waiting rooms and 

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_text.htm. 

Scientific basis 

for generic drug 

review 

We continue to 

articulate the scientific 

underpinnings of our 

review process and to 

work on defining 

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-care 

professionals on how 

our approval assures 

that generic drugs are 

safe, effective and 

high quality products. 
Improving Public Health Through Human Drugs 

29 

Generic drugs 

 344 generic drug 

approvals 

 Median approval 

time: 16.4 months 

 108 tentative 

approvals 

 777 receipts 

Generic drug 

Web site 

You can find more 

information about our 

generic drug program 

at http://www.fda.gov/

cder/ogd/.

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 an 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 the approvals in 2005 represent conversions of 

tentative approvals granted in 2004 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

18.6 18.1 18.3 17.0 15.7 16.4

23.0

18.0 18.2

27.0

19.3

344

380 321

244 234

186

225

273 212

207 263

0

18

36

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Months

0

200

400

Number

Median approval times Number of generic approvals

Generic Drug Tentative Approvals 

56 61 73 63

101 95 108

40

15 25

40

0

60

120

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Improving 

manufacturing 

practices 

The strategic initiative 

to develop a 21st 

century drug quality 

system (page 7) also 

applies to generic 

drugs. 

Reducing 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. 
CDER 2005 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. 

Our steps to improve the content and completeness of generic drug 

applications and assure the applications contain the needed information to 

be evaluated successfully in one cycle include: 

 Enhanced communication with 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 electronic-submission applications (page 32).

Generic Drug Applications Received

296 365 320 392 479

635

777

345 283 307 330

0

400

800

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Applications received (workload in future years)

More Generic Competition Lowers Drug Prices

33% 26% 23% 21% 20% 26% 22% 20% 24% 15% 13% 11% 9% 8% 6%

39%

94%

52% 44%

0%

50%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Number of generic manufacturers

(Analysis of 1999-2004 retail sales data from IMS Health)

Avg. relative price per dose

More generic 

competition 

results in lower 

drug prices 

The entry of a second 

generic competitor 

brings about the 

largest price reduction. 

We concluded this 

from our analysis of 

IMS retail sales data 

for single-ingredient 

brand-name and 

generic drug products 

sold from 1999 

through 2004. Our 

study is at http://

www.fda.gov/cder/ogd/

generic_competition. 

htm.

Restructuring to 

meet increased 

demands 

We have constituted a 

third chemistry review 

division for generic 

drugs. 

We also are 

augmenting our 

clinical, microbiology 

and bioequivalence 

review staffs to meet 

the needs for review of 

a growing number of 

generic drug 

applications. 

Public 

presentations 

encourage 

electronic 

submissions 

Through public 

presentations, we are 

encouraging the 

generic drug industry 

to submit their 

applications 

electronically for 

greater efficiency. 
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 (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 at-risk populations, such as 

children and the mentally impaired. 

We require sponsors to disclose financial interests of clinical investigators 

who conduct studies for them. This helps identify potential sources of bias 

in the design, conduct, reporting and analysis of clinical studies. 

Top 5 deficiencies 

found during 

inspections 

of clinical 

investigators 

in 2005 

 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 2005 

We conducted a total 

of 652 inspections in 

2005: 

 284 U.S. clinical 

investigators 

 70 foreign clinical 

investigators 

 122 institutional 

review boards 

 31 sponsors, 

monitors or contract 

research organizations 

 56 good laboratory 

practices 

 89 in-vivo

bioequivalence 

International 

inspections 

of clinical research 

We conducted 70 

inspections of clinical 

research in 25 

countries in 2005. 

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 54) 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

623 635 652 700 728 730

589 574

650

0

400

800

1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

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

Sponsors, monitors, CROs Good laboratory practices In-vivo bioequivalence
CDER 2005 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, also known as CDISC and HL-7 

respectively. 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. 

We continue to receive electronic submissions using the specifications of 

the electronic Common Technical Document (page 54).

Electronic submission of labeling required 

In 2005, we issued final guidance to assist manufacturers in submitting 

prescription drug label information to us in a new electronic format. These 

electronic product labels are the key element and primary source of 

medication information for “DailyMed”—a new interagency online health 

information clearinghouse that will provide the most up-to-date medication 

information free to consumers, health-care providers and health-care 

information providers (page 5).

Using embedded computer tags, the prescribing and product information 

can be electronically managed, allowing a user to search for specific 

information. These tags can instruct computers to read specific sections of a 

drug label including product names, indications, dosage and administration, 

warnings, description of drug product, active and inactive ingredients, and 

how the drug is supplied. 

With this information, physicians will be able to quickly search and access 

specific information they need before prescribing a treatment, resulting in 

fewer prescribing errors and better informed decision making. In addition, 

the electronic labels will improve our drug labeling review process, so that 

we can provide immediate access to the most recent information about 

medications to prescribers and patients. 

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 5).

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 2004 receipt 

cohort. 

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

fiscal year 2005 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 review letter. In fiscal year 2005, we met our 

performance goal for reviewable unit submissions. 

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

scientific feedback and interactions during the clinical trial phase of 

product development. As of 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 2005 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—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. 

 Safety reviewers propose and evaluate risk management plans as well as 

review proposed brand names, packaging and labeling to minimize 

errors when a drug is prescribed, dispensed or administered.

 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 2005: 

 We presented 30 

scientific seminars and 

scientific rounds. 

 We offered a strong 

and innovative 

curriculum of 45 

scientific courses. 

Subjects included 

therapeutic biologics, 

nanotechnology, 

toxicology for the nontoxicologist and orally 

disintegrating tablets. 

 We brought in 49 

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 2005 include: 

 Improving the electronic infrastructure to support real-time availability 

of the most up-to-date drug information for health-care providers and 

consumers (pages 4-5).

 Establishing and operating the Drug Safety Oversight Board (page 5).

 Processing and evaluating more than 460,000 reports of adverse drug 

events, including more than 25,000 submitted directly from individuals. 

 Issuing 60 letters on violations in drug promotion and more than 600 

letters to help ensure manufacturers comply with regulations concerning 

drug promotion. Included in the total were more than 200 letters 

concerning direct-to-consumer advertising. 

 Issuing warning and other regulatory letters to firms selling drugs that 

were unapproved, poorly poor manufactured or labeled incorrectly. We 

also supported successful federal lawsuits against a firm importing 

unapproved drugs and a firm distributing unapproved and poorly 

manufactured prescription and over-the-counter drugs. 

 Evaluating more than 3,100 reports concerning problems that occur in 

the manufacturing, processing, packing, labeling, storing or distributing 

drugs. 

 Issuing 16 Public Health Advisories regarding drug safety issues. 

 Approving Medication Guides for prescription non-steroidal antiinflammatory drugs with any of 18 active ingredients and for five 

additional prescription drugs. 
CDER 2005 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. In addition to rare events occurring in about 1 in 

10,000 persons,these include long-term effects and unstudied uses and 

populations. 

Capacities 

of current 

postmarketing 

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 

postmarketing risks. 

 Identification of 

adverse events that 

occur after marketing 

with a focus on serious 

adverse events. 

Safety System for Medicines 

Our current system for evaluating drug safety provides: 

 Extensive premarket testing with rigorous review, including evaluation 

of remaining uncertainties. Premarket testing cannot, however, detect 

very rare, serious adverse events (see below). 

 Risk management strategies before and after approval. 

 Mandatory and voluntary adverse event reporting systems, before and 

after approval, with additional population-based information. 

 User-friendly communication through an improved drug label 

compatible with e-prescribing and electronic decision support. 

Knowledge gaps 

in postmarketing 

safety system 

 Differences in the 

frequency of events 

between those taking 

and not taking a drug. 

 Detection of events 

after long-term 

exposure. 

 Adverse events in 

populations not 

normally studied in 

trials, such as those 

who are very sick or 

on multiple drugs. 

 Adverse events 

occurring more 

frequently with offlabel use. 

 Detection of many 

types of medical errors 

or abuse. 

 Unreported events. 

Approaches 

to resolving 

knowledge gaps 

 Surveillance with 

emerging automated 

health-care data 

systems. 

 Randomized trials 

or registries in practice 

settings. 

 Surveillance 

systems in specialized 

settings such as 

emergency rooms or 

nursing homes. 

 Large real-world 

studies of drug use. 
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 (page 40). 

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 (page 39) 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 features both paper and electronic 

submission options, international compatibility and pharmacovigilance 

screening. 

Adverse event 

reporting 

In 2005, we received 

464,068 reports of 

suspected drugrelated adverse 

events: 

 25,325 MedWatch 

reports directly from 

individuals. 

 213,537 

manufacturer 15-day 

(expedited) reports. 

 84,770 serious 

manufacturer periodic 

reports. 

 140,436 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

464,068 423,031 370,898 322,691

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

191,865 156,477

0

250,000

500,000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Direct (MedWatch) 15-day Periodic Nonserious periodic
CDER 2005 Report to the Nation 

38 

User fees support risk assessment, minimization 

In recent years, about half of all new medicines marketed 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 most likely to identify 

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

trials. 

Adverse event reporting compliance 

We monitor the pharmaceutical industry’s processing 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 2005, our field investigators inspected 106 domestic and six

foreign firms to assess compliance with our regulations for adverse event 

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

uncorrected deficiencies. We were able to work with about 40 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.
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 health-care professionals and consumers can subscribe to our 

e-mail notification service, which now has 56,000 members. We also have 

160 MedWatch Partner organizations. In 2005, these individuals and 

groups received: 

 109 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. 

In 2005, we approved Medication Guides for prescription pain relievers 

with any of 18 nonsteroidal anti-inflammatory ingredients (right) and these 

five other drugs: 

 Atomoxetine hydrochloride (Strattera). 

 Lenalidomide (Revlimid). 

 Pramlintide acetate (Symlin). 

 Tamoxifen citrate (Soltamox). 

These Medication Guides must be provided to patients with each 

prescription dispensed. 

Data mining 

We concluded 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. The 

resulting software, 

WebVDME, is now in 

full production use by 

safety evaluators and 

epidemiologists. 

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. 

NSAID MedGuide 

active ingredients 

 Celecoxib 

 Diclofenac 

 Diflunisal 

 Etodolac 

 Fenoprofen 

 Flurbiprofen 

 Ibuprofen 

 Indomethacin 

 Ketoprofen 

 Ketorolac 

 Mefanamic acid 

 Meloxicam 

 Nabumetone 

 Naproxen 

 Oxaprozin 

 Piroxicam 

 Sulindac 

 Tolmetin 
CDER 2005 Report to the Nation 

40 

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. 

Population-based 

drug safety 

evaluation 

New contracts will help 

us evaluate the safety 

of newly marketed 

drugs faster and more 

effectively. We 

awarded four contracts 

that give us access to 

databases that include 

more than 20 million 

patients in different 

geographic areas and 

include special 

populations. The 

contracts, which give 

us more flexibility and 

access to a wider 

range of data 

resources than we 

previously had, can be 

used to: 

 Conduct safety 

analyses. 

 Respond in a timely 

manner to urgent 

public safety concerns. 

 Provide a 

mechanism for 

collaborative research 

designed to test 

hypotheses, 

particularly those 

arising from suspected 

adverse reactions 

reported to us. 

 Enable our rapid 

access to U.S. 

population-based data 

sources to ensure 

public safety when 

necessary. 
Improving Public Health Through Human Drugs 

41 

Risk management 

guidances 

published 

We published three 

risk management 

guidances in 2005: 

 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 

fulfill our commitment 

to the risk 

management goals in 

the 2002 reauthorization of the 

Prescription Drug User 

Fee Act. 

Public Health Advisories in 2005 

We issued 16 advisories to alert health-care providers and consumers to: 

 Increased liver toxicity associated with the anti-HIV drug nevirapine.

 Concerns about the risk of sudden death in patients treated with 

Adderall XR, a drug product containing amphetamines, and a Canadian 

regulatory action on the product. 

 Our warning to avoid using the epilepsy drug tiagabine in patients 

without epilepsy because of seizures. 

 The suspended marketing of natalizumab, a treatment for multiple 

sclerosis, which was remarketed in 2006 with a risk management plan. 

 Our advice that the eczema therapies pimecrolimus and tacrolimus only 

be used as directed—that is for short term use and not at all in children 

younger than 2 years of age—and only after other treatments have 

failed to work because of a potential cancer risk. 

 An increased risk for serious muscle toxicity associated with the 

cholesterol lowering drug rosuvastatin, especially at the highest 

approved dose.

 The increased risk of heart attack and stroke associated with the longterm use of non-steroidal anti-inflammatory drugs.

 Increased deaths when atypical antipsychotic drugs are used to treat 

behavioral disorders in elderly patients. 

 Suicidality in adults being treated with antidepressants.

 The suspended marketing of Palladone, an extended-release 

formulation of an opioid pain medication. 

 Our highlighting the importance of the safety information in the 

labeling when using fentanyl transdermal skin patches for pain control 

because of reports of death and other serious side effects. 

 Four cases of fatal infection in women following medical abortion with 

mifepristone. 

 Suicidal thinking in children and adolescents associated with 

atomoxetine, a drug approved to treat attention deficit hyperactivity 

disorder. 

 Possible increased risk of worsening wheezing and death in some 

people treated with several long-lasting bronchodilator medicines. 

 Increased risk for congenital malformations when the antidepressant 

paroxetine is used in the first trimester of pregnancy. 

 The marketing suspension of a diagnostic imaging agent. 

Internet resources 

Links to our Public 

Health Advisories and 

associated information 

are at http://

www.fda.gov/cder/

news/pubpress.htm.
CDER 2005 Report to the Nation 

42 

Top 10 reasons for 

drug recalls in 

fiscal year 2005 

 Miscellaneous 

cGMP deviations 

(other than below) 

 Failed USP 

dissolution test 

requirements 

 Microbial 

contamination of nonsterile products 

 Lack of efficacy 

 Impurities/

degradation products 

 Lack of assurance 

of sterility 

 Lack of product 

stability 

 Labeling: Label 

error on declared 

strength 

 Misbranded: 

Promotional literature 

with unapproved 

therapeutic claims 

 Labeling: Correctly 

labeled product in 

incorrect carton or 

package 

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. 

Spike in 2005 recalls 

One firm had more than 100 recalls in 2005, which caused a spike in the 

recall figures. 

NME safety 

withdrawals 

Drug name

(FY received 

[bold=PDUFA]/ 

CY approved/ 

CY withdrawn) 

approved use/ 

reason withdrawn

 Azaribine

(1970/1975/1976) 

psoriasis treatment/ 

serious blot clots 

 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/ 

acute kidney failure

 Encainide

(1984/1986/1991) 

irregular heartbeat/ 

fatal arrhythmia

 Temafloxacin

(1990/1992/1992) 

antibiotic/kidney failure 

Drug recalls in 

fiscal year 2005 

 401 prescription 

drugs 

 101 over-thecounter drugs 

Drug Recalls

226 248

176 215

401

53 34

88

72 156

88

71

101

254 316 352

248

354

72

83

0

300

600

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

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. 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. Our time periods are based on 

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

Beginning Oct. 1, 2003, approvals include new therapeutic biologics. 

Applications exempt from user fees are also counted. 

Four safety withdrawals of NMEs or new BLAs in 2005 

 Valdecoxib, a COX-2 selective non-steroidal anti-inflammatory pain 

reliever, was withdrawn because it carried an increased risk of serious 

skin reactions in addition to the risk of heart disease associated with 

NSAIDs. 

 Pemoline, a central nervous system stimulant treatment for attention 

deficit hyperactivity disorder, was withdrawn because it caused fatal 

and life-threatening liver failure. 

 Natalizumab, a treatment for multiple sclerosis, was withdrawn because 

three patients developed a serious viral infection of the brain. It was 

reintroduced in 2006 with a special restricted distribution program. 

 Technetium (99m Tc) fanolesomab, a radiological imaging agent for 

unclear signs and symptoms of appendicitis, was withdrawn for fatal 

and life-threatening cardiopulmonary arrest occurring shortly after 

administration. 

One non-NME safety withdrawal in 2005 

 Palladone, a brand of hydromorphone hydrochloride extended-release 

capsules, was withdrawn because serious and potentially fatal adverse 

reactions could occur if the drug was taken with alcohol, which harmed 

the extended-release mechanism and could lead to dose-dumping. 

 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/ 

serious drug-drug 

interactions leading to 

muscle damage and 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

 Alosetron

[Remarketed in 2002 with 

restricted distribution] 

(1999/2000/2000) 

irritable bowel syndrome/

ischemic colitis, severe 

constipation 

NME safety 

withdrawals (cont.)

NME safety 

withdrawals (cont.)

 Cerivastatin

(1996/1997/2001) 

cholesterol reduction/

muscle damage leading 

to kidney failure 

 Rapacuronium

(1998/1999/2001) 

anesthetic/severe 

breathing difficulty 

 Etretinate

(1985/1986/2002) 

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 

 Natalizumab

[Remarketed in 2006 with 

restricted distribution]

(2004/2004/2005) 

multiple sclerosis/ 

brain infection 

 Technetium 

(99m Tc) 

fanolesomab

(2000/2004/2005) 

diagnostic aid/

cardiopulmonary arrest 

 Pemoline

(1969/1975/2005) 

ADHD/liver failure

Safety-Based Withdrawals

NMEs approved Jan. 1, 1971, to May 31, 2006

BLAs approved Oct. 1, 2003, to May 31, 2006

3.1% 3.5%

0%

2%

4%

Pre-PDUFA (488/15) PDUFA (345/12)

Receipt periods (approvals/withdrawals)

Percentage
CDER 2005 Report to the Nation 

44 

Drug Promotion Review 

The information about a drug available to physicians and consumers is 

criticaly important to its safe use. 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. 

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 prescription of a 

treatment that is not the one advertised but a treatment that is more 

appropriate for the patient. But physicians and others are concerned that 

consumers may not always get a balanced view of the benefits and risks of 

a product and may sometimes be given drugs they do not need or are not 

the best choice. 

Public meeting addresses DTC promotion issues 

In November 2005, we took part in a two-day FDA public hearing on 

direct-to-consumer promotion of regulated medical products, including 

prescription drugs for humans. We heard more than 30 presentations 

representing the viewpoints of consumers, patients, caretakers, health 

professionals, managed care organizations, insurers and the regulated 

industry. Topics included: 

 Various ways of presenting risk and benefit information to consumers, 

including what and how it should be presented in consumer friendly 

language. 

 The impact of DTC promotion on the diagnosis and treatment of 

disease. 

 How DTC promotion might impact under-treated and under-diagnosed 

medical conditions. 

 Data from research conducted related to DTC promotion. 

 The use of celebrities in DTC promotion. 

 The use of disease awareness campaigns. 

 The impact of images and graphics on promotions and reminder 

advertisements. 

We are reviewing the comments from the meeting and an additional 1,200 

written comments submitted to us. 

DTC promotion 

research 

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 2006. 

 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. 

DTC promotion 

letters 

In 2005, 203 or 30 

percent of the letters 

we issued concerned 

direct-to-consumer 

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 letters 

addressing promotion 

have been: 

 2005: 203 (30%) 

 2004: 217 (27%) 

 2003: 254 (34%) 

 2002: 188 (27%) 

 2001: 190 (22%) 

 2000: 215 (24%) 

 1999: 247 (19%) 

 1998: 282 (44%) 

 1997: 240 (31%) 
Improving Public Health Through Human Drugs 

45 

Drug promotion 

letters in 2005 

In 2005, we issued 

688 letters concerning 

drug promotion. These 

were: 

 60 letters citing 

violations 

 29 initial 

 31 follow-up 

 628 advisory 

letters 

 158 launch 

campaigns 

 470 others 

Advisory Drug Promotion Letters

417

558 539 399 350 276 178 158

773

515 597

470

186 185 184

465 510 571

0

600

1200

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Launch campaign advisory letters Other advisory letters

Drug Promotion Letters Citing Violations

109

159 154 158

115

80 71

29

20

61 91 79

56

37 34

31

25 23 29

9 17 33

0

125

250

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Initial letters Follow-up 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 60 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 either 

new drugs or new 

indications or dosages 

for approved drugs. In 

2005, we issued 158 

advisory letters to 

companies regarding 

their promotional 

materials for launch 

campaigns. 

Other advisory 

letters 

We issued 348 other 

advisory letters to the 

industry regarding 

proposed promotional 

pieces, both 

professional- and 

consumer-directed. 

We also issued 122 

other types of 

correspondence to the 

pharmaceutical 

industry, such as 

letters of inquiry, 

closure letters or 

acknowledgement 

letters. 
CDER 2005 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 riskbased strategy that 

targets products with 

the greatest potential 

to harm the public 

health. FDA district 

offices conduct followup inspections to 

determine the cause of 

sample failures and to 

assure corrective 

action by the firms. 

Compounded drugs 

We generally defer to state authorities regarding the regulation of 

traditional pharmacy compounding—on-site compounding of reasonable 

quantities of drugs by a pharmacist in response to a practitioner’s 

prescription for an individual patient to accommodate the specialized 

medical needs of that particular patient. 

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 seizure of violative products. 

Criteria for riskbased sampling 

 Microbial/endotoxin 

concerns. 

 Stability concerns. 

 Sterility issues. 

 Dissolution issues. 

 Impurities/

contaminants. 

 Product quality 

history. 

 Counterfeit drugs. 

 History of 

violations. 
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. 

Prioritizing sites for inspection 

Our 2004 white paper, Risk-Based Method for Prioritizing CGMP 

Inspections of Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking 

Model, creates a formal risk ranking of manufacturing plants by using an 

analytical process to: 

 Pose a risk question. 

 Identify potential hazards and risks. 

 Characterize factors that can be used as variables for quantifying risk. 

 Mathematically combine the variables to yield an overall risk score. 

This program continues to be refined and improved by better evaluation of 

the risk factors available to us. For example, we added adverse experience 

reports data to the model in addition to the many data sources already being 

used. This allows us to maximize our limited resources by focusing our 

field force on those sites that most affect product quality and safety. 

Good manufacturing practice enforcement 

We have acted under our regulatory enforcement program to address 

products not manufactured under current good manufacturing practice 

regulations. We provide expert technical support that employs science and 

risk-based principles in applying these regulations. As a result, many 

corrections are achieved voluntarily or through administrative means. Some 

corrections, though, require the involvement of the judiciary system. One 

case of note resulted in a court-ordered injunction against a firm violating 

cGMPs and selling unapproved drugs. The judge in this case stated that he 

was “simply unwilling as a court of equity to place the health, safety and 

welfare of the general public at risk in order to accommodate the economic 

well-being of defendants.” 

Domestic drug 

plant inspections 

In fiscal year 2005, 

FDA field office 

inspections included: 

 188 preapproval 

inspections in 

support of: 

 105 new drug 

applications 

 98 generic drug 

applications 

 1,437 current 

good manufacturing 

practice inspections 

For these, we 

approved 22 field 

recommendations for 

regulatory action, 

including: 

 15 warning letters 

 6 injunctions 

 1 seizure 

 152 medical gas 

inspections 

We reviewed 152 

medical gas 

inspections and 

approved two warning 

letters. 

Foreign drug 

inspections 

There were 213 

foreign current good 

manufacturing practice 

inspections and 234 

foreign preapproval 

inspections in 2005. 

(page 53).

Biologics license 

inspections 

Our experts conduct 

the preapproval 

inspections in support 

of biologics license 

applications and 

supplements to them. 

In fiscal year 2005, 

there were: 

 9 domestic 

inspections 

 3 foreign 

inspections 

In other work to 

ensure the quality of 

biologics, we 

reviewed: 

 4 supplements for 

which we waived the 

inspection 

 35 supplements 

that did not require an 

inspection 

 63 annual reports 

We held 38 meetings 

with industry and 

answered 38 inquiries 

about good 

manufacturing 

practices. 

Correction 

In previous editions of 

this report, the data 

labeled “preapproval 

inspections” were for 

“establishment 

evaluation requests.” 

All requests are 

evaluated, but only 

some trigger an inplant inspection. 
CDER 2005 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. 

Regulation of overthe-counter drugs 

The formulation of 

OTC drugs and the 

information that 

accompanies them or 

is displayed with them 

is critical to their safe 

use. 

Approved drug 

applications and OTC 

drug monographs 

(page 27) define 

acceptable 

formulations and the 

consumer labeling and 

promotional 

statements for drugs 

sold over-the-counter. 

We monitor the 

statements that 

accompany these 

products along with 

their formulations to 

make sure they 

comply with the 

appropriate application 

or final monograph. 

We also monitor the 

formulations, labeling 

and promotional 

materials associated 

with over-the-counter 

drugs marketed 

without an approved 

application or final 

monograph, including 

fraudulent drugs, and 

take enforcement 

actions against these 

products where 

necessary. 

Council for 

Pharmaceutical 

Quality 

FDA formed a 

Council for 

Pharmaceutical 

Quality in 2005 to 

oversee policy 

development and 

implementation, 

including the ongoing 

implementation of 

internal quality 

management systems 

relating to drug 

quality regulations. 

Through our active 

participation in this 

program, we have 

provided the 

Pharmaceutical 

Inspectorate advanced 

training on risk-based 

approaches to 

inspections, modern 

quality systems and 

the legal and scientific 

application of good 

manufacturing practice 

regulations to 

manufacturing 

operations. We 

certified the first class 

of these highly trained 

investigators and are 

preparing for the next 

class. 
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 39), we receive 

reports from 

consumers and healthcare 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 

 325 field alerts 

 2,864 MedWatch 

reports 

Reported Drug Quality Defects

Other, 9%

Contamination/ 

sterility, 3%

Fill problem, 4%

Packaging, 6%

Delivery system, 10%

Product defect, 14%

Labeling, 14%

Adverse drug 

reports, 18%

Formulation/ 

substitution, 22%

Fiscal year 2005

Drug Quality Reports

2,020 2,125 2,469 2,800 2,846 3,064 2,864

296 281

299

413 447 374 325

0

2,000

4,000

1999 2000 2001 2002 2003 2004 2005

Fiscal year

MedWatch drug quality reports Field alerts
CDER 2005 Report to the Nation 

50 

Product Quality Science 

The Pharmaceutical cGMPs for the 21st Century Initiative (page 7) stresses 

the need to apply more scientific and engineering knowledge to regulatory 

decision making and to the evaluation of manufacturing processes. The 

goal is to improve upon the overall efficiency and effectiveness of 

manufacturing processes and to enhance product quality. We have looked 

closely at manufacturing science to develop recommendations for 

improvements. 

One of the areas that we focused on was the Process Analytical 

Technologies Initiative. The capability to use process analytical 

technologies encourages manufacturers to be innovative and to apply stateof-the-art quality assurance methodologies to their manufacturing 

processes. Process analytical technologies incorporate assessment of a 

product’s characteristics in real-time and feed that information back into 

process control systems that maintain the desired state of product quality 

throughout manufacturing. 

2005 progress highlights 

We moved into the implementation phase after the release of our final PAT 

guidance in 2004. We note the following highlights: 

 PAT review and inspections. PAT applications and implementations 

have been approved or passed inspection for brand-name products, 

generics, over-the-counter drugs and active pharmaceutical ingredients. 

 Training. There have been a number of training sessions for PAT, 

including training of the Pharmaceutical Inspectorate. We have 

developed plans for extensive internal training on PAT concepts to 

prepare our reviewers to routinely incorporate PAT evaluation into 

standard reviews. 

 Industry interactions. We continue to facilitate the adoption of PAT. 

Dialogue continues with all segments of the industry. 

 Academics. We note the development of several academic programs 

dedicated to PAT both domestically and in Europe and Asia. 

We continue to evaluate those scientific and engineering tools that support 

a better understanding of product and process and that will help: 

 Reduce production time and delays in product release. 

 Prevent rejections, scrap and reprocessing. 

 Improve operator safety and reduce human error. 

 Use small-scale equipment to eliminate certain scale-up issues and 

dedicated manufacturing facilities. 

 Improve energy and material use and increase capacity. 

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 54).

We have a new 

program to advance 

rapid microbiology test 

methods. 

PAT Web site 

More information on 

process analytical 

technologies can be 

found at http://

www.fda.gov/cder/

OPS/PAT.htm
Improving Public Health Through Human Drugs 

51 

Internet resources 

More information 

about our international 

activities, including 

Spanish language 

materials, is at http://

www.fda.gov/cder/

audiences/iact/

iachome.htm.

3-drug regimen 

gets tentative NDA 

approval 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. 

We also approved a 

generic version of this 

regimen. 

Generic drugs 

eligible for 

purchase under 

president’s plan 

As of May 11, 2006 we 

had fully approved two 

generic drugs and 

tentatively approved 

another 14. A list and 

more information is at 

http://www.fda.gov/oia/

pepfar.htm.

3 

INTERNATIONAL

ACTIVITIES

To meet our responsibilities to our own citizens we must increasingly look, 

think and act globally. We participate in harmonization committees. We are 

involved in bilateral and multilateral efforts to leverage scientific and 

financial resources with other nations to avoid duplication of effort and to 

cooperate in focusing on high-risk areas. 

President’s Emergency Plan for AIDS Relief 

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

special focus on 15 countries hardest hit by the HIV epidemic. It targets 

three specific areas related to HIV/AIDS: 

 Prevention of HIV transmission. 

 Treatment of AIDS and associated conditions. 

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

for orphans and vulnerable children. 

We are encouraging manufacturers to submit applications for fixed-dose 

combination and co-packaged versions of previously approved 

antiretroviral therapies. 

Tentative approval—whether for a new drug application or a generic drug 

application—will be the regulatory mechanism by which low-cost versions 

of innovator drugs sold in the developed world will become eligible for 

purchase under the emergency plan. Our tentative approval (page 29) 

means that a drug meets our standards for safety, efficacy and quality but 

that existing patents or exclusivity prevent them from being sold in the 

United States. 

We have an expedited review process to ensure that the United States could 

provide safe, effective and affordable quality drugs to developing countries. 

We encouraged U.S. and foreign firms who were developing generic drugs 

to treat HIV disease to apply under the president’s plan. To meet the plan’s 

approval timelines, our generic drug reviewers (page 28) implemented 

many process changes, including a rolling review approach. Our average 

review time for these applications has been six months. 

We lack information about most clinical laboratories and manufacturing 

sites associated with the products seeking approval under the emergency 

plan. Therefore, we also are engaged in outreach activities, manufacturer 

assistance, inspections and postmarketing monitoring. 

President’s plan 

focus countries 

 Botswana 

 Cote d’Ivoire 

 Ethiopia 

 Guyana 

 Haiti 

 Kenya 

 Mozambique 

 Namibia 

 Nigeria 

 Rwanda 

 South Africa 

 Tanzania 

 Uganda 

 Vietnam 

 Zambia 
CDER 2005 Report to the Nation 

52 

Information-Sharing Agreements 

Because of enhanced cooperation among regulators around the world, FDA 

has entered into international agreements in which we play a critical 

implementation role. We have a growing list (left) 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. Examples or our agreements include: 

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 Medicines Agency (EMEA) 

This agreement establishes a basis for exchanging confidential information 

with the European agency primarily responsible for approving drugs. It 

permits our review and compliance staff to share important information 

about pending approvals, post-marketing surveillance and enforcement 

actions concerning products and facilities under the European agency’s 

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

understanding and mutual confidence in one another’s systems. 

Mexico and Canada 

FDA is working jointly with our North American neighbors to develop 

information exchange arrangements about drug manufacturing facilities in 

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

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

effort have been vital in moving this relationship in a mutually beneficial 

direction. Exchanges of product recalls, emerging compliance issues and 

site-specific information have already begun. An agreement with Canada 

provides for the exchange of information about pending approvals, postmarketing surveillance and enforcement actions. 

Switzerland 

The working arrangement with Switzerland began several years ago and 

has continued to progress steadily in 2005. 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 as well 

as inspection information. Successful joint inspections have helped foster 

mutual confidence and improve communications. 

International 

regulators forum 

In 2005, we held the 

first of a series of twice 

yearly week-long 

forums with 

international 

regulators. There were 

27 representatives 

from all but one of the 

15 PEPFAR focus 

countries, 19 from 

seven other African 

and Asian countries 

and three from the 

World Health 

Organization. 

We provided 

information about U.S. 

drug regulatory 

processes and shared 

perspectives on 

approaches to 

common regulatory 

and scientific 

challenges. 

Pharmaceutical 

Inspection 

Cooperation 

Scheme 

As part or of our 

initiative to improve 

manufacturing 

practices, FDA applied 

for membership in this 

international 

organization dedicated 

to drug regulatory 

harmonization and 

collaboration in the 

area of good 

manufacturing 

practices. 

CGMP workshop 

in China 

To foster compliance 

with current good 

manufacturing 

practices, we cosponsored an 

educational public 

workshop in 

collaboration with 

Peking University and 

the International 

Society for 

Pharmaceutical 

Engineering. 

International 

agreements 

 Countries

 Australia 

 Canada 

 France 

 Germany 

 Ireland 

 Israel 

 Japan 

 Mexico 

 Singapore 

 Sweden 

 Switzerland 

 South Africa 

 United Kingdom 

 Organizations 

 EMEA 

 WHO 
Improving Public Health Through Human Drugs 

53 

Assuring International Trade Quality 

While the globalization of pharmaceutical commerce brings the benefits of 

modern drugs to citizens worldwide, it poses many challenges to us and 

regulators in foreign countries. We share with them a common interest in 

ensuring our citizens have access to safe, effective and high quality 

products and are protected from counterfeit drugs and terrorist threats. 

Drug exports 

Export certificates attest that U.S. drug products are subject to inspection 

by FDA and are manufactured in compliance with current good 

manufacturing practices. These certificates enable American manufacturers 

to export their products to foreign customers and foreign governments. The 

demand for certificates remains high due to expanding world trade, 

ongoing international harmonization initiatives and international 

development agreements. 

Drug imports 

Agency resources are particularly focused on counterfeit drugs and 

counterterrorist activities. We work to: 

 Enforce the law. With FDA’s field force, we enforce legal requirements 

determining which drug products may be imported by manufacturers, 

distributors and consumers. 

 Identify and interdict illegal drugs. We take steps to ensure that 

imported drugs are not counterfeit, unapproved, adulterated or 

misbranded and that they meet applicable legal requirements relating to 

safety and effectiveness. 

 Improve technology. Along with the pharmaceutical and advanced 

technology industries, the states and other federal agencies, we are 

monitoring the development and implementation of “track and trace” 

technology that will enhance anti-counterfeiting measures by providing 

real-time monitoring of a drug product through the U.S. drug 

distribution system. 

Export certificates 

 5,207 

Export Certificates Issued

4,762 5,509

4,491 5,207 4,544 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 2005

Fiscal year

Export certificates 

We issue export 

certificates that verify 

the 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. 

Foreign 

inspections 

 234 preapproval 

inspections in 

support of: 

 143 new drug 

applications 

 120 generic drug 

applications 

 213 current good 

manufacturing 

practice inspections 

For most foreign 

inspections, both a 

CGMP and a 

preapproval inspection 

take place and are 

counted twice, once 

under each inspection 

program. 

Our review of 263 

inspection requests for 

foreign establishments, resulted in 

three warning letters, 

two import alerts and 

several regulatory 

meetings. 
CDER 2005 Report to the Nation 

54 

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 12, 2006, 

we had: 

 55 final guidances 

 16 efficacy 

 3 joint safety/

efficacy 

 21 quality 

 15 safety 

 5 draft guidances 

 3 efficacy 

 2 joint safety/

efficacy 

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. 

Internet resource 

More information is on the ICH Web site at http://www.ich.org.

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. 
Improving Public Health Through Human Drugs 

55 

4 

COMMUNICATIONS

In 2005, we met 27 times with outside expert advisors in public discussions 

of difficult scientific and public health issues. We received more than 17 

million visits and nearly 417 million hits on our Internet information site, 

which has nearly 115,000 files and about 700,000 hyperlinks. Our Web site 

accounts for 28 percent of total FDA Web site use. Drugs@FDA (page 14)

is the most used content site 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 participated in scientific workshops to both 

present information and gather a wide variety of viewpoints on major 

scientific and regulatory issues, including: 

 Our risk management communications strategies (page 5).

 The use of pharmacogenomics in drug development (page 6).

 Developing a scientifically sound, risk-based system to assess drug 

quality (page 7).

 Direct-to-consumer promotion (page 44).

Consumer, industry outreach 

 Trade press. We responded to more than 3,200 telephone and e-mail 

requests from the specialized press for the pharmaceutical industry. 

 Exhibits. We exhibited at 25 conferences, reaching an estimated 

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

professionals. 

 Videoconferencing. We held more than 260 domestic and foreign 

videoconferences for academia, industry and associations. 

 General information requests. We answered nearly 34,000 telephone 

inquiries, more than 46,000 e-mails and about 1,000 letters from 

consumers, health professionals and industry. We respond to phone 

calls and e-mails within 48 hours and letters within 30 days. 

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 healthcare professionals 

 Federal, state and 

local government 

agencies 

 Foreign 

governments 

Small business 

assistance 

workshop 

Along with FDA’s field 

operations, we cosponsored a workshop 

in Kansas City, Mo., 

for 125 representatives from the small 

pharmaceutical 

business community. 

The meeting gave 

small businesses the 

opportunity to consult 

with our subject matter 

experts and those 

from FDA’s Office of 

Regulatory Affairs. 

The workshop 

provided an 

introduction to the 

regulatory 

requirements for 

approval and 

marketing of drug 

products. 
CDER 2005 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 200 million 

Americans last year, 

include information on: 

 Antibiotic 

resistance 

 Benefits vs. risks of 

medication use 

 Buying drugs from 

outside the United 

States 

 Buying prescription 

drugs online 

 Using medicines 

safely in children 

 Counterfeit drugs 

 Generic drug 

quality 

 Medicines and the 

elderly 

 Misuse of 

prescription pain 

relievers 

 Over-the-counter 

medicine labels 

 Sedating medicines 

and driving 

These are available on 

the Internet at http://

www.fda.gov/cder/

drug/DrugSafety/

drugSafetyConsumer.

htm. 

Average Monthly Use of CDER Internet Site

1.0 1.4 1.4 0.2 0.03 0.2 0.4 0.5 0.8

35

0.5 3

7

3

9

14

17

24

0.0

1.0

2.0

1997 1998 1999 2000 2001 2002 2003 2004 2005

Calendar year

Visitors (millions)

0

20

40

Hits (millions)

Visitors (millions) Hits (millions)

 CDER Live! We produced one satellite television broadcast and Web 

transmission for a largely pharmaceutical audience estimated at about 

5,000 viewers. The program discussed our initiatives to address drug 

safety issues and to improve the timeliness and availability of drug 

safety information. 

 Leveraging. We work with foundations and health-care organizations to 

help disseminate consumer information on using medicines safely and 

effectively. Public service announcements appeared 180 times in 

magazines, 188 times in newspapers and 63,000 times on 233 radio 

stations. 

Transparency of policies, decisions 

 Regulations. We issued a final rule that will remove albuterol metereddose inhalers containing chloroflourocarbons or other ozone-depleting 

substances from the market by Dec. 31, 2008. This is consistent with 

certain treaty obligations and Clean Air Act requirements. We 

published a proposed rule on current good manufacturing practice 

regulations for positron emission tomography drugs. We want to ensure 

that these drugs meet the requirements for safety, identity, strength, 

quality and purity. In addition, we continued work on a number of other 

regulatory initiatives, including reviewing and considering comments 

on more than 10 previously published proposed rules. 

 Guidances. We published 14 guidances for industry that explain our 

position on best practices in scientific and technical areas. We 

published another 29 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 17 documents last year. 

 Freedom of Information requests. We responded to 4,876 requests 

under the Freedom of Information Act. 
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 41 of 

these requests in 

2005, a large majority 

of which were 

combinations of drugs 

and devices. 

Ombudsman's 

2005 hot topics 

Two hot topics with 

consumers were the 

same as in 2004: 

 Enforcement 

against importing 

prescription medicines 

from Canada. 

 Our non-approval 

letter for over-thecounter sales of 

emergency 

contraception. 

Consumers have 

definitely made the 

Internet their primary 

method of 

communication with 

us. We received many 

times more e-mails 

than telephone 

contacts. Many 

consumers requested 

assistance in reporting 

drug adverse events. 

Others commented on: 

 The high cost of 

medicines. 

 Inconsistency in 

color and shape 

among generic brands 

of prescription drugs. 

 The necessity to 

increase the size of 

OTC labeling. 

 High profile market 

withdrawals (page 43). 

 Abuse of 

oxycodone. 

 Politicizing of FDA. 

Ombudsman’s Activities 

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

small businesses to, among other things: 

 Comment on our programs and actions. 

 Obtain formal and informal dispute resolution. 

 Seek general information on product development and regulation. 

 Report adverse drug experiences. 

Industry, drug and device consultants contacted the office more often than 

consumers. About one-third of industry contacts related to jurisdictional 

and drug development assistance. Several people contacted the office to 

report irregularities and possible fraud in conducting and reporting clinical 

trials, in manufacture’s promotional activities and violations in 

pharmaceutical manufacturing. 

Several hundred people contacted the office to express their opinions 

urging us to approve some drug therapies and to disapprove or rescind the 

approval of other drug therapies. Fewer consumers commented in 2005 

than in 2004 on direct-to-consumer prescription drug advertising and on 

advisory committee members. 

Examples of cases and allegations our ombudsman handled in 2005 

included: 

 Unethical conduct of clinical research including institutional review 

board issues. 

 Whistle blowers’ informing about pharmaceutical companies in 

violation of FDA regulations. 

 Delay in review or drug development. 

 Unfair handling of an issue. 

 Backlog in processing Freedom of Information requests. 

 Management and employee disagreements. 

 Citizen petition delays and advice. 

 Incorrect advice provided to industry by our staff. 

 Import and export issues. 

Internet, e-mail 

 More information and a full report on 2005 activities is at http://

www.fda.gov/cder/ombud/default.htm.

 You can e-mail our ombudsman at Warren.Rumble@fda.hhs.gov.
CDER 2005 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@fda.hhs.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. Immediate notification of new safety information on human 

health-care products. 

 Drug shortages. New, medically necessary drug shortages. 

 Consumer news. New education materials. 

 Small business. Information for small pharmaceutical companies. 
Organizational Structure of the Center for Drug Evaluation and Research 

Office of the Center Director 

 Director 

 Deputy Director 

 Associate Director for Medical Informatics 

 Associate Director for Safety Policy & Communication 

 Associate Director for Policy 

Office of Executive Programs 

 Ombudsman 

 Advisors & Consultants Staff 

 Executive Operations Staff 

 International Programs 

 Quality Assurance Staff 

Office of New Drugs 

 Guidance Policy Team 

 Study Endpoints & Labeling 

Development Team 

 Regulatory Affairs Team 

 Pediatric & Maternal Health Team 

 Pharmacology/Toxicology Staff 

 Program Management Team 

Office of Translational Sciences 

Office of Pharmaceutical Science 

 Operations Staff 

 Program Activities Review Staff 

 Standards & Technology Staff 

 Science & Research Staff 

 Informatics & Computational Safety 

Analysis Staff 

 New Drug Microbiology Team 

Office of Surveillance 

& Epidemiology 

 Div. of Drug Risk Evaluation 

 Div. of Surveillance, Research 

& Comm. Support 

 Div. of Medication Errors 

& Tech. Support 

Office of Business Process 

Support 

 Project Development Staff 

 Business Analysis 

& Reporting Staff 

 Regulatory Review Support 

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 Public Affairs 

 Div. of Training & Development 

 Div. of Information Services 

 Div. of Drug Information 

Office of Compliance 

 Div. of New Drugs 

& Labeling Compliance 

 Div. of Manufacturing 

& Product Quality 

 Div. of Scientific Investigations 

 Div. of Compliance Risk Mgmt. 

& Surveillance 

1-888-INFO FDA 

7/28/2006 

American Consumers 

Office of Information 

Technology 

 Technology Support Services 

Staff 

 Quality Assurance Staff 

 Div. of Applications 

Development Services 

Office of Medical Policy 

 Div. of Drug Marketing, 

Advertising & Communication 

Office of Counter-Terrorism 

& Emergency Coordination 

Safety Policy and Communication Staff 

 MedWatch 

 Drug Safety Oversight Board 

Controlled Substance Staff 

Office of Generic Drugs 

 Div. of Labeling & Program Support 

 Div. of Bioequivalence 

 Div. of Chemistry I 

 Div. of Chemistry II 

 Div. of Chemistry III 

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 Quality 

Assessment 

 Div. of Pre-Marketing Assessment I 

 Div. of Pre-Marketing Assessment II 

 Div. of Pre-Marketing Assessment III 

 Div. of Post-Marketing Evaluation 

Office of Biotechnology 

Products 

 Div. of Therapeutic Proteins 

 Div. of Monoclonal Antibodies 

Office of Biostatistics 

 Quantitative Methods 

& Research Staff 

 Biologic Therapeutics Statistical 

Staff 

 Div. of Biometrics I 

 Div. of Biometrics II 

 Div. of Biometrics III 

Office of Clinical 

Pharmacology 

 Deputy Director for Science 

 Associate Director 

for Pharmacogenomics 

 Associate Director 

for Operations 

 Pharmacometrics Staff 

 Div. of Clinical Pharmacology 1 

 Div. of Clinical Pharmacology 2 

 Div. of Clinical Pharmacology 3 

 Div. of Clinical Pharmacology 4 

 Div. of Clinical Pharmacology 5 

Office of Nonprescription 

Products 

 Div. of Nonprescription Regulation 

Development 

 Div. of Nonprescription Clinical 

Evaluation 

Office of Drug Evaluation II 

 Div. of Anesthesia, Analgesia 

& Rheumatology Products 

 Div. of Metabolism 

& Endocrinology Products 

 Div. of Pulmonary 

& Allergy Products 

Office of Drug Evaluation III 

 Div. of Gastroenterology Products 

 Div. of Dermatology 

& Dental Products 

 Div. of Reproductive 

& Urologic Products 

Office of Antimicrobial 

Products 

 Drug Shortages Program 

 Antimicrobial Resistance Initiative 

 Div. of Anti-Infective 

& Ophthalmologic Products 

 Div. of Anti-Viral Products 

 Div. of Special Pathogens 

& Transplant Products 

Office of Oncology 

Drug Products 

 Div. of Drug Oncology Products 

 Div. of Medical Imaging & 

Hematology Products 

 Div. of Biological Oncology 

Products 

Office of Drug Evaluation I 

 Botanical Review Team 

 Div. of Cardiovascular & Renal 

Products 

 Div. of Neurology Products 

 Div. of Psychiatry Products 

U.S. Department of Health and Human Services 

Food and Drug Administration 
U.S. Department of Health and Human Services

Food and Drug Administration 

Center for Drug Evaluation and Research