Improving Public Health Through Human Drugs

37

Center for Drug Evaluation and Research

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research

CDER 1999 Report to the Nation

Improving Public Health Through Human Drugs
38

CDER 1999 Report to the Nation

MISSION

The Center for Drug Evaluation and Research promotes and protects public

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

The Food and Drug Administration Modernization Act of 1997 affirmed

the center’s public health protection role, clarified the FDA’s mission and

called for the FDA to:

Promote the public health by promptly and efficiently reviewing

clinical research and taking appropriate action on the marketing of

human drugs in a timely manner.

Protect the public health by ensuring that human drugs are safe and

effective.

Participate through appropriate processes with representatives of

other countries to reduce the burden of regulation, harmonize

regulatory requirements and achieve appropriate reciprocal

arrangements.

Carry out its mission in consultation with experts in science,

medicine and public health and in cooperation with consumers,

users, manufacturers, importers, packers, distributors and retailers

of human drugs.

1

2

3

4
Improving Public Health Through Human Drugs

39

CONTENTS

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

1999 HIGHLIGHTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Scientific Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1 DRUG REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

New Drug Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

New or Expanded Use Review . . . . . . . . . . . . . . . . . . . . . 10

Over-the-Counter Drug Review . . . . . . . . . . . . . . . . . . . . 12

Generic Drug Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Manufacturing Supplement Review . . . . . . . . . . . . . . . . . 15

User Fee Review Performance . . . . . . . . . . . . . . . . . . . . . 17

2 DRUG SAFETY AND QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Drug Promotion Review . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Export Certificates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Drug Recalls and Withdrawals . . . . . . . . . . . . . . . . . . . . . 26

Drug Product Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

3 INTERNATIONAL ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

4 COMMUNICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Organization Chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Where to Find More Information . . . . . . . . . . . . . . . . . . . . . . . . 36

i
40

CDER 1999 Report to the Nation

GRAPHS AND CHARTS

Original NDA Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

New Drug Application Approvals . . . . . . . . . . . . . . . . . . . . . . . . 7

New Molecular Entity Approvals . . . . . . . . . . . . . . . . . . . . . . . . . 8

Efficacy Supplement Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Efficacy Supplement Approvals . . . . . . . . . . . . . . . . . . . . . . . . . 10

OTC Drug Approvals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Generic Drug Approvals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Generic Electronic Submissions . . . . . . . . . . . . . . . . . . . . . . . . . 14

NDA Manufacturing Supplement Actions . . . . . . . . . . . . . . . . . 15

NDA Manufacturing Supplement Approvals . . . . . . . . . . . . . . . 15

Generic Drug Manufacturing Supplements . . . . . . . . . . . . . . . . 16

User Fee Goal Review Performance

Original NDAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Resubmissions of Original NDAs . . . . . . . . . . . . . . . . . . . 17

Efficacy Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Manufacturing Supplements . . . . . . . . . . . . . . . . . . . . . . . 18

Refuse-to-File Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Clinical Holds of Commercial INDs . . . . . . . . . . . . . . . . . . . . . 19

Sources of Risk from Drug Products . . . . . . . . . . . . . . . . . . . . . 21

Post-Marketing Adverse Event Reports . . . . . . . . . . . . . . . . . . . 23

Drug Promotion Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Export Certificates Issued . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Drug Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Safety-Based NME Withdrawals . . . . . . . . . . . . . . . . . . . . . . . . 27

Harmonization Topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Average Monthly Use of CDER Internet Site . . . . . . . . . . . . . . . 33

ii
Improving Public Health Through Human Drugs

1

INTRODUCTION

Who we are

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

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

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

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

Services. We are the largest of FDA’s five centers, with nearly 1,700

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

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

computer science, legal affairs and regulatory matters.

What we do

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

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

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

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

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

market, we monitor them for problems.

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

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

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

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

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

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

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

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

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

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

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

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

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

versions of over-the-counter and prescription drugs.

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

States, our consumer protection mission doesn’t stop. We monitor the use of

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

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

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

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

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

from manufacturers, health care professionals and consumers. Sometimes,

manufacturers run into production problems that might endanger the health

What is a drug?

We regulate drugs used

to treat, prevent or

diagnose illnesses.

However, drugs include

more than just

medicines.

For example, fluoride

toothpaste,

antiperspirants,

dandruff shampoos and

sunscreens are all

considered “drugs.”

You can buy some drugs

in a store without a

prescription, while

others require a doctor’s

prescription.

Some are available in

less-expensive generic

versions.

Prescription drugs

Prescription medicines

must be administered

under a doctor’s

supervision or require a

doctor’s authorization

for purchase. There are

several reasons for

requiring a medicine be

sold by prescription:

 The disease or

condition may be serious

and require a doctor’s

management.

 The medicine itself

may cause side effects

that a doctor needs to

monitor.

 The same symptoms

can be caused by

different diseases that

only a doctor can

diagnose.

 The different causes

may require different

medicines.

 Some medicines can

be dangerous when used

to treat the wrong

disease.
2

CDER 1999 Report to the Nation

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

supply of drugs is always available.

Monitoring drug information and advertising. Accurate and complete

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

historically promoted their products directly to physicians. More and more

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

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

we oversee the advertising of prescription drugs. Advertisements for a drug

must contain a truthful summary of information about its effectiveness,

side effects and circumstances when its use should be avoided. We are

monitoring the industry’s voluntary program to provide consumers useful

information about prescription drugs when they pick up their prescriptions.

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

quantity and quality of information.

Protecting drug quality. In addition to setting standards for safety and

effectiveness testing, we also set standards for drug quality and

manufacturing processes. We work closely with manufacturers to see

where streamlining can cut red tape without compromising drug quality.

As the pharmaceutical industry has become increasingly global, we are

involved in international negotiations with other nations to harmonize

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

harmonization will go a long way toward reducing the number of

redundant tests manufacturers do and help ensure drug quality for

consumers at home and abroad.

Conducting applied research. We conduct and collaborate on focused

laboratory research and testing. Research maintains and strengthens the

scientific base of our regulatory policy-making and decision-making. We

focus on drug quality, safety and performance; improved technologies;

new approaches to drug development and review; and regulatory standards

and consistency.

Why we do it

Our present and future mission remains constant: to ensure that drug

products available to the public are safe and effective. Our yardstick for

success will always be protecting and promoting the health of Americans.

Getting consumer input. Protecting consumers means listening to them. We

routinely consult the American public when making 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

many of our proposals in advance. This gives members of the public,

academic experts, industry, trade associations, consumer groups and

professional societies the opportunity to comment and make suggestions

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

FDA-sponsored public meetings with consumer and patient groups,

professional societies and pharmaceutical trade associations. These

stakeholder meetings help us obtain enhanced public input into our

planning and priority-setting practices.

Over-the-counter

drugs

You can buy OTC drugs

without a doctor’s

prescription.

You can successfully

diagnose many common

aliments and treat them

yourself with readily

available OTC products.

These range from acne

products to cold

medications.

As with prescription

drugs, we closely

regulate OTC drugs

to ensure that they are

safe, effective and

properly labeled.

Generic drugs

A generic drug is a

chemical copy of a brand

name drug.

There are generic

versions of both

prescription and overthe-counter drugs.

Generic drugs approved

by the FDA have the

same therapeutic effects

as their brand name

counterparts.

Brand name firms, as

well as generic firms,

make generic drugs.

The biggest difference

between a generic drug

and its brand name

counterpart is usually

price. A generic drug

may be priced anywhere

between 20 percent and

75 percent of the cost of

the brand name version.
Improving Public Health Through Human Drugs

3

1999 HIGHLIGHTS

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

year offered many Americans new or improved choices for protecting and

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

We began the process of engaging our stakeholders in an national effort to

improve the nation’s multicomponent, complex system for managing the

risks and benefits associated with using medicines.

Drug Review

Children, older Americans at risk for stroke, people with rare disorders,

Parkinson’s disease, cancer and AIDS all benefited from significant new

drugs approved in 1999. We met our obligations to the pharmaceutical

industry for prompt and thorough review of drug applications supported by

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

despite the growing complexity of drugs coming off patent. We approved

83 new drugs, including 35 new molecular entities. New molecular entities

contain an active substance never before approved for marketing in any

form in the United Sates. We also approved 97 new or expanded uses of

already approved drugs, four over-the-counter drugs and 186 generic

drugs.

Drug safety and quality

All medicines have risks. Injuries from approved medicines may rank

among the top 10 causes of death in the United States. With modern, stateof-the-art tools and techniques, we are able to detect rare and unexpected

risks more rapidly and take corrective action more quickly. With our

colleagues in the FDA’s other medical product centers, we conducted a

study of the system that has evolved in this country to maximize the

benefits of the use of medicines and minimize their risks. We trained our

own staff on modern methods of risk management and began the process

of using our influence to begin a dialogue with other components of the

system.

International activities

We worked closely with our colleagues in Japan and the European Union

on finding ways to make the drug development process more efficient and

uniform. Our goal is to shorten drug development times, while learning the

most, to make new medicines available with minimum delay. We neared

completion of a common technical document that can be used to submit a

marketing application in all three regions. We began the first year of a

three-year implementation process for the Mutual Recognition Agreement

with the European Union. This agreement will allow reciprocal reliance on

inspections of pharmaceutical manufacturing plants.

Communications

We continued our efforts

begun in 1998 to include

greater input into our

planning and decision

making from consumers,

patients, health-care

professionals, academia

and industry.

We revamped our

Internet site to make it

more interactive and

intuitive to use. We

include cross-linked

information on all new

medicines approved since

January 1998. This

includes plain language

information for

consumers and technical

information for health

professions.

We executed the first

phase of an information

campaign to introduce

the public to the new

over-the-counter drug

labels.

We remain a trusted and

reliable source of

information on drugs.

We had thousands of

contacts with members of

the public, health

professional, sate and

local public health

officials and the industry.

Y2K drug shortage

assurance

We surveyed the

pharmaceutical industry

on their preparedness for

the Y2K transition and

launched a successful

information campaign to

allay public fears of drug

shortages.

Antibiotic resistance

We play an active role on

FDA’s antibiotic

resistance coordinating

committee to address the

growing problem of

antibiotic resistance and

its effects on drug

development and

regulation. We are

developing approaches to

provide education and

information on the

appropriate use of

antibiotics to health care

professionals and

consumers.
4

CDER 1999 Report to the Nation

Scientific Research

We focus on advancing the scientific basis of regulatory policy by

developing new scientific methods and regulatory testing paradigms and

by providing scientific support for the development of regulatory policy.

We have focused specifically on creating tighter linkage between

nonclinical and clinical studies, enhancing the methodology for assuring

product quality, building databases for improved drug development and

review and providing regulatory support through laboratory testing.

We continue to seek ways to leverage our scientific resources. We

collaborated with a scientific professional society and pharmaceutical trade

associations to create the Product Quality Research Institute as a nonprofit

corporation. The institute will bring our scientists together with those from

academia and industry to identify better test methods for assessing the

quality of drugs and to improve manufacturing and management processes.

Other key scientific achievements include:

 Streamlining the productivity of laboratory programs that are used as

an important analytical part of the new and generic drug review

process.

 Refocusing our metabolism research program to examine liver toxicity

issues.

 Developing behavioral assessments and noninvasive imaging

techniques to detect and predict drug induced toxicity to the nervous

system.

 Investigating practical biomarkers to detect and predict drug-induced

damage to blood vessels.

 Developing improved animal models and skin biomarkers for drugenhanced tendency to develop skin cancer.

 Strengthened support for alternative transgenic mouse models that take

less time to test the cancer-causing potential of drugs.

 Enhancing our computational toxicology software to improve drug

safety and provide better support to the drug development and review

process.

Scientific excellence

We received the 2000

FDA Scientific

Achievement Award for

developing and

implementing a

guidance on that

established a

mechanistic basis for

correlating in vitro drug

product dissolution and

in vivo bioavailability.

The award recognizes

the importance of

collaboration between

research and review

staff to establish policy.

Alternative methods

for toxicology

testing

Last year, we assumed

leadership of FDA’s

participation on the

Interagency

Coordinating Committee

on the Validation of

Alternative Methods.

The committee, with

representatives from 14

federal regulatory and

research agencies, works

on the validation,

acceptance and

harmonization of

toxicological test

methods. This process

serves our needs for

responding to

alternative testing

initiatives and provides a

mechanism to interact

with developers of such

tests.
Improving Public Health Through Human Drugs

5

1

DRUG REVIEW

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

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

equivalents. We met or exceeded nearly all goals for reviews supported by

manufacturer user fees. We approved 35 new medicines that have never

been marketed before in this country, 186 generic versions of existing

drugs and authorized four medicines to be sold over the counter without a

prescription. Highlights of new medication options for American

consumers include:

 Three treatments for rare cancers.

 Three drugs for breathing disorders in infants.

 A new protease inhibitor to be used in combination therapy for HIV

infection.

 The second Cox-2 inhibitor to treat arthritis.

 A new treatment for atrial fibrillation, a type of irregular heartbeat.

 Two drugs for type II diabetes that help the body make better use of

insulin.

 A therapy to reduce the risk of stroke in people who have had a stroke

or transient ischemic attack.

 The first in a new class of drugs that enhance standard therapy for

Parkinson’s disease.

 The first in a new class of medicines to prevent organ rejection after

transplant.

 Twelve new drugs for orphan uses in patient populations of 200,000 or

fewer.

 Four new orphan uses for already approved drugs.

Mission

We promote

the public health

by promptly and

efficiently reviewing

clinical research

and taking

appropriate action

on the marketing

of human drugs

in a timely manner.

1999 drug review

accomplishments:

83 new drugs

35 new

molecular entities

97 new uses

for already approved

drugs

4 over-the-counter drugs

4 new uses for an overthe-counter drug

186 generic equivalents

for prescription

and over-the counter

drugs

43 first-ever generic

approvals

16 orphan uses
6

CDER 1999 Report to the Nation

New Drug Review

We took 190 actions on original new drug applications, of which 83 were

approvals. The proportion of total actions that are approvals has risen

steadily from under one-third in 1993 to approximately half in recent

years. The lower number of actions represents a decline in the number of

applications submitted to us. The higher percentage of approvals in recent

years stems from our increased predictability and accountability and

improved performance on the part of manufacturers.

Total original NDA approvals

The median total approval time for new drugs acted on in 1999 was 12.0

months, the same as in 1998. Approval time represents the total review

time at the Agency plus industry response time to the Agency’s requests

for additional information. The median FDA review time—FDA time

only—was slightly shorter at 11.8 months. Twelve of the NDAs were

approved for “orphan” uses in patient populations of 200,000 or fewer. In

1998, nine NDAs were approved for orphan uses.

Priority reviews

Last year’s new drug approvals included 28 priority drugs. We perform a

six-month review on priority drugs because these drugs represent an

advance in medical treatment. The median total approval time for these

priority applications was 6.1 months, and the median FDA review time

was also 6.1 months.

New drug statistics:

 83 new drugs

 35 new molecular

entities

 28 priority approvals

 Median total

approval time:

12.0 months

 Median FDA review

time:

11.8 months

Priority new drug

approvals:

Alitretinoin

Amprenavir

(2 dosage forms)

Aspirin/extended releasedipyridamole

Bexarotene

Busulfan

Caffeine citrate

Cytarabine liposome

Dalfopristin/quinupristin

Epirubicin hydrochloride

Ganirelix acetate

Ketotifen fumarate

Levonorgestrel

Nedocromil sodium

Nitric oxide

Orlistat

Oseltamivir phosphate

Pemirolast potassium

Pioglitazone

hydrochloride

Rofecoxib (2 dosage

forms)

Rosiglitazone maleate

Sirolimus

Sodium ferric gluconate

Somatropin (rDNA

origin)

Technetium Tc 99m

depreotide kit

Temozolomide

Zanamivir

New molecular entity approvals

Thirty-five of the original new drugs we approved in 1999 were new

molecular entities, and 19 of these received priority approvals. The median

total approval time for NMEs was 11.6 months. NMEs contain an active

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

the United States. The median FDA review time was 10.0 months. Sixteen

of the 30 NMEs approved in 1998 were priority reviews. Eight of the 1999

NMEs were for orphan uses compared to seven in 1998.

Original NDA Actions

44% 39%

49% 51%

38% 45%

31%

190 199

235 269

216

161

223

0%

20%

40%

60%

80%

100%

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Percentage

0

60

120

180

240

300

Number

of Actions

Percentage of Actions that Are Approvals Number of Total Original NDA Actions
Improving Public Health Through Human Drugs

7

Notable 1999 new drug approvals

Last year’s approvals benefited people with rare disorders, those with HIV

infection, older Americans and people with diabetes and other disorders.

People with rare diseases

Twelve of the new drugs approved last year are for rare diseases with

patient populations too small to make the development of such drugs and

devices routinely profitable. We approve these drugs under the 16 year-old

Orphan Drug Program which grants special privileges and marketing

incentives for drugs that treat conditions affecting fewer than 200,000

Americans.

Bexarotene (Targretin) offers new hope for patients with rare forms of

cancer, including those who have advanced or recurrent cutaneous T-cell

lymphoma, a slow-growing form of non-Hodgkin’s lymphoma, and who

have not been helped by other treatments. Epirubicin hydrochloride

injection (Ellence) treats early stage breast cancer that has spread to the

lymph nodes under the arm and has been treated surgically. Epirubicin is

commonly used in combination with other medications to slow or halt the

progression of cancer. Adult patients who have anaplastic astrocytoma, a

rare form of brain cancer, and who have relapsed after chemotherapy can

now be treated with temozolomide (Temodar).

Infants and children with rare diseases could benefit from several new

drugs approved under the Orphan Drug Program. Caffeine citrate (Cafcit)

is a short-term pediatric treatment for apnea (breathing interruptions), and

poractant alfa (Curosurf) can be used for relief from the respiratory distress

syndrome. Another new product for respiratory failure in term or near-term

infants is nitric oxide (INOmax).

1999 new molecular

entities:

Alitretinoin (Panretin)

Aminolevulinic acid

hydrochloride (Levulan

Kerastick)

Amprenavir (Agenerase)

Bexarotene (Targretin)

Cilostazol (Pletal)

Dalfopristin/quinupristin

(Synercid)

Dexmedetomidine

hydrochloride (Precedex)

Dofetilide (Tikosyn)

Doxercalciferol

(Hectorol)

Entacapone (Comtan)

Epirubicin hydrochloride

(Ellence)

Exemestane (Aromasin)

Gadoversetamide

(Optimark)

Ganirelix acetate

(Antagon)

Gatifloxacin (Tequin)

Ketotifen fumarate

(Zaditor)

Levetiracetam (Keppra)

Mequinol/tretinoin

(Solage)

Moxifloxacin

hydrochloride (Avelox)

Nitric Oxide (INOmax)

Orlistat (Xenical)

Oseltamivir phosphate

(Tamiflu)

Pemirolast potassium

(Alamast)

Pioglitazone

hydrochloride (Actos)

Poractant (Curosurf)

Rabeprazole sodium

(Aciphex)

Rapacuronium bromide

(Raplon)

1999 new molecular

entities (continued)

New Drug Application Approvals

14.4

12.0

15.4

12.0

24.1

19.0

16.5

14.8 15.8

20.8

12.2 12.0 11.8

15.3

83

90

121 131

62

70

82

0

5

10

15

20

25

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Time in Months

0

28

56

84

112

140

Number

of Approvals

Median Total Approval Time in Months Median FDA Review Time in Months Number of Original NDAs Approved
8

CDER 1999 Report to the Nation

People with Cancer

In addition to epirubicin (Ellence), which was approved under the Orphan

Drug Program, we approved exemestane (Aromasin) for advanced breast

cancer in postmenopausal women whose disease has progressed following

tamoxifen therapy. A potentially cancer-preventing product is

aminolevulinic acid hydrochloride (Levulan Kerastick), the first drug/

device for the treatment of precancerous skin lesions on the face and scalp.

People with HIV and AIDS

Amprenavir (Agenerase), a new protease inhibitor received an accelerated

approval for use in children as young as 4 and in adults in combination with

other anti-retrovirals for HIV infection. Amprenavir is one of five protease

inhibitors that attempt to prevent HIV from making new copies of itself by

interfering with the HIV protease enzyme. Another new HIV product is

alitretinoin (Panretin), a topical gel for the treatment of skin lesions in

patients with AIDS-related Kaposi’s sarcoma.

Older people

Rofecoxib (Vioxx), a new drug for treatment of osteoarthritis, menstrual

pain and the management of acute pain in adults, is a type of nonsteroidal

anti-inflammatory drug (NSAID) known as a “Cox-2 inhibitor.” NSAIDs

temporarily relieve pain by blocking the body’s production of

prostaglandins, the chemicals believed to be associated with the pain and

inflammation of injuries and immune reactions.

A combination of aspirin and extended-release dipyridamole (Aggrenox)

reduces the risk of stroke in people who have had transient ischemia attack

or completed stroke. Dofetilide (Tikosyn) is an anti-arrhythmic agent for the

maintenance and conversion of normal sinus rhythm in patients with highly

symptomatic atrial fibrillation and atrial flutter, types of irregular

heartbeats. Cilostazol (Pletal) is for treating stable intermittent claudication,

a severe pain, aching or cramping in the legs that occurs with walking.

Entacapone (Comtan) enhances the benefits of standard treatment for

Median time

The median time is a

value that falls in the

middle of all times. It

provides a truer picture

of performance than

average time, which can

be unduly influenced by

a few extremely long or

short times.

Information on average,

or mean, approval times

and other statistics are

available on our Web

site at http://www.fda.

gov/cder/rdmt/

default.htm.

Rofecoxib (Vioxx)

Rosiglitazone maleate

(Avandia)

Sirolimus (Rapamune)

Sodium ferric gluconate

complex (Ferrlicet)

Technetium Tc 99m

depreotide kit (NeoTect)

Temozolomide

(Temodar)

Zaleplon (Sonata)

Zanamivir (Relenza)

1999 new molecular

entities (continued)

New molecular

entity statistics

 35 approvals

 19 priority reviews

 Median total

approval time:

11.6 months

 Median total FDA

review time:

10.0 months

New Molecular Entity Approvals

14.3

11.6

12.0

15.9

23

13.4

17.5

12.0

10.0

11.9

15.2

12.8

15.3

21

35

30

28 25 22

53

39

0

5

10

15

20

25

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Time in Months

0

12

24

36

48

60

Number

of Approvals

Median Total Approval Time in Months Median FDA Review Time in Months Number of NMEs Approved
Improving Public Health Through Human Drugs

9

Parkinson’s disease. Zaleplon (Sonata) is for the short-term treatment of

insomnia in adults, including elderly patients.

People with Diabetes.

Patients with type II or adult-onset diabetes who are not adequately

controlled by diet and exercise alone can be treated with pioglitazone

(Actos) or rosiglitazone (Avandia). These medicines are members of the

thiazolidinedione class of drugs that can improve the body’s ability to use

insulin.

Infectious diseases

Dalfopristin and quinupristin injection (Synercid) is the first antibacterial

drug to treat infections caused by vancomycin-resistant Enterococcus

faecium, which has become highly resistant to older antibiotics. This drug

was also approved for complicated skin and skin structure infections.

Gatifloxacin (Tequin) is a new type of quinolone antibiotic for treating

community-acquired respiratory tract infections such as pneumonia, acute

exacerbation of chronic bronchitis and acute sinusitis. Moxifloxacin

hydrochloride (Avelox) is a once-a-day antibiotic to treat common

respiratory tract infections, including bacterial exacerbations of chronic

bronchitis, community-acquired pneumonia of mild to moderate severity

and acute bacterial sinusitis.

Two anti-viral therapies treat people infected with the virus that causes

influenza. These are zanamivir (Relenza), an inhaled drug for adults and

adolescents who are 12 or older, and oseltamivir phosphate (Tamiflu), a

capsule indicated for onset of influenza A and B.

Other significant approvals

Dexmedetomidine hydrochloride (Precedex) is a sedative for people in

intensive care settings who have undergone major surgery. Doxecalciferol

(Hectoral) helps manage secondary hyperparathyroidism in patients

undergoing chronic renal dialysis. Gadoversetamide (OptiMARK) is a

magnetic resonance imaging agent to help diagnose lesions, including

tumors, of the brain, spine and liver. Ganirelix acetate (Antagon) reduces in

vitro fertilization treatment times from four weeks to about 10 days and

simplifies treatment regimens. Ketotifen fumarate (Zaditor) is an

ophthalmic solution for the temporary relief of itchy eyes due to allergic

conjunctivitis. Levetiracetam (Keppra) is a new epilepsy drug that helps

control partial onset seizures in adults. Orlistat (Xenical) is a lipase

inhibitor to treat obesity.

Rabeprazole sodium (Aciphex) is a once-a-day proton pump inhibitor to

heal duodenal ulcers and erosive gastroesophageal reflux disease.

Pemirolast potassium (Alamast) is an ophthalmic solution to prevent itchy

eyes caused by allegic conjunctivitis. Rapacuronium bromide (Raplon) is

an adjunct to general anesthesia to facilitate tracheal intubation and provide

skeletal muscle relaxation. Sirolimus (Rapamune) is the first in a new class

of immunosuppressant agents that prevent organ rejection in people with

transplants. Sodium ferric gluconate (Ferrlecit) treats iron deficiencyin endstage renal disease for patients in hemodialysis who are receiving

erythropoietin therapy. The technetium Tc 99m depreotide kit (NeoTect) is

for imaging suspected malignant tumors in the lung.

Orphan new drug

approvals

Alitretinoin (Panretin), a

topical treatment of

cutaneous lesions in

patients with AIDSrelated Kaposi’s

sarcoma

Bexarotene (Targretin)

for treating cutaneous

manifestations of

cutaneous T-cell

lymphoma in patients

who are refractory to at

least one prior systemic

therapy

Busulfan (Busulfex) as a

preparative therapy in

the treatment of

malignancies with bone

marrow transplantation

Caffeine citrate (Cafcit)

for apnea of prematurity

Cytarabine (Depocyt) for

neoplastic meningitis

Epirubicin hydrochloride

(Ellence) as a component

of adjuvant therapy in

patients with evidence of

axillary node tumor

involvement following

resection of primary

breast cancer

Exemestane (Aromasin)

for treating advanced

breast cancer in

postmenopausal women

whose disease has

progressed following

tamoxifen therapy

Orphan new drug

approvals

(continued)

Lidocaine patch

(Lidoderm) for relief of

allodynia (painful

hypersensitivity) and

chronic pain in postherpetic neuralgia

Nitric oxide (INOmax) for

the treatment of

persistent pulmonary

hypertension in the

newborn

Poractant alfa (Curosurf)

for the treatment of

respiratory distress

syndrome in premature

infants

Somatropin (Nutropin

depot) for the long-term

treatment of growth

failure

Temozolomide (Temodar)

for the treatment of

recurrent malignant

glioma
10

CDER 1999 Report to the Nation

Efficacy supplement

statistics:

 97 approvals

 9 priority approvals

 Median total

approval time:

10.4 months

 Median FDA review

time:

10.2 months

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.

Last year we took action on 184 applications for new or expanded uses of

already approved drugs. We approved 97, including nine that were given

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

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

The median total approval time was 10.4 months, and median FDA review

time was 10.2 months.

Efficacy Supplement Actions

53%

72% 60% 57%

39% 41% 37%

184

122

185

173 189 196

122

0%

20%

40%

60%

80%

100%

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Percentage

0

45

90

135

180

225

Number

of Actions

Percentage of Actions that Are Approvals Number of Efficacy Supplement Actions

Efficacy Supplement Approvals

10.4

12

19

11.9 11.8

16

13.9

11.7

10.2

12.3

11.2 11.9

14.2

18.3

97

124

108

50

118

69 48

0

5

10

15

20

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Time in Months

0

35

70

105

140

Number

of Approvals

Median Total Approval Time in Months Median FDA Review Time in Months

Number of Efficacy Supplements Approved
Improving Public Health Through Human Drugs

11

Notable 1998 new or expanded use approvals

Celecoxib (Celebrex), a nonsteroidal anti-inflammatory drug first approved

in 1998 to treat arthritis, is the first drug treatment (together with

endoscopic surveillance or surgery) for familial adenomatous polyposis, a

genetic disorder. The new indication is for the reduction in the number of

adenomatous colorectal polyps, which greatly increase the risk of

developing colon and rectal cancer in young patients. This indication was

given an accelerated approval as a product that promised therapeutic

benefit for a life-threatening condition that has no other acceptable

treatment.

Docetaxel (Taxotere), which was originally designed for treating patients

with advanced breast cancer, and now is approved for use in non-small cell

lung cancer that does not respond to chemotherapy.

Paroxetine hydrochloride (Paxil) is the first drug to receive FDA approval

to treat social phobia

Sertraline hydrochloride (Zoloft) is the first drug for posttraumatic stress

disorder, which has long been recognized as an important clinical problem.

Somatropin (Nutropin Depot), a genetically engineered drug, was

approved for long-term treatment of growth failure.

Priority efficacy

supplement

approvals

Amifostine

Celecoxib

Didanosine (3)

Docetaxel

Doxorubicin

hydrochloride

Roloxifene hydrochloride

Paclitaxel

Electronic submissions

One of the advantages of the FDA review system is the availability of

complete data for reviewers. A bulky component of the application consists

of case report forms and case report tabulations. We have been accepting

the archive copy of these in electronic format since November 1997. In

January 1999, we published guidances that provide for the receipt and

archiving of a new drug application entirely in electronic format without an

accompanying paper archival copy.

We expanded our electronic document room to manage the receipt and

handling of full electronic new drug applications. We conducted workshops

to assist industry in preparing their electronic submissions and trained our

reviewers in using electronic submissions. The majority of original new

drug applications now include electronic components. In addition, we

expanded our internal electronic document management system so that we

can electronically archive all of our documents for investigational new drug

applications and new drug applications.

Pediatrics

We are authorized to

grant six months of

marketing exclusivity to

manufacturers who

conduct and file pediatric

studies in response to our

written request. We have

reviewed more than 175

proposed study requests

from industry and issued

more than 140 written

requests asking for more

than 200 studies.

Pregnancy labeling

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

women and developed an improved, more comprehensive and clinically

meaningful approach. We consulted multiple government agencies,

medical experts, consumer groups and the pharmaceutical industry in

developing two draft guidances for industry and a preliminary discussion

paper.
12

CDER 1999 Report to the Nation

Over-the-Counter Drug Review

In 1999, we approved four new drugs and four new uses for over-thecounter marketing.

New OTC medicines and new uses

 Cimetidine (Tagamet HB Suspension) and famotidine (Pepcid AC

Gelcaps) are new forms of OTC heartburn treatments.

 The combination naproxen and pseudoephedrine (Aleve Cold and

Sinus) is a pain reliever, fever reducer, and cold and cough treatment.

 Terbinafine (Lamisil Cream) is a topical anti-fungal to treat ringworm

and conditions like athlete’s foot.

 The nicotine patch (Habitrol) was switched to OTC status.

 The combination acetaminophen, aspirin and caffeine (Excedrin

Migraine) is a new use for an existing OTC drug.

Improved Labels for OTC Medicines

Consumers will soon find it easier to use over-the-counter medicines as a

result of a final rule we published in 1999 that will provide new, easy-tounderstand labels on nonprescription drugs. The regulation calls for a

standardized format that will improve the labels on drugs Americans use

most—nonprescription, or over-the-counter drugs. By clearly showing a

drug’s ingredients, dose and warnings, the new labels will make it easier for

consumers to understand information about a drug’s benefits and risks as

well as its proper use.

Titled “Drug Facts,” the new label will make it easier for consumers to

identify active ingredients, which will be listed at the top, followed by uses,

warnings, directions and inactive ingredients. The rule also sets minimum

type sizes and other graphic features for the standardized format, including

options for modifying the format for various package sizes and shapes.

Over-the-counter

drug statistics:

 4 new drug approvals

 4 new use approvals

 11 rules or notices

OTC drug facts

As Americans continue

to participate more

actively in their health

care decisions, many

medications purchased

are OTC drugs.

Currently, there are

more than 100,000 OTC

products on the market.

However, fewer than

1,000 active ingredients

are used in all OTC

products.

The expanding

availability of OTC

drugs reclassified from

prescription status offers

consumers greater

choices.

More than 600 OTC

products use ingredients

and dosages available

only by prescription 20

years ago.

OTC drug

monographs

One of our goals is to

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

further FDA clearance.

OTC New Approvals and New Uses

9 9

4

1 1

4

18

7

5

8

0

5

10

15

20

1995 1996 1997 1998 1999

Calendar Year

Number

New Approvals or Rx-to-OTC Switches New Uses
Improving Public Health Through Human Drugs

13

Generic Drug Review

We received 196 submissions and approved 186 generic products in 1999,

including 43 that represent the first time a generic drug was available for

the brand name product. The median approval time for generic drugs

stabilized last year at 18.6 months, about half a month longer than required

in 1998.

Initiatives to streamline the generic drug review process have paid off in an

overall downward trend in approval times since 1994. The 18.6-month

median approval time last year compares to 18.0 in 1998 and 19.3 in 1997.

We have also seen a drop in the number of review cycles needed to

approve abbreviated applications for generic drugs. In 1999, the average

application required 2.5 cycles to reach approval compared to 2.6 cycles in

1998. These were down from 2.9 in 1997 and 3.6 in 1996.

1999 generic drug

statistics

 186 generic drug

approvals

 Median approval

time: 18.6 months

Quicker approvals

without user fees

We don’t receive user

fees to review

applications for

marketing generic

equivalents of

prescription or over-thecounter drugs.

New Counting

System

Note: Drug approval

data in this report are

based on a new counting

system that allows

certain variations in a

drug product to be

included in a single

application. This year’s

report reflects our final

conversion to the new

system, and numbers in

this report cannot be

directly compared to

those in previous reports.

Notable 1999 generic drug approvals

Examples of first time approvals include:

 Nicotine gum, for use as a smoking deterrent.

 Propofol injectable emulsion, used as a sedative for maintenance of

anesthesia during surgery.

We also issued 56 tentative approvals last year compared to 40 in 1998.

The only difference between a full approval and a tentative approval is that

the final approval of these applications is delayed due to existing patent or

exclusivity on the innovator’s drug product. Examples of tentative

approvals include:

 Lovastatin tablets, a cholesterol lowering agent.

 Fluoxetine hydrochloride capsules used for depression.

Generic Drug Approvals

18.0

27.0

19.3 18.6

26.9

23.0 186 225

273

212

158 207

0

10

20

30

1994 1995 1996 1997 1998 1999

Calendar Year

Time in Months

0

100

200

300

Number

of Approvals

Median Approval Times in Months Number of Generic Approvals
14

CDER 1999 Report to the Nation

The approval of generic versions of these products and other generic

approvals in 1999 could save the American people and the federal

government hundreds of millions of dollars.

“In 1994, purchasers

saved a total of $8

billion to $10 billion on

prescriptions at retail

pharmacies by

substituting generic

drugs for their brandname counterparts.”

—How Increased

Competition from

Generic Drugs Has

Affected Prices and

Returns in the

Pharmaceutical

Industry,

Congressional

Budget Office,

July 1998

How we approve

generic drugs

The abbreviated

mechanism for

approving generic copies

of drug products was

established by the Drug

Price Competition and

Patent Term Restoration

Act of 1984, known as

the Hatch-Waxman Act.

Generics are not

required to repeat the

extensive clinical trials

used in the development

of the original, brandname drug. Instead, they

must show they are

bioequivalent to the

pioneer drug and fall

into acceptable

parameters for

bioavailability, or the

extent and rate at which

the body absorbs the

drug.

Scientists measure the

time it takes a generic

drug to reach the

bloodstream. This gives

them the rate of

absorption or

bioavailability of the

generic drug, which they

then compare to that of

the pioneer drug. The

generic version must

deliver the same amount

of active ingredients into

a patient’s bloodstream

and in the same time as

the pioneer drug. Brandname drugs are subject

to the same

bioequivalency tests as

generics when their

manufacturers

reformulate them.

Generic drug electronic submission initiative

Last year, for original submissions, we received 44 electronic submissions

for bioequivalence data and 55 electronic submissions for chemistry,

manufacturing and controls data. For comparison, we received 32

bioequivalence electronic submissions and 44 CMC in 1998 and ten

bioequivalence and none with CMC data prior to 1998. In continued

support of the electronic submissions initiative, we:

 Enhanced our information technology infrastructure to support the

electronic review process.

 Promoted electronic submissions directly to industry and trade groups.

 Held training sessions for industry.

 Published a Guidance for Industry: Preparing Data for Electronic

Submissions in ANDAs.

Generic Drug Electronic Submissions

44

10

32

44

55

0

0

20

40

60

1997 1998 1999

Fiscal Year

Number

Bioequivalence data Chemistry, manufacturing, controls data
Improving Public Health Through Human Drugs

15

Manufacturing Supplement Review

We review many types of changes in the manufacturing of drugs and their

packaging, including location, machinery, processes and suppliers of raw

materials. We do this so that American consumers can trust in the high

quality of FDA-approved medicines. Manufacturers notify us in advance

of certain manufacturing changes. These are known as “manufacturing

supplements” to new drug or generic drug applications. In many cases,

they represent the industry’s efforts to modernize plants and equipment or

to make manufacturing more efficient.

Manufacturing Supplements to New Drug Applications

In 1999, we took action on 1,747 manufacturing supplements, of which

1,419 were approvals.

NDA manufacturing

supplement

statistics

 1,419 approvals

 Median total review

time: 5.2 months

NDA Manufacturing Supplement Actions

81%

74%

67%

61%

80%

72%

83%

1,747 1,147 1,580 1,674 1,659 1,782 1,630

0%

20%

40%

60%

80%

100%

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Percentage

0

400

800

1,200

1,600

2,000

Number

of Actions

Percentage of Actions that Are Approvals Number of NDA Manufacturing Supplement Actions

NDA Manufacturing Supplement Approvals

5.9

7.7

5.1 5.2 5.4

8.2

4.0

848

1,024

1,065

1,422

1,178

1,375 1,419

0.0

2.0

4.0

6.0

8.0

10.0

1993 1994 1995 1996 1997 1998 1999

Calendar Year

Time in Months

0

320

640

960

1280

1600

Number

of Approvals

Median Total Approval Time in Months Number of NDA Manufacturing Supplements Approved
16

CDER 1999 Report to the Nation

We began tracking manufacturing supplements to new drug applications

and their review times as part of the performance goals agreed to for the

original Prescription Drug User Fee Act.

Generic drug

manufacturing

supplement

statistics

 2,293 approvals

 3,036 receipts

Manufacturing Supplements to Generic Drug Applications

In 1999, we approved 2,293 manufacturing supplements to generic drugs

applications. We received 2,499 manufacturing supplements during the

year. In 1997, we began counting generic drug manufacturing supplements

separately from all supplements to generic drug applications.

Note: Each product’s supplement is tracked individually. A “global

supplement” requires only one review but can apply to multiple products.

Generic Drug Manufacturing Supplements

Receipts and Approvals

1,903

2,284 2,293

3,036

2,370 2,499

0

1,000

2,000

3,000

4,000

1997 1998 1999

Calendar Year

Number

Number of Supplements Approved Number of Supplements Received
Improving Public Health Through Human Drugs

17

User Fee Review Performance

The quick and consistent level of drug reviews in recent years reflects the

importance of our managerial reforms and the additional resources

provided us under the Prescription Drug User Fee Act. The law was first

enacted in 1992 and renewed for an additional five years in the 1997 FDA

Modernization Act. Under the law, the drug industry pays user fees for

new drug applications, efficacy supplements and some other activities.

User fees helped us hire additional scientists to perform reviews. Original NDAs

Improved performance

goals were a key element

of the reauthorization of

user fees:

 Standard drugs began

a phase-in to 10-month

reviews in fiscal year

1999.

 Priority drugs have a

performance goal of 90

percent reviewed and

acted upon within six

months.

 New molecular

entities have the same

review performance

goals as standard and

priority drugs.

Resubmissions

of original NDAs

Beginning in 1998,

resubmissions were

divided into two classes:

 Class I, involving

minor changes, are

targeting 90 percent twomonth reviews by fiscal

year 2001.

 Class II, involving

changes not specifically

identified in the user fee

goals document, retain a

six-month review.

Resubmissions of Original NDAs

Fiscal Year Cohort Within Goal Review Performance

0%

20%

40%

60%

80%

100%

FY '93

2 reviews

100% on- time

FY '94

24 reviews

83% on- time

FY '95

58 reviews

97% on- time

FY '96

89 reviews

99% on- time

FY '97

87 reviews

97% on- time

FY '98

54 reviews

FY '99

64 resubmitted

 User Fee Goal (none in 1993)

 Class I (6-mo.) Class I (4-mo.) Class I (2-mo.) Class II (6-mo.)

 *48 reviewed, 16 pending within goal as of Jan. 31, 2000

Percentage

Original NDAs

Fiscal Year Cohort Within Goal Review Performance

0%

20%

40%

60%

80%

100%

FY '93

84 reviews

65% on- time

FY '94

92 reviews

95% on- time

FY '95

111 reviews 

98% on- time

FY '96

109 reviews 

100% on- time

FY '97

121 reviews 

100% on- time

FY '98

114 reviewed

FY '99

125 filed* 

 User Fee Goal (none in 1993)

 12-month review 10-month review 6-month review

*67 reviewed, 58 pending within goal as of Jan. 31, 2000

Percentage

22 (100%) 6 mo.

18 (82%) 2 mo.32 (100%) 6 mo.

17 (100%) 4 mo.

17 (100%) 2 mo.

47 (100%) 6 mo.

84 (100%)

30 (100%)

95 (100%)

77 (81%)

30 (100%)
18

CDER 1999 Report to the Nation

In 1992, we agreed to specific performance goals for the prompt review of

four categories of submissions:

 Original new drug applications.

 Resubmissions of original NDAs.

 Efficacy supplements to already approved marketing applications.

 Manufacturing supplements to already approved new drug marketing

applications.

We exceeded the progressively more stringent user fee performance goals

for each successive fiscal year except for one goal in fiscal year 1998.

Efficacy

supplements

 Standard efficacy

supplements began a

phase-in to 10-month

reviews in fiscal year

1999.

 Priority efficacy

supplements began a sixmonth performance goal

in fiscal year 1998.

Fiscal year cohorts

When comparing the

fiscal year user fee

performance charts with

the calendar year

performance charts,

remember that work on

one year’s submission

cohort is often

performed in the

following year.

Manufacturing

supplements

 Manufacturing

supplements to NDAs

that require our prior

approval before

implementation have a

phase-in to a four-month

review.

 The goal for those

that don’t require our

prior approval—changes

being effected—remains

at 90 percent reviewed

and acted on within six

months.

Efficacy Supplements

Fiscal Year Cohort Within Goal Review Performance

0%

20%

40%

60%

80%

100%

FY '93

92 reviews

41% on- time

FY '94

86 reviews

77% on- time

FY '95

77 reviews

95% on- time

FY '96

105 reviews

98% on- time

FY '97

146 reviews

99% on- time

FY '98

129 reviews

FY '99

140 filed*

 User Fee Goal (none in 1993)

12-month review 10-month review 6-month review

*80 reviewed (1 overdue), 60 pending (1 overdue) as of Jan. 31, 2000

Percentage

New Drug Manufacturing Supplements

Fiscal Year Cohort Within Goal Review Performance

0%

20%

40%

60%

80%

100%

FY '93

1,045 reviews

50% on- time

FY '94

871 reviews

66% on- time

FY '95

1,249 reviews

90% on- time

FY '96

1,218 reviews

96% on- time

FY '97

1,262 reviews

98% on- time

FY '98

1,442 reviews

99% on- time

FY '99

1,458 filed*

 User Fee Goal (none in 1993)

 Prior Aprvl (6-mo.) Prior Aprvl (4-mo.) Changes Being Effected (6-mo.)

*1,352 reviewed (12 overdue), 106 pending (4 overdue) as of Jan. 31, 2000

Percentage

117 (99%)

10 (80%)

125 (100%)

114 (91%)

15 (87%)

899 (99%)

663 (70%)

559 (98%)
Improving Public Health Through Human Drugs

19

Clinical Holds

By working with sponsors more closely, the

percentage of commercial investigational

new drug applications put on clinical hold

has decreased dramatically.

A clinical hold temporarily halts the testing

of a drug in humans because of concerns

about safety.

We have developed and published

procedures that outline specific

responsibilities and timelines for handling

clinical holds imposed on investigational

new drugs.

Refusal to file an application

As a result of the user fee program, the

quality of applications submitted by

industry has improved. In addition we have

exercised increased consistency in applying

our authority to refuse to file an

application. We refuse to file an application

only when we determine there is a

significant omission of needed information.

Before 1993, we were refusing to file

approximately 25 percent to 30 percent of

submitted original new drug applications.

The percentage of refused-to-file

applications has dropped steadily to

approximately 4 percent in recent years.

In 1997, Congress, with the industry’s and our support, enhanced the user

fee program and extended it for five years as part of the FDA

Modernization Act. We have committed to goals that will help speed the

time it takes for drugs to be appropriately tested and developed before

submitting those results for FDA review.

These new goals include those related to meeting management, clinical

holds, resolving major disputes and reaching agreement on certain

protocols. There are added expectations regarding electronic applications

and submissions, simplification of action letters and expedited notification

of deficiencies in applications.

Refuse-to-File Actions

Original NDAs

5% 4% 5% 3%

26%

17%

2%

135

113

117 114 123

111

132

0%

5%

10%

15%

20%

25%

30%

FY '93

(29)

FY '94

(19)

FY '95

(6)

FY '96

(5)

FY '97

(2)

FY '98

(7)

FY '99

(4)

Fiscal Year (number refused)

Percentag

e

0

25

50

75

100

125

150

Number

Percentage Refused to File Number of Original NDAs Submitted

Clinical Holds of Commercial INDs

(as of December 31, 1999)

11%

12%

8% 7%

15%

9%

360

358 376 446

471

430

0%

4%

8%

12%

16%

FY '94

(55)

FY '95

(43)

FY '96

(30)

FY '97

(33)

FY '98

(42)

FY '99

(46)

Fiscal Year (number of holds)

Percentage on Hol

d

0

125

250

375

500

Number

Percentage of Commercial INDs Received on Hold

Number of Commercial INDs Received
20

CDER 1999 Report to the Nation

Drug Review Team

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

individual special technical expertise to review applications:

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

manufacturing controls, quality control testing and packaging are

adequate to preserve the drug product’s identity, strength, potency,

purity and stability.

 Pharmacologists and toxicologists evaluate the effects of the drug on

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

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

cancer in humans.

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

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

outweigh its known risks at the doses proposed.

 Project managers orchestrate and coordinate the drug review team’s

interactions, efforts and reviews. They also serve as the review team’s

primary contact for the drug industry.

 Statisticians evaluate the designs and results for each important clinical

study.

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

These medicines—antibiotics, antivirals and antifungals—differ from

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

Another group of microbiologists evaluates the manufacturing

processes and tests for sterile products, such as those used

intravenously.

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

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

metabolized and eliminated. They also check for interactions with other

drugs.

 Clinical pharmacologists evaluate factors that influence the relationship

between the body’s response and the drug dose. They assist physician

members of the team in assessing the clinical significance of changes in

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

relationships.

Consumers benefit

from user fee

reforms

Two studies released last

year document the

benefits of FDA’s review

and approvals and

indicate that Americans

have an increasingly fast

access to new

medications of

worldwide origin.

 One of the studies

(Tufts Center for Study

of Drug Development,

July 1999) showed that

since the passage of the

Prescription Drug User

Fee Act of 1992, total

development time for

new drugs in the U.S. has

dropped by 18 percent.

 Another study

(Ashton CMRI

International News,

Spring 1999, Vol. 17, No.

1) found that, in 1998,

about 75 percent of

worldwide new

molecular entities were

first launched in the

United States.
Improving Public Health Through Human Drugs

21

2

DRUG SAFETY

AND QUALITY

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

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

Therefore, a degree of uncertainty always exists about both the benefits and

risks from drugs. The trade-off for accepting these uncertainties is our

continued vigilance along with that of the industry to collect and assess

data during the postmarketing life of a drug.

We 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.

Mission

Protect the public health

by ensuring that human

drugs are safe and

effective.

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. Known side effects cause the majority of injuries and deaths

resulting from using medicines. There are avoidable and unavoidable side

effects:

 Avoidable. In many cases drug therapy requires an individualized

treatment plan and careful monitoring. Other examples of avoidable side

effects are known drug-drug interactions.

Risk management

For a 164-page report on

current and

recommended premarket

and postmarket risk

assessment procedures

and surveillance

programs, last year’s

FDA report, Managing

the Risks form Medical

Product Use: Creating a

Risk Management

Framework, is available

on the World Wide Web

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

tfrm/riskmanagement.pdf

Known side effects

Unavoidable Avoidable

Medication

errors

Product quality

defects

Preventable

adverse

events

Injury

or death

Remaining

uncertainties

Unexpected side effects

Unstudied uses

Unstudied populations

Sources of Risk from Drug Products
22

CDER 1999 Report to the Nation

 Unavoidable. Some known side effects occur with the best medical

practice even when the drug is used appropriately. Examples include

nausea from antibiotics or bone marrow suppression from

chemotherapy.

Medication errors. The drug is administered incorrectly or the wrong drug

or dose is administered.

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

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

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

Drug Safety

We evaluate the ongoing safety profiles of drugs available to American

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

postmarketing surveillance and risk assessment programs to identify

adverse events that did not appear during the drug development process.

We monitor adverse events such as adverse reactions, drug-drug

interactions and poisonings. We use this information to update drug

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

decision.

Adverse event reporting

Last year, we received 258,125 reports of suspected drug-related adverse

events:

 78,539 manufacturer 15-day (expedited) reports.

 15,374 reports directly from individuals.

 164,212 manufacturer periodic reports and other follow-up reports.

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

assessments and decisions about the most appropriate way to manage any

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

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

restricted distribution programs or product marketing termination.

We enforce regulations on adverse event reporting to assure that reports are

accurate, timely and complete. During fiscal year 1999, there were 50

inspections of foreign and domestic firms for adverse event reporting. In

addition, we gave guidance on policy issues and held meetings with

industry to discuss their adverse event reporting practices. We approved

four warning letters and three untitled letters citing adverse event reporting

deficiencies. The 50 inspections in fiscal year 1999 compare to 51

conducted in fiscal year 1998, 33 in fiscal year 1997 and 17 in fiscal year

1996.

Medication errors

We help ensure the safe

use of drugs we approve

by identifying and

avoiding brand names

that contribute to

problems in prescribing,

dispensing or

administration of the

product.

Therapeutic

inequivalence

reporting

We identify and evaluate

reports of therapeutic

failures and toxicities

that could indicate one

produce is not equivalent

to another similar

product.
Improving Public Health Through Human Drugs

23

Information technology

A powerful tool for detecting signals is the computerized spontaneous

reporting evaluation system. We have replaced our previous computerized

system with a new, state-of-the-art system: the Adverse Event Reporting

System. This system combines the voluntary adverse drug reaction reports

from MedWatch and the required reports from manufacturers. These

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

potential for serious, unrecognized, drug-associated events. After the signal

is generated, further testing of the hypothesis is undertaken using various

epidemiological and analytic databases, studies and other instruments and

resources. The Adverse Event Reporting System offers paper and

electronic submissions options, international compatibility and

pharmacovigilance screening activities.

MedWatch

In 1999, we took over administration of MedWatch under which health

professionals and the public can voluntarily report serious reactions and

problems with all FDA-regulated medical products. Reports can be filed by

mail, fax, telephone or the Internet. The program enhances the

effectiveness of postmarketing surveillance by rapidly identifying

significant health hazards associated with them and notifying health

professionals and the public of these hazards. We educate health

professionals and consumers about the importance of recognizing and

reporting serious adverse events and product problems, including

medication errors. We rapidly disseminate safety information through the

World Wide Web and by e-mail notification available to both to health

professionals and the public. Our education program includes speeches,

articles and exhibits.

Report types

15-day (expedited)

reports: Drug

manufacturers report

serious and unexpected

adverse events to us soon

as possible and within 15

days of discovering the

problem.

Direct reports from

MedWatch: An

individual, usually a

health-care practitioner,

notifies us directly of a

suspected adverse event.

Manufacturer periodic

reports and others: Drug

manufacturers report all

other adverse events, for

example, those that are

less than serious or

described in the drug’s

labeling. Reports are

submitted quarterly for

the first three years of

marketing and annually

after that. When

additional information is

required, a follow-up

report is submitted.

Internet resources

You can learn more

about the Adverse Event

Reporting System at

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

aers/index.htm.

The latest medical

product safety

information can be

found on the MedWatch

Website at http://

www.fda.gov/medwatch/.

You can sign up for

immediate e-mail

notification of

MedWatch safety

information at http://

www.fda.gov/medwatch/

new.htm.

Post-Marketing Adverse Event Reports

246,821 258,125

228,611

189,073

154,558 136,836 143,597

117,718

83,310 83,517

68,448

0

50,000

100,000

150,000

200,000

250,000

300,000

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Calendar Year

Number

Manufacturer Periodic Reports & Others Direct Reports Manufacturer 15-Day (expedited) Reports
24

CDER 1999 Report to the Nation

Risk vs. benefit

communications

research

We are conducting

research to assess the

public’s ability to

understand risk and

benefit information.

The goal is to develop

useful and meaningful

ways of presenting

important information

about a drug’s known

risks and benefits.

Drug Promotion Review

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

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

health of Americans by ensuring that drug advertisements and other

promotional materials are truthful and balanced. The Center operates a

comprehensive program of education, surveillance and enforcement about

drug advertising and promotion.

In some instances, we review drug advertisements and other promotional

materials before drug companies launch marketing campaigns that

introduce new drugs or introduce new indications or dosages for approved

drugs. In 1999, the Center issued 337 advisory letters to companies

regarding their promotional materials for launch campaigns.

We issued 171 regulatory action letters to pharmaceutical companies for

prescription drug promotions determined to be false, misleading or lacking

in fair balance. These were either “untitled” letters for minor violations or

“warning” letters for serious or repeat violations. The Center also issued

773 other advisory, acknowledgment or closure letters to the industry

regarding prescription drug promotional materials.

Direct-to-consumer advertising

We issued 247 combined advisory and regulatory action letters regarding

direct-to-consumer promotion. We issued a final guidance on direct-toconsumer broadcast advertisements that covered human and animal

prescription drugs and human biologics. We completed a national

Drug Promotion Review

235 220 245 237

171

221

417 399

129

242

159

350

558 539

0

200

400

600

800

1993 1994 1995* 1996 1997 1998 1999

Calendar Year

(*Change from counting campaigns to letters in last quarter 1995)

Number*

Regulatory Actions Launch Campaigns
Improving Public Health Through Human Drugs

25

telephone survey of patient attitudes and behaviors in relation to direct-toconsumer advertising, focusing on the patient-physician interaction. We

also began research to examine how consumers interpret specific direct-toconsumer advertisements.

Improved patient information for prescription drugs

We continued our research, education and outreach activities in support of

the private plan to provide patients with useful information about their

prescription drugs. We have been working with industry, nonprofit

agencies and academic groups to ensure that 75 percent of patients receive

useful information about their new prescriptions by the year 2000. We

completed a study examining the current status of the private sector plan’s

progress toward achieving the year 2000 goal. We issued a final rule that

requires FDA-approved patient labeling (medication guides) for especially

risky prescription drug products.

Export Certificates

We promote goodwill and cooperation between the United States and

foreign governments through the Export Certificate Program. These

certificates enable American manufacturers to export their products to

foreign customers and foreign governments. The demand for certificates by

foreign governments remained high due to expanding world trade, ongoing

international harmonization initiatives and international development

agreements.

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

FDA and are manufactured in compliance with current good

manufacturing practices.

What export

certificates do

Export certificates

verify that 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.

Export Certificates Issued

3,973 4,499 4,378 4,382

1,747

1,290

0

1,000

2,000

3,000

4,000

5,000

FY '94 FY '95 FY '96 FY '97 FY '98 FY '99

Fiscal Year

Number

Export Certificates Issued
26

CDER 1999 Report to the Nation

Top 10 reasons for

drug recalls in fiscal

year 1999:

 Failure or inability to

validate drug analysis

methods

 Subpotency

 Stability data failing

to support expiration

date

 Failure or inability to

validate manufacturing

processes

 Deviations from good

manufacturing practices

 Failure of drug to

dissolve properly

 Labeling mix-ups

 Marketed without a

new or generic approval

 Lack of assurance of

sterility

 Cross-contamination

with other products

Voluntary recalls

A recall is a voluntary

action taken by a

manufacturer or

distributor to carry out

their responsibility to

protect the public health

when they need to

remove or correct a

marketed drug product

that presents a

significant risk to public

health. A voluntary

recall is more efficient

and effective in assuring

timely consumer

protection than an FDA

initiated court action or

seizure.

Drug Recalls and Withdrawals

We coordinate drug recall information and prepare health hazard

evaluations to determine the risk to public health by products being

recalled. We classify recall actions in accordance to the level of risk, and

we participate in determining recall strategies based upon the hazard and

other factors including distribution patterns and market availability. We

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

public notification.

In some cases, drugs are withdrawn from the market. Last year,

manufacturers withdrew these two drugs for safety reasons:

 Astemizole (Hismanal), a prescription antihistamine approved in 1988,

voluntarily withdrawn after new adverse reaction data had required a

series of labeling changes and warnings.

 Grepafloxacin (Rexar), an oral flurorquinolone antibiotic first marketed

in 1997, voluntarily withdrawn when the company observed a small

number of severe cardiovascular events.

The record of withdrawal of drugs approved in recent years compares

favorably to previous periods when we were criticized for taking too long

to review drug applications. Nonetheless, the increased number of drugs

and the large number of patients taking multiple drugs have created the

potential for more drug safety problems. We are exploring these issues in a

systematic manner with our partners in industry, academia, state and local

Drug Recalls

255

304

191

248

93 102

60 53

34

88

352

177

226

72

0

100

200

300

400

FY '93 FY '94 FY '95 FY '96 FY '97 FY '98 FY '99

Fiscal Year

Number

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

27

Drug Product Quality

We provide comprehensive regulatory coverage of the production and

distribution of drug products. This helps ensure that drugs are safe,

effective and in compliance with applicable current regulations for good

manufacturing practices. We manage inspection programs designed to

minimize consumer exposure to defective drug products. We have two

basic strategies to meet this goal:

 Evaluating the factory inspections that include collection and analysis

of associated samples and the conditions and practices under which

drugs are manufactured, packed, tested and stored.

 Monitoring the quality of finished drug products in distribution through

sampling and analysis.

We identify, evaluate and analyze inspection findings for trends. We

develop guidances to assist drug manufacturers in gaining a better

understanding of our regulations. We communicate the expectations of

compliance through outreach programs. We review all international

pharmaceutical inspection reports. We determine which foreign

manufacturers are acceptable to supply active pharmaceutical ingredients or

finished drug products to the U.S. market.

OTC drug quality

We ensure that all

marketed over-thecounter drugs medicines

are safe and effective for

their intended uses and

are labeled accurately.

When we find OTC drug

products that fail to meet

the appropriate

standards of labeling or

formulation, we advise

firms in writing of the

violations in the hope

that voluntary

corrections will be made.

In some instances it is

necessary to seize

violative products to

ensure that consumers

are protected.

Safety-Based NME Withdrawals

Based on Year of Approval

1.9%

2.7%

4.4%

2.4%

185

126

103

114

0%

1%

2%

3%

4%

5%

1980-1984

(2)

1985-1989

(4)

1990-1994

(2)

1995-1999

(4)

5-Year Approval Cohorts (number withdrawn as of May 1, 2000)

Includes troglitazone withdrawal and announced cisapride withdrawal

Percentage

0

40

80

120

160

200

Number

Percentage of cohort withdrawn Number of NMEs approved in calendar years

Safety-based NME

withdrawals

The record of

withdrawal of drugs

approved in recent years

compares favorably to

previous periods when

we were criticized for

taking too long to review

drug applications.

Nonetheless, the

increased number of

drugs and the large

number of patients

taking multiple drugs

have created the

potential for more drug

safety problems.

We are exploring these

issues in a systematic

manner with our

partners in industry,

academia, state and local
28

CDER 1999 Report to the Nation

Manufacturing plant inspections

FDA field offices conduct inspections of plants that manufacture, test,

package and label drugs. There are more than 18,000 of these plants in the

United States. Before a drug is approved, FDA investigators must

determine if data submitted in the firm’s application are authentic and if the

plant is in compliance with good manufacturing practices. After a drug is

approved, FDA conducts an inspection to make sure a firm can

consistently manufacture the product. Finally, routine inspections evaluate

the firm’s entire operations.

 Preapproval inspections. During fiscal year 1999, FDA evaluated 773

domestic plants in support of new drug applications. No user fee goals

were missed. Also, FDA evaluated 1,775 domestic firms in support of

generic drug applications.

 Postapproval inspections. There were 1,844 good manufacturing

practice inspections, and these resulted in 103 warning letters. We

reviewed 34 of these letters before they were issued, and the remaining

69 were issued directly by the field. We also reviewed 44 field

recommendations for regulatory action and approved 30. These

included two injunctions, 20 seizures and eight warning letters. We

reviewed more than 200 foreign establishment inspection reports.

These reviews resulted in six warning letters and two import alerts.

Import alerts prevent violative foreign drug products from entering the

United States.

Reporting systems for drug quality problems

Two important tools help us rapidly identify significant health hazards

associated with the manufacturing and packaging of drugs:

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

significant problems they discover that may represent safety hazards

for their marketed drug products. Last fiscal year, our review of these

reports resulted in 60 drug product recalls, 15 voluntary corrective

actions, two products withdrawn from the market and 12 products

discontinued.

 Drug Quality Reporting System. We analyze voluntary reports on drug

product quality problems submitted by health care practitioners through

MedWatch and other systems. We maintain these reports in a central

database to aid in detecting problem areas and identify trends requiring

regulatory action. Last fiscal year, our review of more than 2,000 of

these voluntary reports resulted in nine recalls and 29 corrective

actions.

Drug shortages

We attempt to prevent or

alleviate shortages of

medically necessary

drugs. We coordinated

responses to 10 drug

shortage situations in

fiscal year 1999. These

efforts assured the

availability of necessary

drug products for the

treatment several serious

and life-threatening

diseases, such as

myasthenia gravis,

tuberculosis, AIDS and

cancer.
Improving Public Health Through Human Drugs

29

Surveillance sampling of drugs

The Drug Quality Surveillance Sampling Program helps determine the

quality of imported and domestic drugs distributed in the United States.

Samples of drug products are tested for conformance with quality

specifications to ensure that the nation’s drug supply is safe and effective

and to provide rapid identification of emerging problems.

We have intensified surveillance of imported drug products because of the

increased number of imports.

During fiscal year 1999, we surveyed 56 drug products. The analysis of

216 samples was complete as of May 1, 2000. Twenty samples failed

various quality specifications including impurity tests, dissolution

requirements, net content and the limit for free salicylic acid. Although

investigational follow-up is in-process for some samples, compliance

achievements to date include packaging and manufacturing revisions and

other recommendations.

Unsubstantiated claims, fraudulent and hazardous products

We encounter many products that are vitamins, minerals, amino acids and

herbal preparations with labeled drug claims. These products may be

labeled as dietary supplements but make claims that they are safe and

effective for the prevention, treatment or cure of such diseases as AIDS or

cancer. Because these claims are unsubstantiated, they could present a

health hazard when consumers delay or avoid seeking appropriate medical

care.

 We take enforcement action when these products are likely to cause

serious injury.

 We identify fraudulent or hazardous drug products and assist in

developing enforcement strategies involving counterfeit drugs.

Sampling criteria

We chose drugs for the

sampling program based

on the following criteria:

 New molecular

entities.

 Drugs with

dissolution issues.

 Highly active drugs

that have effects in low

doses.

 Drugs with a history

of quality problems, field

alerts or recalls.

 Suspected counterfeit

drugs.

Party drugs seized

The so-called “party

drugs” GHB (gammahydroxybutyrate), GBL

(gamma-butyrolactone)

and 1-4 butanediol are

examples of ingredients

that have been promoted

for illicit activities

including date rape.

We have seized dietary

supplements and other

products that contain

these ingredients because

they pose a significant

risk of injury or death.
30

CDER 1999 Report to the Nation

3

INTERNATIONAL

ACTIVITIES

International Conference on Harmonization

Harmonization—making the drug regulatory processes more efficient and

uniform—is an issue that is important not only to Americans, but to drug

regulatory agencies and pharmaceutical companies throughout the world.

The International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use (ICH)

has worked to bring together government regulators and drug industry

experts from innovator trade associations in the European Union, Japan

and the United States.

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

make new drugs available with minimum delays not only to American

consumers but also to patients in other parts of the world.

The drug regulatory systems in all three regions share the same

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

However, many time-consuming and expensive technical tests have 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. The ICH model applies the most

advanced scientific knowledge and coincides with our top priority of using

state-of-the art science as the basis for efficient and rigorous drug reviews.

Standard terminology

The ICH Medical Dictionary for Regulatory Activities supports the

classification, retrieval, presentation and communication of medical

information throughout a drug’s life cycle. It will be particularly important

in the electronic transmission of adverse event reporting, both in the preand postmarketing areas, as well as in the coding of clinical trial data. We

expect MedDRA to become the accepted standard for all regulatory

activities. The terminology serves a vital public health need: to facilitate the

collection, presentation and analysis of regulatory information on medical

products during clinical and scientific reviews and marketing.

Common Technical Document

An important goal of harmonization is to define a standardized format for

submitting information about a new drug. Our objective is to reach

agreement on an information package of technical data, in the same format

and with the same content, that would be submitted to drug review

Mission

We participate through

appropriate processes

with representatives of

other countries to

reduce the burden of

regulation, harmonize

regulatory requirements

and achieve appropriate

reciprocal

arrangements.

Four areas of focus

The ICH areas of

harmonization are

efficacy, safety, quality

and regulatory

communications. These

terms are used

somewhat differently

than similar American

terms.

 Efficacy refers to

what we know as clinical

safety and efficacy.

 Safety refers to

preclinical safety testing.

 Quality refers to our

terms for production

control or good

manufacturing practices.

 Regulatory

communications focuses

on medical terminology

and standards for the

electronic transmission

of regulatory

information and data.

Mansfield

fellowships

Two of our scientists

have received two-year

fellowships from The

Mansfield Center for

Pacific Affairs. The

fellowships involve one

year of Japanese

language and area

studies training and a

second year in Japan

working with drug

regulators in the

Japanese government.
Improving Public Health Through Human Drugs

31

authorities in all three ICH regions. The project is well on target with a

final document expected in November 2000. Work on making the

Common Technical Document suitable for electronic submission will take

about six months longer.

Second phase launched

The ICH has embarked on a second phase of activities and agreed to

broaden representation to other parties. The second phase of harmonization

will have implications for already marketed drugs, over-the-counter drugs

and generic equivalents. To keep pace with scientific advances, several

guidances are being revised or considered for revision.

U.S.-European Union Mutual Recognition Agreement

This agreement provides for reciprocal reliance on inspection systems in

the United States and the 15 member nations of the European Union. The

globalization of the pharmaceutical industry is outpacing our resources to

inspect pharmaceutical manufacturing plants worldwide. Once fully

implemented, the agreement will allow us to base our regulatory decisions

on inspection data from “equivalent authorities” in the European Union.

Equivalent authorities are those have regulatory systems for good

manufacturing practices that we assess and determine will achieve a

comparable level of public health protection.

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

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

decision will be up to us. Last year marked the first year of a three-year

transition period to implementation. Our experts in good manufacturing

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

European Union to implement this agreement. We held a public meeting in

December to advise our stakeholders about progress on the agreement.

The 5-step ICH

process

1. An expert working

group develops a draft

guidance.

2. We obtain comments

from citizens, industry,

academia and others.

3. The regulatory

members of the expert

working group revise the

draft based on

comments received and

pass it on to the ICH

steering committee.

4. The steering

committee approves the

guidance and hands it

over to the regional

regulatory authorities.

5. The regulatory

authorities implement

the guidance in their

regions according to

their own national

procedures. In this

country, we follow good

guidance practices,

publish the guidances in

the Federal Register and

post them on our Web

site.

Internet sources

We publish the ICH

documents as guidances

to industry. These can be

found on our Internet

site at: http://

www.fda.gov/cder/

guidance/index.htm.

More information about

ICH activities can be

found on the World

Wide Web at: http://

www.ifpma.org/

ich1.html.

The Mutual Recognition

Agreement can be found

on FDA’s Website at

http://www.iep.doc.gov/

mra/mra.htm and at the

European Union’s

Website at http://

dg3.eudra.org/.

Information about the

most recent public

meeting can be found at

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

homepage.htm.

Harmonization Topics

23 22 9 10

20 36 35

4

0

10

20

30

40

50

1993 1995 1997 1999

Biannual Status

Number of Topics

Topics in Development (Steps 1, 2, 3) Finalized Topics (Steps 4, 5)
32

CDER 1999 Report to the Nation

4

COMMUNICATIONS

Public Participation

We participated in the FDA program of public meetings with our

stakeholders. Top issues that emerged included risk management, drug

safety, direct-to-consumer advertising and of our processes. We received

valuable input from consumer groups, professional societies, industry and

trade association on these issues. A number of groups expressed a

willingness to partner with us in meeting our objectives, especially in the

area of providing information to consumers and health care professionals.

Many of these issues will involve us in an on-going dialogue with our

stakeholders as we seek consensus on directions and priorities.

We confer with panels of outside experts about difficult scientific issues.

These advisory committees met almost weekly last year, and we assure that

patient representatives are included on committees considering medicines

for HIV, AIDS, cancer and other serious disorders. In addition to analyzing

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

comments on our nonbinding guidances to industry.

Consumer and Industry Outreach Efforts

We use a number of modern communication methods to reach our

stakeholders including making information available on the Internet;

leveraging with consumer and patient groups to publish brochures; using

videoconferencing and satellite television broadcasting; disseminating

information about new and existing medicines; and making public service

announcements available to print and broadcast media. Highlights of these

activities include:

 Warning consumers about the dangers of products and dietary

supplements that contain the party drug GHB and related substances.

We issued warning flyers and posters to more than 2,500 health and

fitness organizations, health care associations, amateur and professional

sports organizations and health care publications.

 Surveying and auditing the pharmaceutical industry to assess their

readiness for the year 2000 transition. To help Americans prepare for

YK2, we developed an education campaign designed to alleviate the

concerns of consumers, health care professionals and other special

populations about drug product shortages. The campaign discussed the

steps drug manufacturers had taken to assure a sufficient supply of drug

products to meet demand. Messages were channeled through radio,

newspapers, magazines, brochures and FDA’s Website.

 Responding to more than 1,250 telephone and e-mail requests from

Stakeholders in

drug development

and review

We work closely with

many organizations

during the drug

development and review

process:

 Industry and trade

associations

 Consumers and

consumer groups

 Universities, hospitals

and health care

professionals

 Patients, families,

care-givers and patient

groups

 Federal, state and

local government

agencies

 Foreign governments

Mission

Carry out our mission

in consultation with

experts in science,

medicine and public

health and in

cooperation with

consumers, users,

manufacturers,

importers, packers,

distributors and

retailers of human

drugs.

Consumer

information

The FDA

Modernization Act

requires us “to

maximize the

availability and clarity

of information for

consumers and patients

concerning new

products.”
Improving Public Health Through Human Drugs

33

specialized media that concentrates on the pharmaceutical industry.

This was a 25 percent increase from the previous year.

 Completing successful showings our exhibit and information program

at 13 national health care conferences and meetings, nearly double last

year’s number.

 Conducting about 100 domestic and foreign videoconferences for

academia, industry and associations, about the same as last year.

OTC drug labeling campaign

We developed and executed the first phase of a public service campaign

designed to promote awareness and understanding of the new over-thecounter drug labels. We explained the format the new labels and their

benefits for making informed decisions.

We developed and produced two black-and-white print public service

announcements, two radio PSAs, five live-read radio scripts and an exhibit

display. The PSAs were distributed to more than 200 nationwide

publications, more than 10,000 newspapers, 6,000 radio stations and 1,000

television stations. Results from the campaign indicate:

 The radio PSAs were played more than 25,300 times, reaching a total of

more than 135 million listeners and amassing more than $1.3 million

worth of free air time.

 The print PSA appeared in more than 1,000 newspapers across the

country and in Time, Women’s Day, Family Circle and other national

magazines.

Average Monthly Use of CDER Internet Site

226,000

156,000

72,000

32,000

0.5

1.3

2.5

3.1

0

125,000

250,000

1996 1997 1998 1999

Calendar Year

Number of Visitors

0

2

4

Hits (millions)

Average Monthly Visitors Average Monthly Hits (millions)
34

CDER 1999 Report to the Nation

Dissemination Activities

We provide the most current information FDA-regulated drug products and

our processes, policies and regulations in a timely and accurate manner.

 We updated From Test Tube to Patient: Improving Health through

Human Drugs, a popular FDA publication for consumers that describes

new drug development in the United States and highlights our

consumer protection role. The publication consolidates accurate and

timely data about the drug development and review process in an easyto-understand format. The report has been requested by more than

5,000 individuals and is responsible for a large number of Internet

“hits.”

 In conjunction with a nonprofit industry information association, we

conducted three two-hour satellite television broadcasts for industry

called “CDER Live!” Our scientific and regulatory experts engaged in

a panel discussion about electronic submissions, user fees, risk

management, product quality, drug safety and other topical issues in

drug development and manufacturing. Each show is broadcast to about

50 sites across the country. About 5,000 industry executives, scientists

and managers view each telecast.

 Our visible presence on the World Wide Web led to an increase in the

number of general information requests by electronic mail from

consumers, patients and health care professionals. We responded to

more than 18,200 e-mail requests last year, triple the number from the

previous year.

 In addition, we answered nearly 21,000 telephone inquiries, 4,000

faxes and 2,100 written requests from consumers, pharmacists, doctors,

nurses, pharmaceutical and insurance companies, government agencies

and others. Finally, we responded to more than 9,500 requests for

documents and guidance publications..

 We developed consumer-friendly, Web-based fact sheets about new

molecular entities. The fact sheets outline the products’ labeling,

approval dates, uses, possible side-effects, directions for use, any

warnings and other information. In addition, we wrote 33 consumer

information sheets about various drug topics.

Ombudsman’s

activity

In its fourth year of

operations CDER’s

Ombudsman’s Office

handled a number of

activities designed to

settle situations among

employees, the Center,

health professionals and

consumers.

The office handled about

80 complaints.

It answered:

 More than 500

e-mails, mostly from

consumers and health

professionals.

 Approximately 2,000

telephone calls and 20

letters.

In addition, the office

held about 50 meetings

with external parties.
Office of the Center Director (HFD-1)

Janet Woodcock, M.D.

301-594-5400

Deputy Center Director for Review Management (HFD-2)

Murray Lumpkin, M.D.

301-594-5400

Deputy Center Director for Pharmaceutical Science (HFD-03)

Helen N. Winkle (Actg)

301-594-2847

Office of Training and

Communications (HFD-200)

Nancy Smith, Ph.D.

301-827-1651

Div. of Training and Development

Div. of Communications Management

Div. of Library and Info. Services

CENTER FOR DRUG EVALUATION AND RESEARCH

AS OF: 04/26/00

Associate Director for PolicyJane Axelrad

Ombudsman -

James Morrison

Executive Operations Staff -

Deborah Henderson

EEO Staff -

Margaret Bell

Office of Compliance

(HFD-300)

John Taylor (Actg)

301-594-0054

Div. of Labeling and Nonprescription

Drug Compliance

Div. of Prescription Drug Compliance

and Surveillance

Div. of Manufacturing and Product

Quality

Office of Review Management (HFD-20) Office of Pharmaceutical Science (HFD-350)

Regulatory Policy

Staff - Dave Read &

Virginia Beakes

Office of Information

Technology (HFD-070)

Ralph Lillie

301-827-6240

Quality Assurance Staff

Technology Support Services Staff

Div. of Applications Development Services

Div. of Data Management and Services

Div. of Infrastructure Management and Services

Office of Management

(HFD-10)

Russell Abbott

301-594-6741

Div. of Management and Budget

Div. of Management Services

Strategic Planning Staff

Office of New Drug Chemistry

(HFD-800)

Yuan-yuan Chiu, Ph.D.

301-827-5918

Div. of New Drug Chemistry I

Div. of New Drug Chemistry II

Ofc. of Clini. Pharm. and

Biopharmaceutics (HFD-850)

Larry Lesko, Ph.D.

301-594-5690

Office of Testing and

Research (HFD-900)

James T. MacGregor, Ph.D.

301-827-5917

Laboratory of Clinical

Pharmacology

Div. of Applied

Pharmacology Research

Div. of Product Quality

Research

Microbiology Team

Div. of New Drug Chemistry III

Pharmacometrics Staff

Div. of Pharmaceutical Evaluation I

Div. of Pharmaceutical Evaluation II

Div. of Pharmaceutical Evaluation III

Office of Generic Drugs

(HFD-600)

Gary Buehler (Actg)

301-827-5845

Div. of Chemistry I

Div. of Chemistry II

Div. of Bioequivalence

Div. of Labeling and Program

Support

Div. of Pharmaceutical Analysis

Regulatory Research

Analysis Staff

Office of Drug Evaluation II

(HFD-102)

John Jenkins, M.D.

301-827-5920

Div. of Metabolic and Endocrine

Drug Products

Div. of Pulmonary Drug Products

Office of Drug Evaluation IV

(HFD-104)

Diane Murphy, M.D.

301-827-2350

Div. of Anti-Infective Drug Products

Div. of Anti-Viral Drug Products

Office of Drug Evaluation I

(HFD-101)

Robert Temple, M.D.

301-594-6758

Div. of Neuropharmacological

Drug Products

Div. of Oncology Drug Products

Div. of Cardio-Renal Drug roducts

Office of Drug Evaluation III

(HFD-103)

Florence Houn, M.D.

301-827-3144

Div. of Gastro-Intestinal and

Coagulation Drug Products

Div. of Reproductive and

Urologic Drug Products

Div. of Medical Imaging and

Radiopharmaceutical Drug Products

Office of Drug Evaluation V

(HFD-105)

Robert DeLap, M.D.

301-827-2250

Div. of Anti-Inflammatory, Analgesic, and

Ophthalmologic Drug Products

Div. of Dermatologic and Dental Drug

Products

Div. of Over-The-Counter Drug Products

Office of Biostatistics (HFD-700)

Robert O’Neill, Ph.D.

301-827-3195

Quantitative Methods Research Staff

Div. of Biometrics I

Div. of Biometrics II

Div. of Biometrics III

Div. of Anesthetic, Critical Care,

and Addiction Drug Products

Div. of Special Pathogen and

Immunologic Drug Products

Office of Post-Marketing Drug

Risk Assessment (HFD-400)

Peter Honig, M.D.

301-827-3219

Div. of Drug Risk Evaluation I

Div. of Drug Risk Evaluation II

Information Technology Staff

Extramural Program Staff

Advisors and Consultants Staff

Pharmacology/Toxicology Staff

Program Management Team

Reports and Data Management Team

Product Quality Support

Staff

Operations Staff

Office of Medical Policy

(HFD-04)

Robert Temple, M.D.

301-594-6758

Div. Scientific Investigations

Div. of Drug Marketing,

Advertising and Communication

Project Management Program Staff

Medwatch Staff

Div. of Freedom of Information

Microbiology Team

Div. of New Drug Chemistry III
36

CDER 1999 Report to the Nation

WHERE TO FIND

MORE INFORMATION

Selected Internet sites

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

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

 MedWatch safety information and to report serious adverse events:

http://www.fda.gov/medwatch/

 CDER’s consumer drug information sheets for new medicines

approved since January 1998:

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

 FDA Modernization Act of 1997 CDER-related documents:

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

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

States:

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

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

Telephone

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

generic drugs for human use. You can telephone us toll free at 1-888-INFO

FDA or directly at 301-827-4573.

E-mail

We can be contacted at DRUGINFO@CDER.FDA.GOV.

Regular mail

U.S. Food and Drug Administration

Center for Drug Evaluation and Research

Drug Information Branch

HFD-210, Room 12B-31

5600 Fishers Lane

Rockville, MD 20857
Report to the Nation

1999

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research

RAPED MT

ENT OF HEALTH

& HUMAN SERVICES • USA

Improving

Public Health

Through

Human Drugs

Center for Drug Evaluation and Research