Postmarketing Surveillance of Prescription

Drugs

November 1982

NTIS order #PB83-173625
Library of Congress Catalog Card Number 82-600652

For sale by the Superintendent of Documents,

U.S. Government Printing Office, Washington, D.C. 20402
Foreword

Before a drug can be prescribed for use in the United States, it must meet minimum

statutory requirements for proof of its efficacy and safety as these have been established

by the U.S. Food and Drug Administration (FDA). In premarketing testing, the numbers

and types of patients exposed to a drug are necessarily limited compared with the numbers

and types of patients who will eventually be prescribed the drug after it is marketed.

New uses, contraindications, and side effects of drugs will then inevitably be discovered.

Thus, various kinds of postmarketing surveillance have been proposed over the past

decade.

A background paper on postmarketing surveillance of prescription drugs was originally being prepared by the Office of Technology Assessment for the project on strategies

for medical technology assessment, as requested by the House Committee on Energy

and Commerce and its Subcommittee on Health and the Environment. At the further

request of that committee and its subcommittee, that background paper was expanded

into this full report, Postmarketing Surveillance of Prescription Drugs.

Current interest in drug regulation is also focused on the premarketing approval

process, because the process has been criticized as unnecessarily delaying the release

of valuable drugs in this country. As a result of such criticism, efforts are underway

to shorten the approval process through administrative changes within FDA’s Office

of Drugs, and through revisions of the regulatory interpretations of the statutory requirements for “adequate tests” of a drug’s safety and “substantial evidence” of its effectiveness.

This report describes the drug approval process, the history and objectives of postmarketing surveillance, the methods employed to accomplish it, and current activities

in postmarketing surveillance. The report provides guidelines to determine whether

shortening the drug approval process by various means would diminish its ability to

detect adverse drug reactions prior to a drug’s release for marketing. The report also

identifies oversight issues and options for increased postmarketing surveillance both

in the case that Congress decides to relax premarket approval requirements and in the

case that it does not.

Director

,.. ///
Health Program Advisory

Michael

Stuart H. Altman

Florence Heller School

Brandeis University

Waltham, Mass.

Kurt Deuschle

Mount Sinai School of Medicine

New York, N.Y.

Carroll Estes*

School of Nursing

University of California

San Francisco, Calif.

Rashi Fein

Committee

Sidney S. Lee, Chair

Reese Hospital and Medical Center

Chicago, Ill.

C. Frederick Mosteller

Department of Health Policy and

Management

School of Public Health

Harvard University

Boston, Mass.

Mitchell Rabkin

Beth Israel Hospital

Boston, Mass.

Dorothy P. Rice*

Department of Social and

Behavioral Sciences

School of Nursing

Center for Community Health and

Medical Care

Harvard Medical School

Boston, Mass.

Melvin A. Glasser

Committee for National Health Insurance

Washington, D.C.

Patricia King

Georgetown Law Center

Washington, D.C.

Joyce C. Lashof

School of Public Health

University of California

Berkeley, Calif.

Mark Lepper

Rush-Presbyterian-St. Luke’s Medical Center

Chicago, Ill.

Margaret Mahoney

The Commonwealth Fund

New York, N.Y.

University of California

San Francisco, Calif.

Richard K. Riegelman’

School of Medicine

George Washington University

Washington, D.C.

Walter L. Robb*

Medical Systems Operations

General Electric

Milwaukee, Wis.

Frederick C. Robbins

Institute of Medicine

Washington, D.C.

Rosemary Stevens

Department of History and Sociology

of Science

University of Pennsylvania

Philadelphia, Pa.

Kerr L. White

Rockefeller Foundation

New York, N.Y.

‘Appotnted summer of 1982

iv
OTA Postmarketing Surveillance of Prescription Drugs Project Staff

H. David Banta, Assistant Director, OTA

Health and Life Sciences Division

Clyde J. Behney, Health Program Manager

Lawrence H. Miike, Project Director

Kerry Britten Kemp, Editor

Mary E. Harvey, Secretary

Pamela J. Simerly, Secretary

Virginia Cwalina, Administrative Assistant

contractor

Renée G. Ford

OTA Publishing Staff

John C. Holmes, Publishing Officer

John Bergling Kathie S. Boss Debra M. Datcher Joe Henson

Doreen Cullen Donna Young
Contents

Chapter Page

Glossary of Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

The Drug Approval Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

History and Objectives of Postmarketing Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Methods of Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Issues and Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2. THE DRUG APPROVAL PROCESS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Notice of Claimed Investigation for a New Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

IND Application Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Compassionate or Treatment ID. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

The New Drug Application Process ...,...,...,,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Abbreviated New Drug Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Requirements Following Approval .,....,...,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

3. HISTORY AND OBJECTIVES OF POSTMARKETING SURVEILLANCE . . . . . . . 23

4. METHODS OF DRUG EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Types of Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Detection and Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Case Studies in Drug Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

5. CURRENT ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

6. ISSUES AND OPTIONS . . . . . . . . . . . . . . . . . . . . . . . . . ! . . . . . . . . . . . . . . . . . . . . . . . . . 49

Appendixes Page

A. Selected Excerpts From the Statutes Governing Drugs and Medical Devices . . . . . . . 57

B. Conclusions and Recommendations of the Joint Commission on Prescription

Drug Use, Jan.23, 1980 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

List of Tables

Table No. Page

1. Guidelines for Duration of Animal Toxicity Studies for Oral and

Parental Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2. Studies Required in FDA’s Premarketing Drug Approval Process..,.. . . . . . . . . . . . . 15

3. FDA’s Drug Classification System ....,.....,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4. Percentage of Reports of Suspected ADRs in Great Britain by Class of Reporter

and Method Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

5. Likelihood of Observing an ADR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

6. Number of Patients Required To Detect One, Two, or Three ADRs With No

Background Incidence of Adverse Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

7. Number of Patients Required in Drug-Treated Group To Detect One ADR With

Background Incidence of Adverse Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

vii
8. Number of Patients Required in Drug-Treated Group To Allow for Examination

of 100 Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

9. Potential Uses by FDA of Medicaid Data From Michigan and Minnesota . . . . . . . . . 43

10. Data Sources Available to FDA for Estimating Actual Populations of Drug Users.. 43

11. Number and Percentage of FDA’s Adverse Event Reports by Source, 1972-78 . . . . . 45

Figures

Figure No. Page

I. Yellow Card Report Form Used in Great Britain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

2. Comparison of Additional Drug-Induced Effects of Decreasing Incidences . . . . . . . . . . 35

3. Drug Experience/Epidemiologic Sources Available to FDA for Postmarketing

Surveillance and Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

. . Vlll
Glossary of Acronyms

ADAMHA

ANDA

ADR

CDC

CDS

CFR

DEA

DES

DHHS

DRA

ETIP

FDA

HMO

IND

Alcohol, Drug Abuse, and Mental

Health Administration (PHS)

abbreviated new drug application

adverse drug reaction

Centers for Disease Control

Center for Drug Surveillance

Code of Federal Regulations

Drug Enforcement Agency

diethylstilbestrol

Department of Health and Human

Services

drug regulatory authority

Experimental Technology Incentives

Program (NBS)

Food and Drug Administration

health maintenance organization

investigational new drug

NBS

NCHS

NCI

NDA

NIDA

NIH

NHLBI

PHS

PMS

SOAR

U.S.C.

WHO

National Bureau of Standards

(Department of Commerce)

National Center for Health Statistics

(DHHS)

National Cancer Institute (NIH)

new drug application

National Institute on Drug Abuse

(ADAMHA)

National Institutes of Health (DHHSI

National Heart, Lung, and Blood

Institute (NIH)

Public Health Service (DHHS)

postmarketing surveillance

screening of adverse reactions

(method)

United States Code

World Health Organization

ix
Summary
Summary

INTRODUCTION

To market a drug, the manufacturer must provide evidence of its efficacy and safety to the U.S.

Food and Drug Administration (FDA). Once these

premarketing requirements are met and the drug

has been released, FDA can remove a drug from

the market—after giving due notice and an opportunity for a hearing—because of new evidence on

the drug’s efficacy and safety, the discovery that

the drug was approved on the basis of any untrue statement of a material fact, or the failure

of the drug to meet manufacturing standards. In

cases where a drug may be an “imminent hazard

to the public health, ” FDA can suspend the drug’s

approval immediately, giving prompt notice of

the action and offering the opportunity for an expedited hearing.

In premarketing testing, the numbers and types

of patients used to demonstrate a drug’s efficacy

and safety are limited compared with the numbers

and types of patients who will eventually be prescribed the drug after it is marketed. The initial

decision to approve a drug for use, however, must

be made on the basis of the available knowledge.

Although postmarketing surveillance cannot

provide knowledge of the safety or efficacy of

drugs at the time of their introduction on the market, various kinds of postmarketing surveillance

have been proposed over the past decade to monitor and aid in modifying the use of drugs. The

principal focus of postmarketing surveillance proposals has been on the safe use of prescription

drugs, even though the range of issues has encompassed both efficacy and safety considerations,

e.g., concern over refinements in use as well as

better definition of drug risks.

Current interest in prescription drug evaluation

and monitoring is focused on the premarketing

approval process and the length of time it takes

for a drug to be approved by FDA; postmarketing

surveillance appears to have waned as a policy

issue. Thus, policy formulation and implementation for the premarketing approval process is being pursued without parallel efforts for the postmarketing period.

However, postmarketing surveillance deserves

attention as a policy issue for both short- and

long-term objectives. Regarding short-term action, if current testing requirements for the premarketing approval process are reduced, pharmaceutical manufacturers could be required to maintain their drug evaluation responsibilities by increasing postmarketing surveillance. Regarding

long-term action, postmarketing surveillance remains a policy issue irrespective of current interest

in the premarketing approval process: it is only

after marketing that a drug’s full therapeutic and

harmful potentials can be determined.

One way to shorten the premarketing period

of the drug approval process would be by reinterpreting the regulations for assessing safety and efficacy. This report provides theoretical and experiential criteria for evaluating how such changes

may affect the ability of current guidelines to

detect a drug’s harmful and beneficial effects. It

also discusses the kinds of qualitative changes in

the evidence required for drug approval that FDA

is implementing. Finally, the report identifies options relating to FDA’s postmarketing surveillance. These options could be implemented regardless of whether there is a change in current

premarketing drug approval requirements.

3
4 . Postmarketlng surveillance of Prescription Drugs

THE DRUG APPROVAL PROCESS

A drug’s sponsor must provide: 1) “adequate

tests by all methods reasonably applicable to show

whether or not such drug is safe for use under the

conditions prescribed, recommended, or suggested;” and 2) “substantial evidence that the drug

will have the effect it purports or is represented

to have” (2 I U. S. C., sec. 355 (d)). This statutory

language has led in practice to FDA’s establishing

a premarketing phase of drug testing that consists

of two parts: 1) the investigational new drug

(IND) application process, and 2) the filing of a

new drug application (NDA).

The IND application describes the investigators’

qualifications and the planned clinical trials, the

chemical composition of the drug, and data on

the pharmacology and toxicology of the new drug

collected in animal studies and in prior human

studies, if any, such as those conducted in other

countries.

The clinical investigations in the IND process

are divided into three phases (24):

Phase I: Clinical Pharmacology is that phase

in which a drug is first used on humans to

confirm dose ranges and pharmacologic effect. The number of subjects in phase I varies

depending on the drug, but is usually in the

range of 20 to 80 (excluding control patients).

Pharmacodynamic and metabolic studies, in

whichever stage of investigation they are performed, are considered to be phase I clinical

pharmacologic studies.

Phase II: Clinical Investigation consists of

controlled clinical trials to demonstrate a

drug’s effectiveness and relative safety. These

are performed on closely monitored patients

of limited number, usually 100 to 200 patients, with equal numbers of control patients.

Phase 111: Clinical Trials are expanded controlled and uncontrolled trials to gather additional evidence of a drug’s effectiveness for

specific indications and to more precisely

define its adverse effects. Phase 111 studies

observe a total of 500 to 3,000 patients in

more natural settings—in clinics, outpatient

hospital facilities, and private practice. Phase

111 usually consists of more than two controlled trials.

After completion of the testing required under

the IND application, the sponsor may file an

NDA. At least two well-controlled studies establishing each indication for which the drug is intended are required. More than one indication can

be established in a single study. (These requirements are under review; see chs. 3 and 6.)

All INDs are classified by chemical type and

therapeutic potential, so that those drugs considered by FDA to be of particular therapeutic importance can receive priority review. The highest

classification is given to drugs that are new molecular entities (type 1) and that may represent important therapeutic gains (type A)—type 1A

drugs.

Several mechanisms are available to FDA to obtain information about drugs once they have been

approved for marketing. Once the NDA has been

approved, the sponsor is required to monitor information and submit reports about the drug.

Other information on adverse drug reactions

(ADRs) is monitored by FDA in a number of

ways:

●

●

●

●

●

●

the Spontaneous Reaction Reporting Program, in which information on ADRs is sent

to FDA by physicians, pharmacists, and hospitals;

a monthly review of the medical literature

on ADRs (reports and letters to the editors

of medical journals, etc.);

intensive surveillance and epidemiologic

studies of ADRs in selected hospitalized and

ambulatory populations;

several specialized registries that collect and

analyze possible ADRs;

in-house monitoring and research studies of

such data bases as those of the Medicaid

Medical Information Systems of some States

and those of commercial sources of drug use

data; and

the World Health Organization, which exchanges reports with FDA, each summarizing the ADRs added to their systems in the

previous year.
——

Ch. l—Summary ● 5 ——————. . — ——— . —— —

This postmarketing information is useful for answered by the phase 111 studies, but which dc~

two purposes. First, it may provide the grounds not warrant delaying the release of what promises

for FDA to remove a drug from the market, when to be a useful new product (24). Although FDA

such action is appropriate. Second, it is used by has no explicit authority to require such studies,

FDA to ensure that limits are placed on advertis- these “phase IV” studies are almost always pering and promotional claims and that the drug’s formed, as the alternative would be nonapproval

labeling is appropriate. of the drug.

FDA may request further studies when there are

questions about a drug that were not sufficiently

HISTORY AND OBJECTIVES OF POSTMARKETING SURVEILLANCE

As a result of 1974 hearings before the Senate

Committee on Labor and Human Resources’ Subcommittee on Health, the Department of Health,

Education, and Welfare formed a Review Panel

on New Drug Regulation. The panel issued its

report in May 1977 (16).

A bill was subsequently introduced in the Senate in early 1978 to revise the drug provisions of

the Food, Drug, and Cosmetic Act. A revised bill,

S. 1075, the Drug Regulation Reform Act of 1979,

passed the Senate in September 1979. A similar

bill, H.R. 4258, was not acted on by the House

of Representatives. Included in the Senate bill

were the following specifications: 1) drug sponsors could be required to conduct postmarketing

surveillance of a drug for up to 5 years; 2 ) a

prescription drug could have its distribution

limited if the drug could not otherwise be found

to be safe and effective; 3) the standard for a

drug’s immediate removal from the market would

be changed from the drug being an “imminent

hazard to the public health” to the less stringent

standard of “unreasonable risk of illness or injury

to any segment of the population;” and 4)

establishment of a “National Center for Drug

Science. ”

During this period, in a speech to the Pharmaceutical Manufacturers Association, Senator Edward Kennedy (D-Mass. ) suggested that a better

system was needed for monitoring the use and effects of prescription drugs after they were marketed. As a result, the Joint Commission on Prescription Drug Use was established in 1976,

funded largely by the drug industry, with the

mandate to design a postmarketing surveillance

system to detect, quantify, and describe the anticipated and unanticipated effects of marketed

drugs, and to recommend a means by which information on the epidemiology of prescription

drug use in the United States could be distributed

regularly to interested parties. The Joint Commission issued its report in January 1980 (42), but by

this time, interest in postmarketing surveillance

had waned, and the commission’s report and recommendations were little noticed.

In 1976, the year in which the Joint Commission was formed, an interagency agreement was

signed between FDA and the Experimental Technology Incentives Program (ETIP) of the National

Bureau of Standards in the Department of Commerce. The purpose of ETIP was to provide incentives or reduce barriers to technological innovation through changes in the regulatory process.

ETIP’s agreement with FDA was to jointly fund

a program to determine if improvement in postmarketing surveillance could help reduce the

regulatory requirements of the premarketin~

period, principally those of phase III of the IND

process and those of the NDA process. The specific experiment was to develop postmarketing

surveillance systems and a method of managing

and evaluating the reform (11). The project concentrated on collecting the information required

to design these systems (12). By 1982, FDA had

assumed most of the funding, as ETIP was to be

phased out that year.

A Commission on the Federal Drug Approval

Process was convened in mid-1981 to examine

how FDA’s procedures for the approval of new

drugs could be expedited without compromising
6 ● Postmarketing Surveillance of Prescription Drugs — — —

public safety and to make recommendations on

the development of cost-effective postmarketing

surveillance to guarantee the quick withdrawal

from the market of drugs that cause significant

adverse effects. The commission had its genesis

in a joint hearing held in April 1981 by the House

Science and Technology Committee’s Subcommittee on Natural Resources, Agriculture Research,

and Environment and its Subcommittee on Investigations and Oversight. The first meeting was

held in July 1981. The commission completed its

work and announced its general findings in the

spring of 1982, and its printed report was to be

released in late 1982.

FDA is examining specific ways to speed up the

drug approval process. It is reviewing past phase

111 trials to see if longer trials or those with large

samples have contributed useful information beyond that obtained in phase 11 and early phase

III testing. Past postmarketing studies that FDA

required are also being reviewed to see if they provided the information that they were designed to

obtain. Data on FDA approval time are being reviewed to see what other factors may slow the

approval process. And, as a pilot test, an FDA

committee is reviewing the pharmacologic and

clinical data on selected drugs at the end of phase

11 testing, and will make recommendations about

the best time for gathering additional information

(e.g., phase III v. the postmarketing period) (11).

METHODS OF SURVEILLANCE

The primary objective of postmarketing studies

is to develop information about drug effects under

customary conditions of drug use. Initial clues

about a drug’s potential effects come from the experimental studies carried out with both animals

and humans in the premarketing period. Spontaneous or voluntary reporting (e. g., in letters to

the editors of medical journals) is the oldest, and

to date, the most productive source of new information about a drug’s possible effects once a

drug is marketed. Other types of studies are used

to examine in more detail the possible effects of

a drug. In general, these other types of studies use

either cohort or case-control methods.

In March 1982, the FDA Commissioner began

a related organization by merging the Bureau of

Drugs with the Bureau of Biologics, and replacing the Director of the New Drug Evaluation Division. The merged bureaus have since been designated the National Center for Drugs and Biologics.

Finally, in a related development, the Senate

passed by a voice vote, in the first session of the

97th Congress, the Patent Term Restoration Act

of 1981 (S. 255). The bill would restore to the term

of a patent the time lost in complying with the

Government’s premarketing testing and review requirements, up to a maximum of 7 years, Patented

products eligible for extension would not be limited to human drugs, but would include “human

drugs and biological, antibiotic drugs, animal

drugs and biological, food additives, color additives, pesticides, other chemical substances,

medical devices, and any other product subject

to Federal premarket requirements” (72). In September 1982, the House of Representatives voted

on the bill under suspension of its rules. Under

such conditions, a two-thirds vote was required

for passage, and although the bill received a majority of the votes, it fell just short of the twothirds majority needed.

Thus, four types of studies are generally used

to identify drug effects: 1) controlled clinical trials,

2) spontaneous or voluntary reporting, 3) cohort

studies, and 4) case-control studies (23,50,61,77).

Controlled clinical trials match treatment and

control groups as closely as possible, minimize

bias through such methods as randomization and

“double-blinding,” and directly monitor patients

for the duration of the study. Controlled clinical

trials are considered the most definitive method

for evaluating a drug’s efficacy and safety, but

they are often costly or impractical in specific situations, for example, when a drug’s effects are
Ch. l—Summary ● 7

rare, or appear only after long-term use or a long

latency period.

Voluntary reporting by physicians and other

health providers, hospitals, and consumers may

act to alert FDA and pharmaceutical firms to possible adverse effects of drugs, so that the inference

of an association between a drug and an observed

health condition may be further studied by cumulative, careful reporting, and confirmed or disconfirmed by more vigorous methods. Underreporting may be a serious deficiency of this method.

A drug may also be erroneously associated with

an adverse effect until the suspected association

fails to show up in repeated, statistically validated

studies.

Cohort studies follow a defined group of patients (the cohort) for a period of time. In this

method, patients are not randomly assigned to

groups, and there is no blinding. Cohort studies

are usually prospective and observe the cohort

from the beginning of drug use. A group of patients taking the drug of interest is assembled and

followed to see, for example, if adverse reactions

occur. A second group of patients (the controls)

with the same medical condition, who are not taking the drug and who may be receiving alternative

treatment, but who are otherwise matched as

closely as possible with the cohort, may also be

studied in parallel. The control group is used to

identify the frequency of occurrence of any condition observed in the drug-exposed group which

is due to causes other than the drug (i. e., the

“background incidence” of the condition). In this

method, patients can be directly monitored to ensure they take the drug appropriately, and to

observe the drug’s effects; or monitoring can be

less controlled. With less control, a larger cohort

can be followed, but bias is thus increased.

Case-control studies identify patients with the

adverse effects to be studied (the cases), and compare them with a sample (the controls), drawn

from the same cohort that gave rise to the cases.

Controls are matched as closely as possible with

the cases, except with regard to the drug’s suspected adverse effect, to examine whether exposure to the drug is the cause. Patients with conditions suspected of being associated with a certain drug would have their medical records reviewed or be interviewed concerning the use of

that drug. The histories of the controls would also

be studied for information about drug use in the

general population. By comparing the proportion

of drug users among the cases with the proportion of drug users in the general population, it is

possible to infer the relative frequency with which

adverse reactions occur in users of certain drugs

as compared with nonusers. A sufficient number

of appropriate cases must be identified and accurate histories of exposure to drugs must be obtained.

Controlled clinical trials and prospective cohort

studies can be used to determine a drug’s beneficial

as well as adverse effects. Case-control studies are

usually used to trace adverse effects back to prior

drug use. Voluntary reporting can uncover additional uses of drugs as well as their adverse effects, but reporting of adverse effects is much

more common.

The ability of a particular surveillance method

to detect a drug’s effect depends on two factors:

1) the time that transpires between use of that drug

and the occurrence of the drug’s effect (the latency period), and 2) how often the effect occurs (its

frequency). There are many other determining

factors, such as accuracy of observation, and accuracy and completeness of medical records, but

these factors present more of a problem in the

design of a study’s details.

Controlled clinical trials, because of their relatively short duration, will detect only acute or

subacute effects. Long-term cohort studies can

detect delayed effects, but the data bases necessary

for such long-term, large studies are still sparse.

Voluntary reporting is usually the way in which

long-term effects are first identified. Long-term

effects are usually confirmed through retrospective case-control studies, but such studies’ reliance

on historical data such as medical records can limit

their accuracy.

The chance that a particular study will discover

a drug effect also depends on the study’s sample

size and the frequency of the drug effect, For example, in a cohort study, if a drug causes blindness in 1 out of every 100 users (1/100), how many

users must be observed to find one case of blind-
8 ● Postrnarketing Surveillance of Prescription Drugs

ness? If there are 1 million users of the drug, there

would be 10,000 users blinded. But in a small sample of only 100 users, the probability of finding

one or more cases of blindness would only be 63

percent. If the sample were 200 users, the probability of finding one or more cases would increase

to 86 percent. With a sample of 500, the probability would be 99 percent that at least one case

of blindness would be found in the observed users.

To state it another way, what number of users

would have to be observed to be 95 percent sure

of finding one or more cases of blindness when

they occur at a frequency of 1 in 100 users? The

answer is 300 users, and the general rule is that

the number of users in the sample must be three

times the reciprocal of the frequency; e.g., for a

frequency of 1 in 1,000, the sample would have

to be 3,000 to be 95 percent sure of observing at

least one case.

Except for some effects that are unique to a specific drug, many drug effects (e. g., stroke, bleeding, skin rashes) are indistinguishable from conditions due to other causes. The “background incidence” of a condition must be known before purported drug effects observed in a study can rightly

be attributed to a drug.

Larger sample sizes are needed to determine a

drug’s effect as the background incidence of a condition increases and as the frequency of a drug’s

contribution to a condition decreases. For example, given a background incidence of 1/100, as

the incidence of a drug’s added effect decreases

from 1/100 to 1/10,000, the sample size would

have to increase from 1,600 to 11 million to remain 95 percent sure of observing at least one case

of the added effect. The relationship between

ISSUES AND OPTIONS

Issue 1:

Revising premarketing tests and shortening the drug approval process.

The efficacy and safety tests in animals and humans specified in FDA regulations for premarketing approval are based on broad statutory language. Efforts to shorten the drug approval procbackground and added incidence is also revealed

in considering sample sizes at the extremes. For

a known background incidence of 1/1,000 and an

added incidence of 1/100, the sample size needed

to observe at least one case of the added effect

is only 500. But when the background incidence

is 1/10 and the added incidence is only 1/10,000,

the sample size must be 98 million. These illustrations merely indicate what sample size is required

to observe an effect when background incidence

is known.

Controlled clinical trials are used primarily for

evaluating drug efficacy, not safety, because they

are carried out on hundreds, or, at the most, a

few thousand drug users. Their use for evaluating

drugs already on the market is also limited by

their high cost and logistical problems. In fact,

the use of controlled clinical trials for determining efficacy alone is already constrained by these

two factors (9,46).

These limitations of controlled clinical trials in

evaluating the safety of marketed drugs have led

to relying on cohort and case-control methods for

postmarketing studies. While these latter methods

can only indicate an association between a drug

and observed conditions, not that the relation is

causal (49,77), the cumulative experience of multiple cohort and case-control studies showing consistent associations between a drug and such an

effect can lead to a high degree of confidence that

the relationship is causal. The most prominent

examples of drug studies showing consistent

associations are those on oral contraceptives and

the risks of cardiovascular disease; similar examples of nondrug studies are those on the risks

of smoking.

ess have focused not on the statutory language

but on the regulations issued by FDA to implement the law. Thus, the focus here is on oversight

issues, not on legislative changes.

Proposals to curtail or eliminate phase 111 premarketing tests, or shift them to the postmarketing

period, can be evaluated both theoretically and

experientially.
Ch.1—summary ● 9

Theoretically, phase III testing is significantly

more sensitive than phase II testing. Adverse effects with an incidence of 1 /100 or more are more

likely than not to be detected in the 100 to 200

patients given a drug in phase II. But the theoretical sensitivity of detection rises in phase III to

1/500 with 500 patients and to 1/1,000 with 1,000

to 3,000 patients (see ch. 4, table 5).

These observations are relevant to the detection

of adverse reactions, but they are not so relevant

to the detection of therapeutic effects. Since a drug

that helps only 1 in 100 patients would not be very

effective, efficacy should be established in phase

II. Phase III is intended to gather additional evidence on a drug’s effectiveness for specific indications.

If phase 111 testing were curtailed or eliminated,

there is also the question of whether premarketing evaluations would test sufficient numbers of

patients to reasonably ensure a drug’s safety or

give substantial evidence of its efficacy. Even

under current regulations, the use of a drug on

human subjects is very limited before the drug is

released for market: 20 to 80 patients in phase I;

100 to 200 patients in phase II; and 500 to 3,000

patients in phase III—a range of only 620 to 3,280

patients per drug (excluding controls).

In addition to theoretical criteria, experiential

criteria could be applied in considering proposals

to curtail or eliminate phase 111 tests. The diminished power to observe adverse drug effects that

such changes theoretically entail may not in fact

be found, judging on the basis of actual experience

in phase 111 testing, or if it is, it may only concern infrequent, minor effects. Agreement of the

experiential data with the differences theoretically

expected would strengthen the hypothesis that

curtailing phase 111 would lower the capacity of

current premarketing tests to identify adverse

reactions. If the experiential data fail to detect the

theoretical differences, then a better case can be

made for curtailing phase 111, with or without

transfer of some of its testing to the postmarketing

period.

Current interpretations of the statutory requirements for “adequate tests” of safety and “substantial evidence” of efficacy emphasize methodology,

as reflected in the requirement that each indication for which a drug is intended be supported

by at least two well-controlled clinical trials. But

FDA can alter the criteria by which it approves

drugs. For example, propanolol, the first betablocking drug approved for use in the United

States, was approved by an advisory committee

on the basis of all the evidence presented to FDA,

even though no one study was found to be adequate and well controlled (21). And in late 1981,

timolol, another beta-blocker, was approved, on

the basis of evidence from a foreign study, for use

in preventing death and recurrent heart attacks

in patients who have survived initial heart attacks

(26).

The approval of propanolol and timolol illustrates that FDA can grant exceptions to its usual

requirement of two well-controlled U.S.-based

clinical trials. In such cases, expert judgment relies

on qualitative, not quantitative, criteria in approving a drug, and such an approach falls outside the theoretical and experiential guidelines outlined above. If FDA is to rely increasingly on such

qualitative criteria through increased use of advisory committees, it will be necessary for FDA to

develop general guidelines to aid the advisory

committees in their deliberations. Otherwise, in

a case-by-case analysis, evidence of the same quality may lead to approval for one drug and nonapproval for another.

Issue 2:

Improving postmarketing surveillance

and its role in the drug approval process.

Even if phase 111 testing were not curtailed or

eliminated, FDA’s powers in the postmarketing

period could be strengthened to enhance its surveillance role.

Postmarketing surveillance “systems” that have

been advocated are not systems in the formal

sense, but a series of related activities oriented

toward several purposes, with the regulatory ap

-

proval process being only one. Three activities are

most frequently mentioned. First is the building

of a resource base through training of additional

experts and improving epidemiologic tools such

as methods for cohort and case-control studies.

Second, unless a drug effect has a sufficient fre-
10 ● Postmarketing Surveillance of Prescription Drugs

quency of occurrence (usually identified as I/

1,000) and for delayed effects of, for example,

greater than I year, strengthened voluntary reporting is the most realistic method of identifying possible adverse drug reactions. Once such

reactions are suspected, clinical trials, casecontrol, and cohort studies could be used to determine whether an association with drug use in fact

exists. Third is the development of an efficient

method for monitoring selected drugs after their

release into the market. The most frequently mentioned mechanism is formation of prospective

cohorts of drug users.

These aforementioned components of a postmarketing surveillance “system” and FDA’s role

in supporting and using them are oversight issues.

There are also several legislative options that

could strengthen FDA’s powers in the postmarketing period. The following legislative options are

presented for congressional consideration.

Option 1: Give FDA the power to require postmarketing studies.

A variation of this option is for FDA to use its

existing regulatory powers over advertising and

promotional practices to “certify” an industrysponsored postmarketing study.

Option 2: Give FDA the power to restrict the

distribution, dispensing, and administration of a

drug.

A variation of this option is for FDA to use its

existing regulatory powers to develop a parallel

approval process for the use of a limited group

of drugs during phase III testing, such as for drugs

of unusual need and promise.

Option 3: Change the standard for a drug’s removal from the market from “imminent hazard

to the public health” to “unreasonable risk of illness to any segment of the population” or some

other less stringent standard.
2

The Drug Approval Process;
2.

The Drug Approval Process

A drug’s sponsor must provide: 1) adequate

tests by all methods reasonably applicable to show

whether or not such drug is safe for use under

the conditions prescribed, recommended, or suggested; and 2) substantial evidence that the drug

will have the effect it purports or is represented

to have. “Substantial evidence” means “evidence

consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience

to evaluate the effectiveness of the drug involved,

on the basis of which it could fairly and reasonably be concluded by such experts that the drug

will have the effect it purports or is represented

to have” (21 U. S. C., sec. 355(d)). (See app. A for

selected sections of the act. )

This statutory language has led the Food and

Drug Administration (FDA) in practice to establish a premarketing phase of drug testing that consists of two parts: 1) the investigational new drug

(IND) application process, and 2) the filing of a

new drug application (NDA).

NOTICE OF CLAIMED INVESTIGATION FOR A NEW DRUG

IND Application Process

A new drug is defined as any drug: 1) that is

not generally recognized by experts to be safe and

effective for the use described in the drug’s labeling (except for certain so-called “grandfather

drugs, ” i.e., those approved prior to the 1962

amendments); or 2) that has been shown to be

safe and effective in clinical investigations, but has

not been used to any material extent or for a material time.

A drug is considered to be new for any of the

following reasons: 1) it is composed in whole or

in part of a new substance (this includes active

components and inert ones, such as a coating or

carrier); 2) it is a new combination of approved

drugs; 3) it is an approved combination in a new

ratio; 4) it is an approved drug with a proposed

new use (i. e., a use for which the drug has not

been approved); or 5) it is an approved drug with

a proposed new dose or new method or duration

of administration (21 CFR 310.3(g)).

A sponsor is the entity responsible for the entire investigation of a new drug. The sponsor can

be an individual, a partnership, a corporation, or

another agency of the Government (e. g., the National Cancer Institute). In testing a new drug, a

sponsor may use a number of different investigators.

A sponsor wishing to investigate a new drug

by means of clinical tests in humans must first

carr y out various studies in animals (see table 1).

Such studies examine acute and chronic drug toxicity at different dose levels, by different routes

of administration, and in different species. Biochemical data are also obtained on the drug’s absorption, distribution, metabolism, and excretion.

The data from chronic animal studies, which can

take over 2 years to collect and analyze, are not

ordinarily required for permission to proceed to

human trials. Long-term animal tests must also

be undertaken at the same time that the drug is

being tested in humans, particularly for drugs intended for use over long periods of time, as for

chronic diseases and oral contraception. The purpose of long-term animal tests is to investigate the

drug’s toxicity (e.g., carcinogenicity) when taken

chronically, and its effects on fertility, reproduction, and fetal development (e.g., teratogenicity).

The point at which FDA becomes involved in

the development process for a new drug is when

a sponsor desires to investigate the drug’s safety

and effectiveness via clinical tests in humans, Be13
14 ● Postmarketing Surveillance of Prescription Drugs

Table 1 .—Guidelines for Duration of Animal Toxicity Studies for Oral

and Parenteral Drugs

Expected duration of continuous Phase of clinical Duration of subacute or chronic

administration to humans investigation toxicity studies in animals

Several days. . . . . . . . . . . . . . . . . . . I, II, Ill, NDAa

Two species; 2 weeks

Up to 2 weeks . . . . . . . . . . . . . . . . . I Two species; 2 weeks

II Two species; 2 months

Ill, NDAa

Two species; up to 3 months

Up to 3 months . . . . . . . . . . . . . . . . 1, II Two species; 4 weeks

Ill Two species; 3 months

NDAa Two species; up to 6 months b

6 months to unlimited . . . . . . . . . . 1, II Two species; 3 months

Ill Two species; 6 months or longer

NDAa

Two species; 12 monthsb (nonrodent)

18 monthsb (rodent)

aNew drug application

bAlthough as yet there has been no formal updating of these guidelines, they have been expandedto include 2.Year animal

toxlclty and carc!nogenlclty stud!es for those drugs that would be administered chronically or intermittently (n a large population

(e g , contraceptives) These studies are presently being required on a drug-by .drug basis as investigational new drugs are

reviewed

SOURCE U S Food and Drug Administration

fore proceeding, the sponsor must file an IND application with the Office of Drugs in FDA’s National

Center for Drugs and Biologics. The 1962 amendments to the Food, Drug, and Cosmetic Act, by

empowering the Secretary of Health and Human

Services to write specific requirements, effectively

require that all results from testing a new drug

in humans be submitted by the sponsor of the

drug and approved by FDA under an IND. In filing the IND application, the sponsor agrees to

refrain from beginning studies for 30 days, but

may begin them after that time unless FDA asks

the sponsor to continue to avoid or to restrict use

of the drug in humans. The 30-day delay can be

waived upon a showing of good reason.

The IND application describes the qualifications

of the investigators and the planned trials, and

includes a chemical description of the drug and

available data on its pharmacology and toxicology as collected in animal studies and in prior

human studies, if any (e.g., those conducted in

foreign countries). If the necessary animal tests

have been carried out and give evidence for the

safety of the proposed human use, if the drug is

adequately characterized so that the tests will be

meaningful, and if the proposed human studies

appear reasonably safe, the IND application is

usually approved. The sponsor may then proceed

with clinical testing if FDA does not raise objections within 30 days.

Once the IND application is approved, additional protocols and investigations can be added.

FDA sets no time limit on the IND process as long

as annual reports in the form of summaries are

submitted and serious adverse reactions are

promptly reported. All data on drug effectiveness,

including that from clinical studies in patients, as

well as chemical and animal data, are considered

to be the sponsor’s property and subject to protection as trade secrets. If, at any time during the

tests on human subjects, the continuance of those

tests is determined to endanger public health, they

can be stopped immediately.

The clinical investigations of a new drug—i.e.,

studies in humans—are divided into three phases

that in actual practice are not so distinctly separated (see table 2) (24).

Phase I: Clinical Pharmacology is the initial use

of the drug on humans. The purpose of this phase

is to determine levels of tolerance (toxicity), to

begin to ascertain safe dose ranges, and, in some

cases, to study drug efficacy in selected patients.

The total number of healthy volunteer subjects

and patients administered the drug ranges from

about 20 to 80. At this stage, many drugs are

screened out because their safety is found to be

seriously questionable or because they are found

to be inactive in humans. If the drug appears to

be well tolerated, it may go on to the next stage

of testing.
. —-—

Ch. 2— The Drug Approval Process ● 15

Table 2.—Studies Required in FDA’s Premarketing

Drug Approval Process

Phase 1:

— Studies in normal volunteers or relatively healthy

patients to determine safety and pharmacologic

effects.

— Small studies in patients to determine clinical

effectiveness.

— Total number of subjects—up to 80 administered

the investigational drug.

Phase 11:

— Controlled clinical trials to determine appropriate

doses, safety, and effectiveness.

— Total number of patients—about 200 administered

the investigational drug.

Phase Ill:

— Controlled and uncontrolled clinical trials to determine safety and effectiveness and to support labeling claims.

— Total number of patients—about 500 to 3,000

administered the investigational drug.

SOURCE U S Food and Drug Administration

Phase II: Clinical Investigations are the earliest

investigations specifically designed to demonstrate

effectiveness and relative safety, and to include

controlled studies. In this phase, the drug is administered to 100 to 200 patients, under rigid protocols and close monitoring. If the therapeutic value of the drug has been demonstrated, and it appears to have no serious adverse effects, it may

then enter the final stage of testing.

Phase 111: Clinical Trials are expanded controlled and uncontrolled trials. They are carried

out on 500 to 3,000 patients in situations similar

to those of actual clinical practice—in clinics, outpatient hospital facilities, and private practice.

These studies are performed after a drug’s efficacy

has been established, at least to some degree, and

are intended to gather additional evidence of drug

effectiveness, to discover rarer drug effects or effects that develop after longer periods, and to better define the frequency and severity of more common effects as well as the proper use of the drug

(e.g., by identifying best dose, dose interval, and

the drug’s interactions with other drugs). Adequate and well-controlled trials that give evidence

of a drug’s effectiveness, accompanied by complete case records for each patient, are sometimes

termed pivotal studies. FDA usually requires at

least two independent well-controlled studies to

approve an NDA, the following stage of the drug

approval process, though more than one drug indication can be evaluated in a single study. (These

requirements are currently under review; see

ch. 3.)

Compassionate or Treatment IND

FDA has recognized that under special circumstances, when a patient has exhausted all other

therapies for a life-threatening disease, a drug that

might be of value but is still unapproved should

be made available. Investigational drugs can be

made available under a “compassionate” or “treatment” IND. The drugs made available are generally in phase III of clinical testing.

Physicians can obtain an investigational drug

if they have a patient with a disease that is lifethreatening or significantly impairs the quality of

life, and the patient is allergic or resistant to existing methods of treatment. Under such circumstances, FDA usually recommends that the physician contact the medical director of the company

investigating the drug to inquire whether the company will accept the physician as an investigator

under its IND application for that particular patient. The company may also supply the drug to

the physician, who files his or her own IND application.

Sometimes these treatment uses can become

quite extensive, especially when available therapy

is unsatisfactory, for example, in the treatment

of serious cardiac arrhythmia and angina pectoris.

According to Robert Temple, recently appointed

director of the Office of Drugs’ New Drug Evaluation Division, promising new antiarrhythmics and

antianginal drugs have been given to thousands

of patients under these circumstances. But the

compassionate IND procedure may be inadequate

for providing a needed drug that is still in the

process of being approved when patients are distant from a medical center or when physicians are

not familiar with FDA procedures.
76 Ž Posfmarketlng Surveillance Of Prescnptlon Drugs

——— . ——————— — — . ——— —

THE NEW DRUG APPLICATION PROCESS

After the completion of required testing under

the IND, if the sponsor believes that the drug’s

safety and effectiveness have been proved and that

the drug has commercial potential, the sponsor

may file an NDA, a request for FDA’s permission

to market the drug in interstate commerce. This

application includes everything the sponsor considers necessary for meeting the statutory requirements: 1) full reports of animal and clinical studies

carried out to determine whether the drug is safe

and effective; 2) a statement of the drug’s composition; 3) a description of the methods, facilities,

and controls used in the drug’s manufacturing,

processing, and packaging; 4) samples of the drug

and its components as may be required; and 5) a

copy of the proposed labeling. The labeling describes what is known about the drug: the approved uses, dosages, the indications for which

its effectiveness is approved, and its known adverse side effects. The final wording of the labeling is negotiated between FDA and the sponsor,

and must be formally approved as part of the

NDA.

All INDs are classified by chemical type and

therapeutic potential so that those drugs considered by FDA to be of particular therapeutic importance can receive priority review (see table 3).

The highest classification is for a drug that is both

a new molecular entity (type 1) and that might

represent an important therapeutic gain (type A)

—a type 1A drug. The next highest classification

is given to a new molecular entity that represents

a modest therapeutic gain (a type IB drug). But

skepticism has been expressed by some industry

representatives as to whether a correct determination of the potential benefits of a drug can be made

at the time of NDA submission,

After the NDA is filed, a team of FDA reviewers analyzes the sponsor’s summaries of the data

or, when needed, the actual data. The review team

includes a physician, who reviews the clinical test

results; a pharmacologist, who reviews the animal

test results; and a chemist, who reviews the chemical data and manufacturing controls and processes; supported by a biopharmaceutic specialist,

a biometrician, and, when applicable, a microbiologist. The main objective of the process is to

ensure that the data from the clinical experiments

support the claims for the drug’s safety and efficacy in the labeling the sponsor submitted.

NDAs may be presented for consideration to

advisory committees composed of experts (mostly

nongovernmental) in the various subspecialties of

medicine, in clinical pharmacology, and in biometrics. The committees recommend whether or

not an NDA should be approved to market a drug

and, if the drug is approved, what wording should

appear in its labeling. They also may recommend

whether the sponsor should be requested to carry

out additional studies after the drug is marketed.

If the committees recommend against approval,

they identify deficiencies and may suggest new

studies that need to be done by the sponsor to further investigate the drug’s safety and efficacy.

FDA invites a sponsor to confer with FDA

about important new therapeutic drugs during the

drugs’ investigational phases, Usually, such conferences are arranged at the end of phase II, when

a drug’s degree of efficacy and safety has been

Table 3.—FDA’s Drug Classification System

Chemical type

Type 1 New molecular entity

Type 2 New salt, ester, or derivative

Type 3 New formulation

Type 4 New combination

Type 5 Duplicate of an already marketed

drug

Type 6 Already marketed product by same

firm—primarily used for new

indications

SOURCE U S Food and Drug Administrat~on –

Therapeutic type

Type A Important therapeutic gain

Type B Modest therapeutic gain

Type C Little or no therapeutic gain

Type D Decreased safety or efficacy

compared with other drugs but

has some compensating virtue
——.. —-—

Ch. 2— The Drug Approval Process ● 17

— — ——.

largely established. The purpose of the conferences is to discuss whether the studies to date are

acceptable, in view of the drug’s proposed indications and the claims made for the drug, and

whether the additional controlled studies proposed for phase III will be adequate for the NDA’s

approval.

FDA must approve or disapprove a submitted

or resubmitted NDA within 180 days. It may take

longer if the sponsor and FDA agree on an additional period of time. An FDA study of the review

time for approved NDAs found that in 1976, it

was 25.9 months, in 1977, 26.6 months, and in

1978, 33.3 months (12). In the first half of 1979,

however, the average time had been reduced to

20 months (30). These approval times include

several resubmissions of the NDAs either to correct deficiencies noted in them during FDA review, or because the sponsor obtained a large

amount of additional data. Furthermore, the total

amount of information required for an NDA has

increased markedly since 1938, when the 180-day

limit was imposed. In 1938, the required information consisted of data from short-term animal

toxicology studies, along with that from a few

studies in humans. Today, an NDA must contain

the reports of numerous short- and long-term

animal studies along with the reports of various

clinical trials to demonstrate the drug’s safety and

effectiveness in humans.

Should FDA decide to refuse approval, the

sponsor receives a “nonapprovable” letter explaining why the NDA fails to fulfill statutory requirements. An applicant’s approval can be refused for any of the following reasons:

Drug safety has not been studied by all reasonably applicable tests.

The drug is not safe for the intended use.

The drug’s manufacturing processes are not

adequate to ensure its identity, strength,

quality, and purity.

Substantial evidence of the drug’s effectiveness is lacking; i.e., the clinical investigations

were not adequate or well controlled or their

results do not adequately support the claims

made.

The labeling is false or misleading in any particular.

Ž The application is missing data, e.g., on bioavailability or bioequivalence or on the environmental impact of the manufacturing process.

If the clinical trials establish that a drug is effective for its intended indications, FDA must decide

whether the drug’s benefits outweigh its risks.

FDA does not require a sponsor to prove that a

drug is safer than available drugs, nor more effective, nor even as effective as other treatments in

order to receive permission to market the drug.

In some cases, a drug may be less safe than an

alternative therapy. Although most manufacturers

normally would not be interested in marketing a

drug whose benefit/risk ratio is less than that of

a treatment already available, FDA recognizes

that there are times when such drugs should be

made available.

When presented with an NDA in which the data

clearly show a drug to have an inferior benefit/

risk ratio, FDA considers the indications for which

the drug is offered. Thus, such drugs when intended to treat a life-shortening condition might

receive approval, while such drugs when intended

for lesser indications (e.g., mild analgesics that

are less safe and no more effective than aspirin)

would not. Obviously, the decisions that cause

the most difficulty are those concerning drugs between these extremes (22).

Abbreviated New Drug Application

FDA has established an abbreviated new drug

application (ANDA) for generic versions of drugs

first marketed between 1938 and 1962. These

drugs require less testing for approval than do

original versions of a drug. The amount of information required for approval of such generic

drugs varies, depending on the nature of the drug.

The ANDA policy does not apply to drugs marketed after 1962. Approval of generic copies of

these recent drugs requires a standard NDA, but

FDA has been willing to accept published reports

demonstrating the safety and efficacy of these

drugs. NDAs that rely on published reports are

sometimes referred to as “paper” NDAs.
18 ● Postmarketing Surveillance of prescription Drugs

REQUIREMENTS FOLLOWING APPROVAL

Once the NDA has been approved, the sponsor is required to keep records and submit reports

about the drug. This information is used to: 1)

maintain the procedures and safeguards for manufacturing established during the approval process,

2) ensure that there are limits placed on advertising and promotional claims and that the drug’s

labeling is appropriate, and 3) provide the basis

for FDA’s removal of a drug from the market,

when such action is appropriate.

The studies carried out before a drug is released

have a number of inherent limitations with respect

to the amount and kind of information they generate, limitations that include the following:

●

●

●

●

The patients in premarketing studies (even

in phase III) do not represent all those who

would ultimately take the drug. Thus, a

drug’s effects on special patient populations

not specifically studied in premarketing tests

may not be known. Such special populations

include patients who are taking several

medications concurrently, those having

diseases in addition to the one treated by the

drug, and those who suffer more severely

from the disease being treated than the patients in the study groups. Similarly, when

phase 111 studies are conducted on children

(e.g., when they are to be a drug’s chief recipients), usually only very small groups of

patients are studied, and the entire age range

of concern (e.g., including newborns) is not

studied for ethical and other reasons.

The total number of people exposed to the

drug in premarketing studies is relatively

small; therefore, uncommon adverse reactions (i.e., those less frequent than 1/1,000)

are unlikely to be detected.

The duration of exposure to the drug in premarketing studies is relatively brief (12 to 24

months at most); therefore, adverse effects

that only appear after long-term use or that

require a latent interval after exposure to

develop (e.g., cancer) cannot be detected.

Clinical trials must be conducted according

to strict protocols (regarding dosages, duration of treatment, etc.), and they are usually

carried out by specialists in large medical

●

centers where such research can be done.

Thus, the effects a drug might have when administered by a regular physician in an office or outpatient clinic, when patient compliance to a treatment regimen is less controlled, cannot be fully assessed.

In premarketing studies, a drug is often

evaluated for only one purpose (e.g., treatment of hypertension), but it may have another use (e.g., treatment of angina pectoris).

(In its labeling, the only drug indications that

may appear are those that have been explicitly tested and approved).

FDA has several mechanisms to obtain information about drugs once they have been approved for marketing.

FDA may request further studies when questions about a drug remain unanswered by phase

111 studies but do not warrant delaying the release

of what may be a useful new product. These studies are referred to as “phase IV” studies. Although

this designation is not defined in FDA regulations,

it is discussed in the guidelines (24). The studies’

nature depends on the question to be resolved,

and their design is negotiated between the drug’s

manufacturer and FDA through its New Drug

Evaluation Division in the Office of Drugs.

Phase IV postmarketing studies can be of several

●

●

●

●

types (24):

Additional studies to elucidate the incidence

of adverse reactions, to explore a specific

pharmacologic effect, or to obtain information of a circumscribed nature.

Large-scale, long-term studies to determine

the effect of a drug on morbidity and mortality.

Additional clinical trials similar to those in

phase III, to supplement premarketing data

where it has been deemed in the public interest to release a drug for more widespread use

prior to acquisition of all data which would

ordinarily be obtained before marketing.

Clinical trials in a patient population not adequately studied in the premarketing phase;

e.g., children.
Ch. 2—The Drug Approval Process ● 19

• Clinical trials for an indication for which it

is presumed that the drug, once available,

will be used.

In general, phase IV studies have been requested

when a drug is likely to be widely used, and important safety and efficacy questions about it remain. Phase IV studies may be requested, for example: 1) when there are suspected or known adverse drug reactions (ADRs) associated with the

drug, in order to confirm the ADRs and to determine their true incidence; 2) when a drug belongs

to a class of drugs known to be associated with

a serious ADR, but its incidence may not be high

enough to observe in the limited number of patients in phase 111 studies; 3) when the drug is one

that will be used with children, and it was not

tested on them in the premarketing studies; 4) if

the drug is likely to be used therapeutically in

combination with another drug, and there is reason to be concerned about the toxicity of the combination; and 5) if a drug approved for one indication is very likely to be used for several other

indications. (Studies may be required for each of

the other uses. For example, most beta-adrenergic

blocking agents, such as propanolol, are used in

the treatment of angina, hypertension, and arrhythmia, but an NDA may be approved when

the use of a drug for only one of these indications

has been documented. Even though the drug has

only one approved use, it will likely be prescribed

for the other two uses. )

Phase IV studies may be typical clinical trials

similar to those carried out in the premarketing

period. They may also use other surveillance

methods. (See ch. 4 and its case studies of streptokinase and cimetidine. )

Finally, FDA receives information on marketed

drugs through various kinds of monitoring of adverse drug reactions carried out by the Division

of Drug Experience in the Office of Drugs:

●

●

●

●

●

the Spontaneous Reaction Reporting Program, in which ADRs are reported to FDA

by physicians, pharmacists, hospitals, and

manufacturers (the last kind of reporting is

mandatory);

a monthly review of the medical literature

on ADRs (reports to medical journals, letters

to the editor, etc.);

intensive surveillance and epidemiological

studies of ADRs in selected hospitalized and

ambulatory populations;

several specialized registries that collect and

analyze possible ADRs; and

the World Health Organization (WHO),

which sends reports to FDA summarizing the

ADRs added to its system in the previous

year. FDA reciprocates by providing U.S.

data to WHO.

This report focuses on the regulatory uses of

such postmarketing surveillance. Past studies of

this issue have also focused on the need for systematic evaluations in the postmarketing period

regardless of their importance for regulation, for

example, in order to build a resource base of scientists, evaluation methods, and data sources for

the better understanding and use of drugs once

they are marketed. The evolutionary context of

postmarketing surveillance is summarized in chapter 3.
3

History and Objectives of

Postmarketing Surveillance
—

3.

History and Objectives of

Postmarketing Surveillance

In the 1960’s, at least two serious drug reactions

were observed in many patients. The drug thalidomide, taken worldwide, led to limb deformities

(phocomelia) in the newborns of those mothers

who took the drug while pregnant. Less known,

and almost exclusively observed in Japan, was the

optic nerve damage (subacute myelo-optic-neuropathy) and other adverse effects from the drug

clioquinol, over which almost 4,000 civil suits

were still pending in 1979 (68). And in Great Britain in the early 1970’s, more than 4 years after

the drug had been introduced there, the “practolol

syndrome” was uncovered. Practolol, a drug used

to treat cardiovascular disease, was eventually

found to cause skin rashes, eye lesions, hearing

impairment, and sclerosing peritonitis (56), with

deaths occurring in about 2 percent of reported

cases (37).

Great Britain, with its national health system,

already had a voluntary reporting system (37).

The national health system had instituted the use

of “yellow cards” for reporting suspected adverse

drug reactions (see fig. 1). As a guide to reporting, certain drugs are marked the first 4 years after

they are marketed with an inverted black triangle

in a booklet, the Monthly Index of Medical Specialties, which is distributed to physicians and

used as a source of information for prescribing

drugs more frequently than any other publication.

In 1976, a slip of yellow paper was inserted into

prescription pads to remind physicians to report

reactions, leading to a large and consistent increase in the rate of reporting. Many British drug

companies now use the yellow card, and the

yellow card system and reports from drug companies together yield 90 percent of all reports of

suspected adverse drug reactions (ADRs) (see table

4).

The delayed discovery of practolol’s adverse effects spurred efforts to improve postmarketing

surveillance, and several international meetings

quickly followed in Sestri Levante, Italy (20),

Honolulu, Hawaii (33), and London (53). In Great

Britain, efforts focused on “early detection of

adverse drug reactions by recording all adverse

events occurring in a specified number of patients

for an appropriate period of time; endeavoring

to avoid collecting masses of unusable data and

minimizing costs” (75). Thus, the early impetus

was toward monitoring new drugs for adverse effects through some type of program that would

help fill the gap between identifying those adverse

effects sufficiently common to be detected in the

premarketing trials, and identifying those so rare

that voluntary reporting after marketing is their

most feasible form of monitoring. The proposed

methods all centered around the prescribing practices of physicians, with the experience of their

patients on new drugs being examined periodically

through questionnaires to the prescribing physicians. Such methods of monitoring include registered release (17), recorded release (36), and monitored release (45,79).

More recently, the objectives of postmarketing

surveillance in Great Britain have been expanded,

though not implemented (35):

The need for PMS [postmarketing surveillance]

is not restricted to new drugs. Some of those already marketed for many years may increase the

risk of chronic disease or may have long-delayed

carcinogenic effects, as illustrated in the United

States by the cases of vaginal adenocarcinoma in

the adolescent female children of women who

took diethylstilbestrol during pregnancy.

PMS should also include assessment of efficacy, especially of long-term treatment. Very little is known of the relative merits of members of

groups of drugs such as hypotensive or anti-diabetic agents, anti-rheumatics or psychotropic.

Prescribers need to know the most effective treatment available just as much as they need to know

the risks involved, but government drug regulatory authorities (DRAs) are reluctant to become

involved in relative efficacy, and drug companies

are not naturally inclined to invest in comparisons of closely related compounds which may not

show their own product to be the best.

23

< -. 2 . -
24 ● Postmarketing Surveillance of Prescription Drugs

Figure 1 .—Yellow Card Report Form Used in Great Britain

1.

2.

3.

4.

IN CONFIDENCE–REPORT ON SUSPECTED ADVERSE DRUG REACTIONS

Please report all reactions to recently introduced drugs and serious or unusual reactions to other drugs. (Vaccines should be regarded

as drugs).

Record on the top line the drug you suspect of causing the adverse reaction.

Record all other drugs, including self-medication, taken in the previous 3 months. With congenital abnormalities, record all drugs taken

during pregnancy.

Do not be deterred from reporting because some details are not known.

NAME OF PATlENT SEX AGE OR DATE OF WEIGHT

(To allow linkage with other re- BIRTH

ports for same patient. Also give

record number for hospital patient)

DRUGS* (Give brand name if known) ROUTE DAILY DATE INDICATIONS

DOSE STARTED ENDED

● For Vaccines give Batch No.

REACTIONS STARTED ENDED OUTCOME (e.g. fatal, recovered)

ADDITIONAL NOTES REPORTING DOCTOR

Name

Address

Tel. No.

Signature

Date
— .— -

Ch. 3—History and Objectives of Postmarketing Surveillance . 25

Figure 1 .—Yellow Card—Continued

REPORTING ADVERSE REACTIONS: GUIDELINES

DO NOT REPORT 1. Deliberate or accidental overdose

2. Overdose due to errors of prescribing or administration

3. Excessive but otherwise ‘normal’ effects of drugs whose dose has to be carefully titrated (e.g., insulin,

hypotensives, anticoagulants)

4. Familiar relative overdose—excessive effect of a normal dose due to known predisposing factors (e. g., digoxin

toxicity in presence of hypokalaemia; toxicity in patients with impaired renal function)

5. Inevitable side effects produced by known pharmacological activities of a drug (e.g., dry mouth with anticholinergic

drugs, tricyclic antidepressants, etc.; and hyperuricaemia with diuretics)

REPORT ALL 1, Drug interactions—known or suspected

2, Reactions to new drugs marketed for less than 3 years

3. Totally unexpected or unexplained events (including death) which could be drug induced

4. Congenital abnormalities

5. Infrequent reactions causing significant morbidity even if well known

CHECK LIST FOR REPORTING (not comprehensive)

General a. anaphylaxis

b. all serious skin rashes

c. all blood dyscrasias

d. thrombosis associated with

oestrogens or oral contraceptives

Gastro-lntestinal a, jaundice

b. malabsorption

c, intestinal ulceration

d. severe bleedlng

Cardiovascular a. myocardial toxicity, e.g., unexpected

arrhythmias (exclude digoxin)

b. hypertensive reactions

Respiratory a. brohchospasm

b. non-infect!ve lung disease, e.g.,

pneumonitis, fibrosis

Nervous System a. convulsions

b. unexpected confusional states

(hallucination or psychotic reactions)

c. unexpected extrapyramidal effects (exclude

phenothiazines and butyrophenones)

Renal

Joints

d. peripheral neuropathy

e. neuromuscular blockade

f. myopathy and myalgia

Eye & Ear all reactions

Endocrine a. unexpected reactions

b. amenorrhea

c. infertility

Exclude gynaecomastia, fluid retention,

hypokalaemiaemia, hyperkalaemia,

hypoglycemia, hyperglycemia,

hyperuricaema porphyria (if produced by

drugs known to have these effects)

ail nephrotoxicity

Exclude urinary retention induced by diuretics

or due to anticholinergic drugs

a. all arthropathies

b. D. LE. syndrome

SOURCE Committee on Safety of Medicines. London

Table 4.— Percentage of Reports of Suspected ADRs in Great Britain

by Class of Reporter and Method Useda

Percentage of reports by class of reporter

General Hospital Hospital Others (e.g,,

Method used practitioner consultant junior coroner) All reporters

Yellow card. . . . . . . . . . . 58.3% 6.30/o 9.7% 1 .7%0 76.00/o

Drug company . . . . . . . . 6.2 4.5 2.9 — 13.6

Correspondence . . . . . . 1.7 0.8 0.4 4.6 7.5

Death certificates . . . . . 0.2 — 1.3 0.9 2.4

Medical journal . . . . . . . — 0.2 0.3 — 0.5

All methods . . . . . . . . 66.40/, 11 .80/0 14.60/o 7.20/, 100.0%0

aBased on random 10 percent sample of approximately 12,000 recent reports UP to June 1978

SOURCE W H W Inman (ed ), “The United Kingdom, ” In &for? /torirtg for Drug Safety (Philadelphia’ J B. Llppincott Co , 1980)
26 ● Postmarketing Surveillance of Prescription Drugs

Furthermore, an earlier suggestion linked postmarketing surveillance with restricted release of

drugs (75):

A case could be made for an immediate or restricted release system for the introduction of new

drugs before their widespread use, half way between clinical trials and the monitored release

proposals. Because of inevitable delays, it is possible that by the time 5,000-10,000 cases have

been fully monitored by any of the above

schemes, many more patients will have been exposed to the drug so that any serious adverse

reactions in the monitored group are duplicated

in those patients not fully monitored. The duration of the “restricted release” phase would depend on the drug and disease concerned. Monitoring of patients would continue, when appropriate, after the drug became generally available.

In the United States, the Food and Drug Administration’s (FDA’s) drug approval process was already under intense scrutiny in the early 1970’S.

As a result of 1974 hearings before the Subcommittee on Health, Senate Committee on Labor and

Human Resources, chaired by Senator Edward

Kennedy (D-Mass.), the Department of Health,

Education, and Welfare formed a Review Panel

on New Drug Regulation. This panel, which convened in February 1975 and issued its report in

May 1977 (16), addressed two issues: 1) whether

the drug law requirements for premarketing testing unnecessarily delayed the availability of

valuable prescription drugs, and 2) whether the

drug industry exerted undue influence on FDA

decisions. The panel concluded that there was insufficient evidence on the first question and no

widespread improper influence. It also identified

four categories of deficiencies in the regulation of

drugs: 1) openness and public accountability,

2) FDA’s science environment, 3) standards and

procedures for premarketing approval, and

4) FDA’s role in the postmarketing period (16,18).

Senators Kennedy, Javits, and others then introduced a bill in early 1978 to revise the drug provisions of the Food, Drug, and Cosmetic Act. A

revised bill, S. 1075, the Drug Regulation Reform

Act of 1979, passed the Senate in September 1979.

However, a similar bill, H.R. 4258, was not acted

on by the House of Representatives. Included in

the Senate bill were these proposed changes in existing law: 1) drug sponsors could be required to

conduct postmarketing surveillance of a drug for

up to 5 years; 2) a prescription drug could have

its distribution limited if it could not otherwise

be found to be safe and effective; 3) the standard

for a drug’s immediate removal from the market

would be changed from the drug being an “imminent hazard to the public health” to the less

stringent standard of “unreasonable risk of illness

or injury to any segment of the population;” and

4) establishment of a “National Center for Drug

Science. ”

During this period, in a speech to the Pharmaceutical Manufacturers Association, Senator Kennedy suggested that a better system was needed

for monitoring the use and effects of prescription

drugs after they were marketed. As a result, the

Joint Commission on Prescription Drug Use was

established in 1976, funded largely by the drug

industry, with the mandate to design a postmarketing surveillance system to detect, quantify, and

describe the anticipated and unanticipated effects

of marketed drugs, and to recommend a means

by which information on the epidemiology of prescription drug use in the United States could be

distributed regularly to interested parties. The

Joint Commission issued its report in January 1980

with the following five conclusions and recommendations identified as its most important ones

(see

1.

2.

3.

4.

app. B for the complete list) (42):

A systematic and comprehensive system of

postmarketing drug surveillance should be developed in the United States.

Such a system should be able to detect important adverse drug reactions that occur more

frequently than once per thousand uses of a

drug, to develop methods to detect less frequent reactions and to evaluate the beneficial

effects of drugs as used in ordinary practice.

New methods will have to be developed for the

study of delayed drug effects, including both

therapeutic and adverse effects.

An integral function of the postmarketing surveillance system should be to report the uses

and effects of new and old prescription drugs.

Recognizing the progress that FDA has made

in the area of postmarketing drug surveillance

in the last 3 years, the Commission recommends that PMS [postmarketing surveillance]

should be a priority program of the FDA and

that the FDA should continue to strengthen its

program in this area.
Ch. 3—History and Objectives of Postmarketing Surveillance ● 2 7

.— —

5.

In

sion

A private, nonprofit Center for Drug Surveillance (CDS) should be established to further

the development of a postmarketing surveillance system in the United States. This center

should foster cooperation among existing postmarketing surveillance programs, develop new

methods for carrying out surveillance, train

scientists in the disciplines needed for doing

postmarketing surveillance, and educate both

providers and recipients of prescription drugs

about the effects of these drugs.

1976, the year in which the Joint Commiswas formed, an interagency agreement was

signed between FDA and the Experimental Technology Incentives Program (ETIP) at the National

Bureau of Standards of the Department of Commerce. The purpose of ETIP was to provide incentives or reduce barriers to technological innovation through changes in the regulatory process.

ETIP’s agreement with FDA was to jointly fund

a program to determine if improvement in postmarketing surveillance could help reduce the

regulatory requirements of the premarketing

period, principally those of phase III of the investigational new drug process and those of the

following new drug application process. The

specific experiment was to develop postmarketing

surveillance systems and a method of managing

and evaluating the reform (11).

The project concentrated on collecting data to

design such systems, and issued a status report

in 1981 (12). Another report will be issued by the

project in 1982. FDA has assumed most of the

funding, and the Department of Commerce was

to phase out ETIP in 1982. FDA is continuing the

activities originated or stimulated by the program

(see ch. 5).

A Commission on the Federal Drug Approval

Process was convened in mid-1981 to examine

how FDA’s procedures for the approval of new

drugs can be expedited without compromising

public safety; it is to also make recommendations

on the development of cost-effective postmarketing surveillance to guarantee the quick withdrawal

from the market of drugs that cause significant

adverse effects. The commission had its genesis

in a joint hearing held in April 1981 by the House

Science and Technology Committee’s Subcommittee on Natural Resources, Agriculture Research,

and Environment and its Subcommittee on Investigations and Oversight. The commission’s first

meeting was held in July 1981, and its report was

to be released in late 1982.

FDA is also examining specific ways to speed

up the drug approval process. It is reviewing past

phase 111 trials to see if longer trials or those with

large sample sizes have contributed useful information beyond that obtained in phase II and early

phase III testing. Past postmarketing studies that

FDA has required are also being reviewed to see

if they provided the information that was originally sought. FDA data on approval time, validated by interviews with FDA and the manufacturers, are being reviewed for factors that may

slow the approval process. And, as a pilot test,

an FDA committee is reviewing the pharmacologic

and clinical data on selected drugs at the end of

phase II testing, and will make recommendations

about the best time to gather additional safety information (e.g., phase III v. the postmarketing

period) (11). FDA Commissioner Hayes has been

quoted as saying that one possible methodological

change is to accept foreign data in the premarket

approval process (67). These activities have

resulted in proposed new rules for new drug

regulation (47 Federal Register, pp. 46622-66, Oct.

19, 1982). In March 1982, the FDA Commissioner

began a related reorganization by merging the

Bureau of Drugs with the Bureau of Biologics, and

replacing the Director of the New Drug Evaluation Division. The merged bureaus have since

been designated the National Center for Drugs

and Biologics.

Finally, in a related development, the Senate

passed by a voice vote, in the first session of the

97th Congress, the Patent Term Restoration Act

of 1981 (S. 255). The bill would restore to the term

of a patent the time lost in complying with the

Government’s premarket testing and review requirements, up to a maximum of 7 years. Patented

products eligible for extension would not be

limited to human drugs, but would include

“human drugs and biological, antibiotic drugs,

animal drugs and biological, food additives,

color additives, pesticides, other chemical

substances, medical devices, and any other product subject to Federal premarket requirements”
28 ● Postmarketing Surveillance of Prescription Drugs

(72). In September 1982, the House of Representatives voted on the bill under suspension of its

rules. Under such conditions, a two-thirds vote

was required for passage, and although the bill

received a majority of the votes, it fell just short

of the two-thirds majority needed.

Thus, in the United States, the issue of postmarketing surveillance has involved more than

identifying the serious adverse effects of newly introduced drugs. It has also led to the recommendation to monitor all drugs for their effectiveness

and appropriate use by patients and physicians.

In addition, improvements in postmarketing surveillance have been linked to changes in the drug

regulatory process. Proponents of more rapid

drug approval claim that phase III testing (e.g.,

the chronic trials) adds little to the data collected

in phase II, and that, as a consequence, phase 111

testing could be curtailed or shifted to the postmarketing period. On the other hand, those concerned about drug deficiencies discovered after

drug approval point out that FDA has limited options once a drug has been released. Since FDA

lacks authority to limit drug distribution or use,

it can only try to remove a drug from the market,

if such action appears appropriate.
4

Methods of Drug Evaluation;
4

Methods of Drug Evaluation;

TYPES OF STUDIES

The primary objective of postmarketing studies

is to develop inforrnation about drug effects under

customary conditions of drug use.

The initial clues about a drug’s potential effects

come from the experimental studies carried out

with both animals and humans in the premarketing period. Spontaneous or voluntary reporting

(e.g., in letters to the editors of medical journals)

is the oldest, and to date, the most productive

source of new information about a drug’s possible effects once a drug is marketed. Other types

of studies are used to examine in more detail the

possible effects of a drug. In general, these other

types of studies use either cohort or case-control

methods. Thus, four types of studies are generally

used to identify drug effects: 1) controlled clinical trials, 2) spontaneous or voluntary reporting,

3) cohort studies, and 4) case-control studies (23,

50,61,77).

Controlled clinical trials match treatment and

control groups as closely as possible, minimize

bias through such methods as randomization and

“double-blinding,” and directly monitor patients

for the duration of the study. For example, patients can be randomly assigned to either the control or treatment group. The control group receives a placebo or an active comparison drug that

looks exactly like the drug being tested, and both

the investigators and patients do not know who

is receiving the real drug. (Personnel not directly

involved in the tests would of course know what

substance each patient was receiving). In this

method, possible drug effects, both therapeutic

and adverse, are closely monitored, so that they

are discovered as they occur.

The controlled clinical trial is considered the

most definitive method for evaluating a drug’s efficacy and safety, but the use of rigorous criteria

for patient selection usually means that the patients tested represent only a special class of the

anticipated users of the drug(s), and the carefully controlled conditions allow for study of fewer

patients than in the other methods, Thus, for example, to observe drug effects that are rare or that

appear only after long-term use, controlled clinical

trials might be impractical or too expensive.

Voluntary reporting may be spontaneous, such

as in a “letter to the editor” of a medical journal

about an unusual condition observed in a patient

on a particular drug, or it may be more organized,

as with the “yellow card” system in Great Britain.

Most of the reporting to the Food and Drug Administration (FDA) is by pharmaceutical manufacturers, who are required by law to report adverse

reactions. In practice, most of the information obtained by the manufacturers originates from physicians and other health professionals. Such observations serve as warnings of possible adverse drug

effects, so that the inference of an association between a drug and an observed health condition

may be further studied by cumulative, careful

reporting, and confirmed or disconfirmed by more

vigorous methods. Underreporting is a serious

deficiency of this voluntary method, and a drug

may also be wrongly associated with an adverse

effect until the suspected association fails to show

up in repeated, statistically validated studies.

Cohort studies follow a defined group of patients (the cohort) for a period of time. In this

method, patients are not randomly assigned to

groups, and there is no blinding. Cohort studies

are usually prospective, and observe the cohort

from the beginning of drug use. A group of patients taking the drug of interest is assembled and

followed to see, for example, if any adverse reactions occur. A second group of patients (the controls) with the same medical condition, who are

not taking the drug and who may be receiving

alternative treatment, but who are otherwise

matched as closely as possible with the cohort,

may be studied in parallel. The control group is

used to identify the frequency of occurrence of

31
32 Ž Postmarketing Surveillance of Prescription Drugs

any condition observed in the drug-exposed

group, but which must be due to causes other than

the drug (the “background incidence” of the condition). In this method, patients can be directly

monitored to ensure they take the drug appropriately and to observe the drug’s effects; or monitoring can be less systematic. With less monitoring,

a larger cohort can be followed, but bias is thus

increased.

Although uncommon, a retrospective cohort

study may also be conducted when purported

drug-induced effects have already been observed

at the time the study is started. A retrospective

cohort study must accurately ascertain patients’

past drug use. In principle, this could be done by

a “closed” pharmacy record system, in which users

have been restricted to a single supplier or payment source. In practice, the use data on individuals needs to be connected to data on their outcome, as through computer files. Medicaid, Medicare, the military, and some prepaid health maintenance organizations could be employed for this

purpose (76).

Case-control studies identify patients with the

adverse effects to be studied (the cases), and compare them with a sample (the controls), drawn

from the same cohort that gave rise to the cases.

Controls are matched as closely as possible with

the cases, except with regard to the drug’s suspected adverse effect, to examine whether exposure to the drug is the cause. Patients with conditions suspected of being associated with a certain

drug would have their medical records reviewed

or be interviewed concerning the use of that drug.

The histories of the controls would also be studied

for information about drug use in the general population. By comparing the proportion of drug

users among the cases with the proportion of drug

users in the general population, it is possible to

infer the relative frequency with which adverse

reactions occur in users of certain drugs as compared with nonusers. A sufficient number of appropriate cases must be identified and accurate

histories of exposure to drugs must be obtained.

Among the advantages of retrospective casecontrol studies compared with prospective cohort

studies are the smaller number of patients required

in retrospective case-control studies, the relative

ease of carrying out the study, the lower cost, and

the shorter time needed. A disadvantage of the

retrospective case-control method is that a condition must have been already identified and suspected as the effect of drug use. It is also harder

to reduce bias in a retrospective study than to do

so in a prospective one (65).

Bias is equally possible in cohort and case-control studies, though each kind of study is liable

to a different kind of bias. For example, bias in

the observations can arise with respect to identifying the effects of the drug in cohort studies and

with respect to identifying the exposure in casecontrol studies.

Controlled clinical trials and prospective cohort

studies can be used to determine a drug’s beneficial

as well as adverse effects. Case-control studies are

usually used to trace adverse effects back to prior

drug use. Voluntary reporting can uncover additional uses of drugs as well as their adverse effects, but reporting of adverse effects is much

more common.

DETECTION AND ASSOCIATION

The ability of a particular surveillance method these factors are more a problem in the design of

to detect a drug’s effect depends on two factors: a study’s details,

1) the time that transpires between use of that drug

and the occurrence of the drug’s effect (the laten- The latency of some drug effects presents a sericy period), and 2) how often the effect occurs (its ous problem for their study. Some effects occur

frequency). There are many other determining immediately, or within days or weeks after drug

factors, such as accuracy of observation, and ac- use, or with continued use of a drug. But other

curacy and completeness of medical records, but effects may occur long after a drug has been dis-
.

Ch. 4—Methods of Drug Evaluation ● 3 3

continued, or only when another drug is taken

simultaneously, or only in patients with certain

predisposing conditions. Other effects may not

be manifest in the patients themselves, but rather

in their children. The use of DES (diethylstilbestrol), in pregnant women, for example, has been

associated with vaginal cancer in their daughters,

but only after the daughters have reached adolescence.

Controlled clinical trials, because of their relatively short duration, will detect only acute or

subacute effects. Long-term cohort studies can

detect delayed effects, but the data bases necessary for such long-term, large studies are still

sparse. Voluntary reporting is usually the way in

which long-term effects are first identified. Longterm effects are usually confirmed through retrospective case-control studies, but their reliance on

historical data such as medical records can limit

the accuracy of these studies.

The chance that a particular study will discover

a drug effect also depends on the study’s sample

size and the frequency of the drug effect. For example, in a cohort study, if a drug causes blindness in 1 out of every 100 users (1/100), how

many users must be observed to find one case of

blindness? If there were 1 million users of the drug,

there would be 10,000 users blinded. But in a small

sample of only 100 users, the probability of finding one or more cases of blindness in the sample

would only be 63 percent. If the sample were 200

users, the probability would increase to 86 percent. With a sample of 500, the probability would

be 99 percent that at least one case of blindness

would be found in the observed users.

To state it another way, what number of users

would have to be observed to be 95 percent sure

of finding one or more cases of blindness when

they occur at a frequency of 1 in 100 users? The

answer is 300 users, and the general rule is that

the number of users in the sample must be three

times the reciprocal of the frequency; e.g., for a

frequency of 1 in 1,000, the sample would have

to be 3,000 to be 95 percent sure of observing at

least one case. Table 5 summarizes: 1) the probabilities of observing an adverse drug reaction

(ADR) for different sample sizes and frequencies,

and 2) the sample size required for various frequencies of an adverse reaction to be 95 percent

sure of observing that reaction. The numbers in

the bottom row are the sample sizes needed to be

95 percent sure of observing at least one ADR.

In table 6 are shown the sample sizes needed to

be 95 percent sure of observing one, two, or three

adverse reactions for the frequencies shown.

In a sample of 3,000, effects occurring at any

rate higher than 1/1,000 (e.g., 1/10, 1/50, 1/200,

etc. ) should be observed, and there will be a 95

percent probability of observing at least one effect that occurs at a frequency of 1/1,000. HowTable 5. —Likelihood of Observing an ADR (95% likelihood)

Threshold for an ADR

1 /100 1 /500a1/1,000b

1/5,000c 1/10,000d1/50,000e

Number of patients in

ADR study:

100 ., . . . . . . . . . . . . ... . 0,63 0.18 0.10 0,02 0.01 0.002

200 . . . . . . . . . . . . . . . . . . . . 0.86 0.33 0.18 0.04 0.02 0.004

500 . . . . . . . . . . . . . . . . . . . . 0.99 0.63 0.39 0.10 0.05 0.01

1,000, . . . . . . . . . . . . . . . . . . 0.99 0.86 0.63 0.18 0.10 0.02

2,000 . . . . . . . . . . . . . . . . . . . . 0,99 0.98 0.86 0.33 0.18 0,04

5,000 .., . . . . . . . . . . . . . . . . . 0.99 0.99 0.99 0.63 0.39 0.10

10,000 . . . . . . . . . . . . . . ., . . . 0.99 0.99 0,99 0.86 0.63 0.18

Number of patients required

to be 95°/0 likely to

observe an ADR . . . . . . . . . 300 1,500 3,000 —.

15,000——.

30,000 150,000

aForr example, Iymphoma from azothioprine

bFor ~xampl

e

, eye damage from practolol

CFor example, heart attack I n older women frp, oral contraceptives

dFor example, anaphylaxls from penlclllan

e Fo

r example aplastlc anemia from chloramphenlcol

SOURCE D L Sackett, et al ‘Compliance,”’ I n Monftorfng for Drug Safety W H W I n man (ed ) (Phi I adel ph la J B LI ppI ncot t

CO 1980)
34 . Postmarketing Surveillance of Prescription Drugs

Table 6.—Number of Patients Required To Detect

One, Two, or Three ADRs With No Background

incidence of Adverse Reaction (950/0 likelihood)

Required number of

Expected incidence of adverse reactions

adverse reaction 1 ADR 2 ADRs 3 ADRs

1 in 100 . . . . . . . . . . . . . . . 300 480 650

1 in 200 . . . . . . . . . . . . . . . 600 960 1,300

1 in 1,000 . . . . . . . . . . . . . 3,000 4,800 6,500

1 in 2,000 . . . . . . . . . . . . . 6,000 9,600 13,000

1 in 10,000 . . . . . . . . . . . . 30,000 48,000 65,000

SOURCE J A. Lewis, “Post-Marketing Surveillance How Many,” Trends in Phar. macological Sciences 2.93, 1981

ever, except for some effects that are unique to

a drug, many drug effects (e. g., stroke, heart attack) are indistinguishable from conditions due

to other causes. This “background incidence” of

a condition must be known before purported drug

effects observed in a study can rightly be attributed to a drug.

The sample size needed to be reasonably sure

that an observed condition is the drug’s effect

depends on the following factors: 1) the background incidence of the condition, 2) the additional incidence due to the drug, and 3) the size

of the control group, if the background incidence

is unknown (47). The quantitative relationships

among those factors are summarized in table 7,

which presents the sample sizes required to be 95

percent sure that an observed condition is due to

the drug and not to some other cause.

Larger sample sizes are needed to determine a

drug’s effect as the background incidence of a condition increases and as the frequency of the drug’s

added contribution to a condition decreases. This

is best explained graphically, as in figure 2. In this

example, the background incidence in every case

is 1/100. As the incidence of the added effect

decreases from 1 in 100 to 1 in 10,000, the sample size has to increase from 1,600 to 11 million

to remain 95 percent sure of observing the added

effect (see the rows in table 7 representing a

known background incidence of 1 in 100).

The relationship between background and

added incidence is also revealed in considering

sample sizes at the extremes. For a known background incidence of 1 in 1,000 and an added incidence of 1 in 100, the sample size needed to

observe at least one case of the added effect is only

500. But when the background incidence is 1 in

10 and the added incidence is only 1 in 10,000,

the sample size must be 98 million (table 7).

Table 7 also illustrates that another factor could

increase the sample size that a study requires. If

the background incidence is not known and has

to be estimated through observation of control

groups, the smaller the size of the control group,

the larger the sample size of drug users must be

for the same degree of confidence in the results

(compare the sample sizes required for control

groups equal to the treated group and for those

five times its size).

If there is a background incidence, the sample

size needed to observe a drug-induced effect rises

dramatically. Recall that a sample size of 3,000

was needed to be 95 percent sure of observing at

least one drug-induced effect with a frequency of

Table 7.–Number of Patients Required in Drug-Treated Group To Detect One ADR

With Background Incidence of Adverse Reaction (95% likelihood)

Number of patients required

with additional incidence of

Background incidence of adverse reaction to drug

Size of control group adverse reaction 1 in 100 1 in 1,000 1 in 10,000

“Infinite” (background incidence known) . . . . . . . . . . . 1 in 10 10,000 980,000 98,000,000

1 in 100 1,600 110,000 11,000,000

1 in 1,000 500 16,000 1,100,000

Five times as big as treated group . . . . . . . . . . . . . . . . 1 in 10 12,000 1,200,000 120,000,000

1 in 100 1,900 130,000 13,000,000

1 in 1,000 700 19,000 1,400,000

Equal to treated group . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 10 20,000 2,000,000 200,000,000

1 in 100 3,200 220,000 22,000,000

1 in 1,000 1,300 32,000 2,300,000

SOURCE J A Lewis, “PostMarketing Surveillance How Many, ” Trends m Pharmacological Sciences 2“93, 1981.
.

Ch. 4—Methods of Drug Evaluation ● 3 5

Figure 2.—Comparison of Additional Drug-Induced

Effects of Decreasing Incidence

1 in 100

Added incidence

Background incidence

1 in 1,000

I in 10(

SOURCE Office of Technology Assessment

1 in 10,000

I in 10(

—

1 in 1,000 and with no background incidence (table 6). If the background incidence is also 1 in

1,000, the sample size required rises to 16,000. A

background incidence higher than the drug’s

added incidence increases the sample size required

even more dramatically (to 110,000 and 980,000

for background incidence of 1 in 100 and 1 in

10 in table 7).

Many studies monitor for several effects, not

just one, and some apparent drug effects may have

occurred by chance. Minimizing these chance relationships also increases the sample size required.

Table 8 illustrates the hypothetical case where 100

effects will be examined in one study, and the sample size reflects a 95 percent chance that the observed effects will be related to use of the drug.

These sample size illustrations reflect, at the 95

percent confidence level, that an effect will be

observed and whether that effect can be attributed

to drug use. They do not provide a good estimate

of the added incidence of the effect from the drug

(recall from table 6 that a sample size of 3,000 is

needed just to detect at least one effect that has

an incidence of 1 in 1,000).

Controlled clinical trials are used primarily for

evaluating drug efficacy, not safety, because they

are carried out on hundreds, or, at the most, a

few thousand drug users. Their use for evaluating

drugs already on-the market is also limited by

their high cost and logistical problems, In fact,

the use of controlled clinical trials for determining efficacy alone is already constrained by these

two factors (9,46).

Table 8.—Number of Patients Required in Drug-Treated Group To Allow for

Examination of 100 Adverse Reactions (950/’ likelihood)

Number of patients required

with additional incidence of

Background incidence of adverse reaction to drug

Size of control group adverse reaction 1 in 100 1 in 1,000 1 in 10,000

“Infinite” (background incidence known) . . . . . . . . . . . 1 in 10 23,000 2,200,000 220,000,0%

1 in 100 3,100 250,000 24,000,000

1 in 1,000 800 321000 2,500,000

Five times as big as treated group . . . . . . . . . . . . . . . . 1 in 10 27,000 2,600,000 260,000,000

1 in 100 4,000 300,000 29,000,000

1 in 1,000 1,300 40,000 3,000,000

Equal to treated group . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 10 46,000 4,400,000 440,000,000

1 in 100 7,200 510,000 48,000,000

1 in 1,000 2,900 73,000 5,100,000

SOURCE” J A Lewis, “Post-Marketing Surveillance How Many, ”Trends m Pharmacological Sciences 2:93, 1981.
36 ● Postmarketing Surveillance of Prescription Drugs

These limitations of controlled clinical trials in

evaluating the safety of marketed drugs have led

to relying on cohort and case-control methods for

postmarketing studies. While these latter methods

can only indicate an association between a drug

and observed conditions, but not that the relationship is causal (49,77), the cumulative experience of multiple cohort and case-control

studies that show consistent associations between

a drug and a suspected effect can lead to a high

degree of confidence that the relationship is

causal.

The following three case studies illustrate the

use of the four methods of drug evaluation: controlled clinical trials, voluntary reporting, cohort

studies, and case-control studies.

CASE STUDIES IN DRUG EVALUATION

Oral contraceptives, the most investigated

drugs in use, were first associated with cardiovascular disease in 1966 by British researchers. Earlier

that year, they had noticed that Britain’s yellow

card system had revealed that relatively more reports of thromboembolism (heart attacks, strokes,

deep vein thrombosis of the legs with or without

emboli to the lungs) were associated with one type

of oral contraceptive than with another. A casecontrol study later that year established that there

was a significant association between oral contraceptive use and thromboembolism, but it found

no significant difference between the two contraceptive types (38). Publicity over these adverse

effects increased voluntary reporting, so that within 3 years more than 1,300 reports of thromboembolism had been received. By 1969, researchers

established that it was the total dose of estrogens,

not the different types of estrogen, that was responsible for any differences (39). As a result,

high-dose estrogen oral contraceptives were removed from the market in 1970. The association

between oral contraceptives and thromboembolism has been confirmed in other studies (15,51,

52,73,74).

It is now known that the risk of thromboembolic disease from oral contraceptives increases

with age. Young women have a chance of 1 in

20,000 of dying from the cardiovascular effects

of oral contraceptives (62); but a woman taking

oral contraceptives from age 35 to 45 has a risk

of death of about 1 in 1,000 over the 10-year period (32). The risk of heart attack from oral contraceptives has also been found to increase for patients who smoke cigarettes (52), so that older

women who smoke have the greatest risk.

Other conditions associated with oral contraceptives include gall bladder disease (6, 7), liver

tumors (l), yeast infections of the vagina (27), and

increased bacteria in the urine (78). Oral contraceptives have also been associated with jaundice,

but only in patients with a rare genetic condition

in which there is impaired biliary excretion of bilirubin, the Dubin-Johnson syndrome (14). Decreased effectiveness of oral contraceptives has

been associated with the use of anticonvulsants

and other drugs (54), but oral contraceptives have

also been associated with reduced incidence of

nonmalignant breast disease (8) and ovarian cysts

(58). Most, if not all, of these other conditions

associated with oral contraceptive use have been

observed in only a few studies, and the role of

contraceptives in producing them is not so clear

as it is in the case of the occurrence of cardiovascular conditions.

To illustrate that an association between a drug

and an observed condition may be too casually

inferred, it should be noted that in 1970, a

Swedish physician reported Down’s syndrome (or

trisomy 21, the most obvious symptoms of which

are mental deficiency and mongoloid features) in

two children whose mothers had taken oral contraceptives before pregnancy. At the same time,

one hospital reported increased numbers of children born with the syndrome. Sweden’s monitoring system therefore compared the incidence of

the syndrome during a period (1968-70) when oral

contraceptives were widely used with earlier

periods when oral contraceptives were not available. The incidence of the syndrome turned out

to be lower in the period of oral contraceptive use

(48). The public did not know of the investiga-
Ch. 4—Methods of Drug Evaluation ● 3 7

— — . ——

tion until it was completed. “One can easily imagine the worldwide alarm such a suspicion could

have caused” (3).

Streptokinase, a drug derived from group C

beta-hemolytic streptococci for use in dissolving

blood clots, was released for marketing in the

United States in November 1977, following its use

in Europe for many years. Bleeding, allergic reactions, and fever had been found in the premarketing clinical trials carried out on 535 patients.

Hoechst-Roussel Pharmaceuticals, manufacturers

of the drug, implemented a postmarketing surveillance study at the request of FDA. The study

lasted until May 1980, at which time FDA lifted

the postmarketing study requirement.

Hoechst-Roussel included a reporting form in

each package of the drug vials sent to hospital

pharmacies, and requested that the pharmacist

have treating physicians complete the forms.

Based on sales, the company estimated that reports were returned for about 20 percent of treated

patients, a total of 306 patients of 260 physicians

in 44 States and the District of Columbia,

Physicians were asked to rate treatment outcomes as “successful, ” “partially successful, ” or

“unsuccessful. ” Thirty-nine percent were reported

as “successful, ” 32 percent as “partially successful, ” and 30 percent as “unsuccessful” (percentages

rounded to nearest point).

Fifty percent of the patients (153/306) had a total of 208 adverse reactions, with 49 patients reported to have 2 or 3. The reactions reported were

the same as those seen in the clinical trials—allergic reactions, fever, and bleeding. Fifteen patients

suffered severe bleeding, and 48 less severe bleeding. Three patients with severe bleeding died, and

one had nerve damage secondary to bleeding

(femoral hematoma). Most patients recovered

from the drug reaction, but a total of 25 of the

306 patients died during or within a few weeks

of therapy. The investigators concluded that no

adverse reactions were discovered that were not

already known from the premarketing clinical trials and that their incidence and severity were similar (71).

This postmarketing study is instructive for a

number of reasons. First, it was necessary to select

the sample from marketing sources and to rely

on voluntary reporting, so there was a bias in patient selection, there were no controls, and the

criteria for effectiveness were vague. The low reporting rate of 20 percent is also typical of voluntary methods. Second, the purpose of the study

was “to determine whether the incidence and severity of adverse reactions with widespread use

would differ from that seen during clinical trials. ”

The investigators concluded that incidence, severity, and type of reaction were similar, but noted

that the final sample size was only 306, smaller

than that of the 535 patients in the premarketing

clinical trials. Adverse reactions with incidence

less than those observed in the clinical trials were

not likely to be discovered in the smaller postmarketing study. The strongest conclusion that can

be reached on the basis of the later study is that

the types of drug reactions in an uncontrolled patient population were similar to those of the more

carefully selected patients in the clinical trials.

Finally, this study illustrates a problem that is

often encountered in evaluating drugs. In contrast

to patients taking oral contraceptives, these patients were being treated for underlying diseases,

which can complicate the interpretation of what

is observed. For example, 25 of the 306 patients

died, 15 from pulmonary emboli and 4 from deep

vein thrombosis, both conditions that are related

to the diseases being treated, The investigators

concluded that these deaths occurred about as frequently as they did during the premarketing trials.

Cimetidine, an anti-ulcer drug that blocks the

release of stomach acid, was approved for marketing in August 1977. Because it was a new class

of therapeutic agent and was expected to be widely used—it was an alternative to surgery in reducing stomach acidity—a postmarketing study was

requested of the drug’s sponsor—Smith, Kline &

French Laboratories. The drug had become available a few years earlier in some other countries,

including Great Britain.

The sponsor established a cohort of about

10,000 patients by using its sales representatives

to enroll over 1,000 physicians who were asked

to complete case report forms on at least 10 patients for whom they would prescribe cimetidine

during a 3-month period starting in March 1978.
38 ● Postmarketing Surveillance of Prescription Drugs — ——————— . — —

A second phase (not reported by early 1982) was

to cover the following 6-month period. The expected 10,000 patient cohort would provide a 90-

percent probability of observing a drug effect with

an incidence of 1/4,348 and an 80-percent probability of observing one with an incidence of 1/

6,250. The physician response rate was 85 percent, with 9,907 case reports used in the study.

A control group was not included because of design and cost problems.

A total of 577 adverse reactions were reported

in 442/9,907 (4.4 percent) cases. The investigators

concluded that these adverse reactions did not differ in type or incidence from those observed in

the premarketing controlled clinical trials (31).

The most common drug reactions observed in

the patients were diarrhea and nausea or vomiting, Previous reports in the literature (i. e., spontaneous reporting) from Great Britain had postulated an association between cimetidine use and

mental confusion, blood dyscrasias, and endocrine effects. Some patients did develop such

symptoms, but the investigators concluded that

only the 18 cases of gynecomastia (breast swelling in males) and one case of blood abnormality

were related to cimetidine use.

There were 65 patient deaths during the 3-

month review period, none considered to be

cimetidine-related. Previous spontaneous reports

had also led to postulating an association between

cimetidine use and stomach cancer (19,34,60,70).

However, the hypothesis was viewed with skepticism, as people who have ulcers also have a higher

chance of developing stomach cancer. Though the

investigators did not address this possible effect

of cimetidine, they reported that the 19 patients

with tumor-related deaths were diagnosed for corresponding conditions before cimetidine therapy

began.

The year after this study was published, British

researchers reported experiments in humans on

the basis of which they speculated about how cimetidine could produce stomach cancer (59). The

investigators pointed out that the toxicological

data from long-term studies in rats and dogs did

not uncover any evidence of the drug’s carcinogenicity, but they contrasted these findings with

their experimental findings and with the spontaneous reports associating cimetidine use and stomach cancer in humans.

In contrast to the streptokinase study’s enrollment of a smaller cohort than the number of patients evaluated in the premarketing tests, the cimetidine postmarketing study was able to enroll its

goal of a cohort of nearly 10,000 patients. The

cimetidine postmarketing study, however, is of

interest for other reasons.

The published report covering only the first 3

months of cimetidine use found no difference from

the premarketing controlled clinical trials in the

types or incidence of adverse reactions. One

problem with postmarketing studies, however, is

to detect adverse reactions without prejudice

about what will be found. The findings of the premarketing clinical trials can provide guides for

what reactions to anticipate, but such guides

might cause the observer to overlook other adverse reactions associated with the drug under

study.

In contrast to the published preliminary findings, FDA’s review of this study, not yet complete

as of early 1982, suggests a lower rate of adverse

reactions than that observed in the premarketing

trials, although the types of adverse reactions and

their relative rates in the two are similar (10). This

last observation is in agreement with at least one

pharmaceutical company’s experience (66):

Some people might think postmarketing surveillance can sharpen up estimates of incidence

of adverse reactions seen in phase III trials. Phase

III trials, however, use trained investigators and

they ordinarily are treating the more severe patients. Both of these facts contribute to higher

adverse reaction rates in phase III studies than

one expects to get and actually gets in postmarketing surveillance studies.

Thus, in designing postmarketing studies, the

investigator must both be guided by the results

of the premarketing clinical trials and not be overly influenced by them.
5.

Current Activities

I
5.

Current Activities

The following discussion suggests only some of

the kinds of activities and resources that can contribute to postmarketing surveillance.

The Food and Drug Administration (FDA) obtains information on the postmarketing status of

drugs from four main sources: 1) pharmaceutical

manufacturers, 2) FDA contracts and grants,

3) other governmental agencies, and 4) international centers such as the World Health Organization (WHO). Figure 3 summarizes the data

sources available to FDA in its monitoring of

drugs.

Pharmaceutical manufacturers are required to

report all adverse reactions regardless of whether

a causal connection is believed to exist between

the drug and the symptom (CFR 21.310.301).

Most of these adverse events are reported by

physicians, and many manufacturers have routine

Figure 3.— Drug Experience/Epidemiologic Sources Available to FDA for

Postmarketing Surveillance and Risk Assessment

- — — — — — — —— - ——-—————— - — — — — . — — — — — — — — - — — — — — — — . — — — —

; FDA contracts/grants

I

P P

m

Boston ?uget Boston Boston

I Collaborative Sound Drug Children’s

I Drug Study HMO Epidemiology Hospital

I Unit Surveillance

I ——— ————— ——— —— —————— ———

Medicaid

Drug-Event

Data

— I ——I

Adverse reaction

registries

● Hepatic

● E y e

● Radio contrast

● Tissue (pathology)

● Radiopharmaceut ical

i

I

I

I

I

I

I

● Dermatologic

i

I I

I

I ● prescription Data Services I ] ● Medicaid

L

I

.——————————— — - i

Other Federal agency data sources

(partial list)

— ● Drug abuse warning network (DEA, NIDA)

l_- ~ c National morbidity, mortality data (NCHS)

Ž NIH-funded studies (e. g., NC I epidemiology

studies, etc.)

● N IDA drug abuse surveys

Pharmaceutical industry

SOURCE U S Food and Drug Adm(nlstratlon

47
42 ● Postmarketing Surveillance of prescription Drugs

_.—

procedures for responding to such spontaneous

reports. A number of companies also carry out

“product support studies” to interest physicians

in their products, and to defend a drug if it is

suspected of causing an adverse effect, or if questions are raised about its therapeutic value (12).

Manufacturers may also have to conduct a

“phase IV” postmarketing study as a condition of

marketing approval. Two examples of such research, that on streptokinase and cimetidine, were

described in chapter 4.

Some manufacturers are also attempting to develop their own surveillance programs. For example, Upjohn used group medical practices to

form a pharmacy-based cohort for prospective observational studies of selected drugs in order to

establish a large registry of patients to identify and

analyze important medical events through followup patient questionnaires (5).

FDA grants and contracts cover a number of

activities. Voluntary reporting by physicians to

medical journals and directly to FDA is augmented by several specialized registries:

●

●

●

●

The National Registry of Drug-Induced Ocular Side-Effects collects data from U.S. ophthalmologists on drugs and their effects.

The Registry of Patients Exposed to Radiopharmaceutical Drugs collects information

from a random sample of hospitals licensed

to practice nuclear medicine. All patients exposed to radiopharmaceuticals are registered,

and adverse effects are reported.

The Registry of Hepatic Toxicity to Drugs

collects data on drug reactions that affect the

liver.

The Registry of Dermatological Reactions to

Drugs, administered by the American Academy of Dermatology, was recently initiated

to collect data on reactions affecting the skin

and on reactions to dermatological drugs.

FDA purchases data from private organizations

to estimate the actual population using a drug.

One use of this data might be to determine

whether patients exposed to a drug have an increased risk of experiencing an adverse effect.

Another use might be to estimate the number of

patients who would be using a new drug to help

decide whether a postmarketing study of the drug

would be needed.

For example, FDA’s Division of Drug Experience contracted to use the Medicaid Medical Information Systems of Michigan and Minnesota

to link individual prescription and diagnostic

claim files for 1.2 million patients, to access and

tabulate the data, and to provide FDA with online terminal access to the data, to update the patient profiles on a quarterly basis, and to provide

specified reports. The Division of Drug Experience

plans to use this Medicaid data base for the following purposes: 1) investigation of what FDA

considers high-priority issues on adverse reactions, 2) development of data on drug utilization,

3) development of a screening system for hypothesis generation of unsuspected adverse effects, and

4) studies to describe and validate the usefulness

of the data base (25). Table 9 summarizes the anticipated uses of this data base. Table 10 identifies

this and other data sources available to FDA for

estimating actual populations of drug users.

In addition to using the Medicaid data from

Michigan and Minnesota to develop cohorts for

studies of drug use, FDA contributes to the support of several ongoing surveillance programs,

some of which include data collected from other

countries (e. g., Great Britain, New Zealand,

Israel).

The Boston Collaborative Drug Surveillance

Program (44) has accumulated data on the past

hospitalizations of more than 50,000 patients. This

data base is still useful for evaluating older drugs.

The program also uses current data from the

280,000 members of the Group Health Cooperative of Puget Sound (Washington State) and the

data files of the Commission on Professional and

Hospital Activities-Professional Activity Study in

Ann Arbor, Mich. These data sources are useful

for evaluating new drugs.

The Drug Epidemiology Unit at the Boston University Medical Center conducts case-control

studies (e.g., on birth defects), and also intensively

monitors pediatric hospital patients in collaboration with the Children’s Hospital Medical Center

in Boston.
—

Ch. 5—Current Activities ● 4 3

Table 9.— Potential Uses by FDA of Medicaid Data From Michigan and Minnesota

General descrlpt!on of study General use Example Anticipated future impact

Drug utilization

1. Overall characterization of drug

use by Medicaid population -

2.

3.

4.

Demographics of drug use

Drug use combinations

Drug use in diseased

individuals,

Drug adverse effects

1. Relative prevalence/incidence

of known adverse effects.

2, Rate of recognized drug

adverse effects.

3. Identification of drug adverse

effects by means of rate ratios

from case control or cohort

modules.

4. Detection of acute druginduced disease from temporal

clustering of events following

exposure.

Cross-validation with data on

drug use.

Identification of potential

high drug exposure problem areas,

Inappropriate drug use along

demographically defined

high-risk groups.

Inappropriate use of interacting drugs in individuals.

Inappropriate use of drugs

in certain risk groups defined by disease

Current rates of ADRs are

known only for common

drugs— this data base allows definition of relative

risk for most ADRs (except

rarest)

Supplement to spontaneous

reporting system.

Source of information on

perception and reporting

of ADRs.

Identify possible druginduced disease for further

investigation.

Identify possible druginduced disease for further

investigation.

.

Oral contraceptive use.

Use of isoxsuprine in pregnancy.

High codeine use,

Association of high-dose estrogen

oral contraceptives with older

premenopausal women.

Use of steroids in individuals on

oral hypoglycemic agents.

Use Of indomethacin in individuals with history of GI bleeding.

Relative rate of hepatic disorders

in erythromycin (estolate v, other

salt users).

Relative rate of heart failure in

disopyramide v. quinidine or procainamide users (alone and/or in

combination).

Estimates of rate of reporting (or

physician recognition) of ADRs

such as hepatitis, etc.

Association of Iaryngospasm with

NSAID.

Association of phenylpropanolamine with CVA.

SOURCE U S Food and Drug Administration

Table 10.—Data Sources Available to FDA for

Estimating Actual Populations of Drug Users

(current and future)

1. IMS America, Ltd.

● National Prescription Audit—survey of prescriptions

dispensed at pharmacies

● National Disease and Therapeutic Index—survey of

physician-patient contacts listing diagnoses and

therapies (not prescriptions)

● U.S. Hospital —survey of bulk sales to hospitals

● U.S. Drug Store— survey of sales to drug stores

Ž Audatrex —sample of physicians and their prescribing habits over time

2. Prescriptlon Card Service (PCS)—data on third-party

paid prescriptions, usually union, with national

estimates

3. Medicaid (exploratory) -data will be available on all

drug use, linked to clinical events, for 1.2 million patients in Michigan and 0.25 million patients in

Minnesota

Other than bulk sales to hospitals, there are no current national samples of hospital drug use.

SOURCE: US Food and Drug Administration

Confirmation of suspected problems (e.g., unlabeled uses).

Label changes.

Publication in medical literature,

ADR Highlights.

Labeling changes to indicate

demographically defined highrisk groups, ADR Highlights.

Labeling changes and publications

to warn against untoward drug

combinations that appear prevalent. ADR Highlights.

Publication to warn of apparent

prevalent misuse of drugs. Labeling changes as indicated. ADR

Highlights.

Labeling changes,

Publications (ADR Highlights and/

or medical literature).

General ability to place in perspective ADRs due to disease v. drug.

Also serves as information base

for insight into perceived druginduced disease.

Stimulate further research using

other data bases.

Labeling change/warning.

Stimulate further research using

other data bases.

Other governmental agencies also collect data

that may be of use to FDA:

●

●

●

The National Center for Health Statistics collects a wide variety of health data. FDA has

asked the center to collect drug data on death

certificates, and also to investigate the possibility of collecting drug information in its

National Ambulatory Medical Care Survey.

The National Centers for Disease Control

have a Birth Defects Monitoring Project to

alert for possible increases in the incidence

of birth defects. This project could help detect

birth defects due to drugs taken during pregnancy.

The National Cancer Institute’s Environmental Epidemiology Branch sponsors case-control studies to investigate associations between environmental agents (including drugs)
44 • Postmarketing Surveillance of Prescription Drugs

. —

●

and the development of specific types of cancer, using data from prepaid health plans.

The Drug Enforcement Agency and the National Institute on Drug Abusesurvey emergency rooms and coroners through their

Drug Abuse Warning Network to monitor

drugs that are abused and their association

with adverse reactions.

International monitoring activities include

WHO’s Program for International Monitoring of

Adverse Reactions, which has 23 participating

countries. FDA’s Division of Drug Experience is

the designated National Monitoring Center for the

United States. It exchanges reports with WHO,

each organization summarizing the adverse drug

reactions (ADRs) added to their systems in the

previous year. The purpose of WHO’s monitoring program is to increase the probability of detecting effects that might be overlooked by individual countries. Its chief value to the United

States is in providing information about drugs that

are available elsewhere in the world, but are not

yet marketed here.

Drugs may be introduced and used abroad for

a number of years before they are approved in

the United States. In fact, the more rapid approval

and introduction of drugs in other countries has

been one of the reasons behind the charge that

the U.S. drug approval process is too slow, keeping valuable drugs from the market. However,

this earlier introduction of drugs in other countries also uncovers adverse effects and helps

modify the indications for use before the drug is

released in this country, because the international

community can pool and share information on

the effectiveness, safety, and use of drugs.

Currently, FDA’s Division of Drug Experience

receives about 12,000 adverse event reports annually from industry (reports that are mandatory), the medical community, and others.

About three-quarters (60 to 80 percent) of these

reports come from manufacturers, who, in turn,

receive most of their reports from physicians.

Table 11 summarizes the sources of adverse event

reports for 1972-78, and table 12 identifies individual sources for fiscal year 1978. The relationship between these reported effects and drug use

varies greatly. For example, in 1977, approximately 150 reports were on deaths that were “definitely” or “probably” drug related, but more than 400

other reports were not clearly drug related or due

to overdoses (63).

The reports of the Division of Drug Experience

have been computerized and, depending on their

accuracy and completeness, can be screened or

retrieved in the following classifications (63):

by drugs or drug class related to the suspected

adverse reactions;

by adverse reaction related back to suspected

drugs;

by one of four cause-and-effect relationships:

definite, probable, possible, and remote;

by alert “yes” or “no,” meaning that the reaction is or is not novel, unanticipated, previously unreported, or not mentioned in the

product labeling;

by demographic data;

by source of report;

by possible interactions; and

by outcome of reaction.

Retrieval can also extend to original reports

on microfilm.

Table 11.— Number and Percentage of FDA’s Adverse Event Reports by Source, 1972-78

Source 1972 1973 1974 1975 1976 1977 1978

Manufacturers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9,750 6,700 6,807 8,097 7,664 8,945 9,143

(76.0% (62.20/o) (70.1 0/0) (7!j.2°/0) (63.80/,) (71.80/.)(81.2”/.)

Physicians/other health professionals . . . . . . . . . . . . . . . . . 2,189 985 699 2,138 1,862 1,335

(1.8°/0) (20.30/,) (10.1 ”Io) (6.6%) (17.8%) (15.0%) (11.90\o)

Hospitals. . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . . . . . . . . . . 2,559 1,690 1,306 859 423

(20.0%) (15.8%) (13.5°/0) (8.7%) (8.7%) ~ ,65 (6.9%) (4.0°/0 )

All other , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 182 611 917 358

(2.2%) (1.7%) (6.3%) (8.5%) (9.7%) (6.3% ——— — ) (3.7°/0)

Totals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12,837 10,761 9,709 10,756 12,012 12,459 11,259

SOURCE A Ruskin and C. Anello, “The United States of America, ”In Monitoring for Drug Safety, W. H, W, Inman (cd.) (Philadelphia’ J B. L}ppincolt Co , 1980)
Ch. 5—Current Activities . 45

Table 12.—Number of FDA’s Adverse Event Reports

by Specific Sources, Fiscal Year 1978

--

Number of

Source reports

Manufacturers . . . . . . . . . . . . . . . . . . . . . . . . . . .

Physicians/other health professionals:

Physicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Pharmacists . . . . . . . . . . . . . . . . . . . . . . . . . .

Dentists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hospitals:

Federal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Non-Federal . . . . . . . . . . . . . . . . . . . . . . . . . . . .

All other:

Consumer . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

District of Columbia, . . . . . . . . . . . . . . . . . . . .

Methadone Centers . . . . . . . . . . . . . . . . . . . . .

SOURCE US Food and Drug Administration

9,143

1,199

105

31

182

241

24

68

266

These reports are supplemented by a separate

but parallel literature search by FDA of l40 journals (in English) that focuses on serious adverse

effects not mentioned in the drug labeling. This

literature search is published monthly in FDA’s

“Current Drug Experience Literature.”

FDA has begun to use the computerized file of

ADRs in a screening method (screening of adverse

reactions, or SOAR) to assist its clinical reviewers

in identifying previously unsuspected adverse

reactions that might warrant in-depth clinical investigations. The SOAR method compares a

drug’s proportional share of specific adverse reactions (relative to its therapeutic class) with its

respective proportional share of drug use for a

particular time period. The latter data are derived

from national estimates of the total amount of a

particular drug dispensed during a 3-month

period, divided by the amount that would be used

per day. The resulting number would represent

the potential number of days a patient was exposed to the drug. An in-depth review may be

considered when the proportional share of reported adverse events relative to the proportional

share of drug use is greater than that predicted.

FDA’s postmarketing surveillance of ADRs is

not a surveillance “system” per se, but rather a

group of potentially related activities. Many of

these activities are not exclusively carried out for

FDA’s monitoring program. For example, the intensive monitoring programs to which FDA contributes support also collaborate in large-scale

clinical trials of drug efficacy that are sponsored

by the National Institutes of Health. Many of the

voluntary reporting systems, such as the specialized registries (e. g., those for ocular side effects,

dermatological reactions, and hepatic toxicity),

also have multiple purposes.

FDA’s monitoring is based primarily on voluntary reporting. The agency is just beginning to

establish the data bases needed to confirm or reject those possible associations between drugs and

adverse reactions that are first identified through

the various kinds of voluntary reporting.

These observations point to the following areas

of inquiry:

First, how can FDA’s coordination of its postmarketing surveillance activities be improved?

Currently, it is difficult to evaluate the monitoring activities in which FDA is involved, because

their emphasis so far has been on collection of

data, not on its final use; thus, the potential uses

of the data are largely unrealized.

Second, are FDA’s own voluntary reporting

and data-gathering programs and the other, more

specialized drug reaction registries it supports appropriately targeted and sufficiently utilized? A

recent General Accounting Office reevaluation of

FDA’s voluntary reporting system criticizes FDA’s

tardiness in evaluating and using these reports

(29). The relative value of the various specialized

registries to FDA’s monitoring responsibilities is

not known.

Finally, should FDA be responsible for testing

the hypothesis that a drug maybe associated with

an adverse reaction, or should that be the responsibility of the drug’s manufacturer? FDA could

support the formation of various prospective cohorts and coordinate that activity with the information FDA receives from voluntary reporting.

But FDA’s role could also be limited to helping

identify the most important drugs to monitor,

with the actual monitoring performed by the

drug’s manufacturers.
6.

Issues and Options
— .

Current interest

and monitoring is

approval process,

Issues and Options

n prescription drug evaluation

focused on the premarketing

while postmarketing surveillance has waned as a policy issue. The recommendations of the Joint Commission on Prescription

Drug Use, issued in January 1980, have not been

implemented, and the linchpin of its recommendations, a national Center for Drug Surveillance,

reached its zenith before the commission issued

its report when the center concept (renamed as

the “National Center for Drug Science”) was included in the 1979 bill that passed the Senate but

was not acted on by the House of Representatives.

In contrast, in the first session of the 97th Congress, the Senate passed the Patent Term Restoration Act of 1981, in large part as a direct

response to the length of the drug approval process. As mentioned earlier, the House of Representatives also voted on the bill, but under suspension of its rules. Although the bill received a majority of the votes, a two-thirds vote was required

for passage under such conditions, and the bill

fell just short of the two-thirds majority needed.

Shortly prior to publication of this report, the

report of the Commission on the Federal Drug Approval Process and the current Food and Drug

Administration {FDA) review will both also be

complete. Both focus on methods to hasten drug

approval by FDA.

Thus, policy formulation and implementation

for the premarketing approval process is being

pursued without parallel efforts for the postmarketing period. As one person has remarked (43):

I don’t really see that any significant shortening of approval time can be engaged in as a result

of a tradeoff in regard to postmarketing surveillance, although this was originally thought to be

a possibility when a former FDA commissioner

suggested that such was the case.

Others do see a linkage between the approval

process and postmarketing surveillance, although

they agree that there are no direct tradeoffs in the

kinds of information obtained (4):

Postmarketing evaluation studies can be conducted much more cheaply than clinical

trials . . . As a motivator for industry, it is

desirable to have the drug marketed sooner with

a return on investment while studies are being

conducted. At the same time, much larger observational studies can be done, at the same cost,

[to] evaluate drugs in their customary use situation. It is important to recognize that phase III

clinical trials and postmarketing drug evaluation

studies are not alternatives. They address different issues and are complementary. The appropriate question is whether it would not be better to reduce the size and cost of phase III with

limited likelihood of losing meaningful information and conduct much larger studies after

marketing.

Hence, some relationship does exist between

proposed changes in the premarketing approval

process and the monitoring activities of the postmarketing period. This relationship can be clarified by the answers to two questions. Can the size

and cost of phase III clinical trials be reduced with

limited likelihood of losing meaningful information? And, should pharmaceutical manufacturers

be required to maintain the level of their drug

evaluation responsibilities by increasing postmarketing surveillance?

Issue 1:

Revising premarketing tests and shortening the drug approval process.

The efficacy and safety tests in animals and

humans specified in FDA regulations for premarketing approval are based on broad statutory language (21 U. S. C., sec. 355 (d)). “Adequate tests

by all methods reasonably applicable” are necessary to show that a drug is safe for use. There

must also be “substantial evidence that the drug

will have the effect it purports or is represented

to have, ” where “substantial evidence” is defined

as “evidence consisting of adequate and wellcontrolled investigations, including clinical investigations, by experts qualified by scientific

49
50 . Postmarketing Surveillance of Prescription Drugs

training and experience to evaluate the effectiveness of the drug involved, on the basis of

which it could be fairly and responsibly concluded

by such experts that the drug will have the effect

it purports or is represented to have. ”

Efforts to shorten the drug approval process

have focused not on the statutory language but

on the regulations issued by FDA to implement

the law. Thus, the focus here is on oversight

issues, not on legislative changes.

Proposals to curtail or eliminate phase III premarketing tests, or shift them to the postmarketing

period can be evaluated both theoretically and

experientially.

Theoretically, phase III testing is significantly

more sensitive than phase 11 testing. Adverse effects with an incidence of 1/100 or more are more

likely than not to be detected in the 100 to 200

patients in phase II. But the theoretical sensitivity of detection rises in phase 111 to l/500 with

500 patients, and 1/1,000 with 1,000 to 3,000 patients (see ch. 4, table s).

These observations are relevant to the detection of adverse reactions, but they are not so relevant to the detection of therapeutic effects. A drug

that helps only 1 in 100 patients would not be very

effective, so effectiveness should be established

in phase II. Phase 111 is intended to gather additional evidence on a drug’s effectiveness for specific indications.

If phase 111 testing were curtailed or eliminated,

there is also the question of whether premarketing

evaluations would test sufficient numbers of patients to reasonably ensure a drug’s safety or give

substantial evidence of its efficacy. Even under

current regulations, the use of a drug on humans

is very limited before the drug is released for

market: 20 to 80 patients in phase I; 100 to 200

patients in phase II; and 500 to 3,OOO patients in

phase III—a range of only 620 to 3,280 patients

per drug (excluding controls). Curtailing the larger

phase 111 tests would lower the range of patients

tested to 620 to 780, and eliminating phase III tests

altogether would reduce that range further to 120

to 280 patients who would be tested with a drug

before it is released for general use.

In addition to theoretical criteria, experiential

criteria could be applied in considering proposals

to curtail or eliminate phase III tests. The diminished power to observe adverse drug effects that

such changes theoretically entail may not in fact

be found, or if it is, it may concern only infrequent minor effects. As was mentioned previously, FDA is reviewing past phase III tests to see if

the trials for chronic effects or those with large

sample sizes have contributed useful information

beyond that obtained in phase II and early phase

III. This review should indicate whether or not

actual experience reflects the theoretical differences discussed above between phase 11 and

phase III tests involving 500 versus l,500 to 3,000

patients. Agreement of the experiential data with

the differences theoretically predicted would

strengthen the hypothesis that curtailing phase 111

tests would lower the capacity of current premarketing tests to identify adverse reactions. If the

experiential data fail to reflect the theoretical differences, then a better case can be made for curtailing phase III, with or without transfer of some

of its testing to the postmarketing period.

Current interpretations of the statutory requirements for “adequate tests” of safety and “substantial evidence” of effectiveness emphasize methodology, as reflected in the requirement that each

indication for which a drug is intended be supported by at least two well-controlled clinical trials. This is the reason for the preceding discussion of statistical guidelines and the complementarity of normative guidelines in evaluating how

FDA revises its drug approval regulations and

procedures. But FDA can alter the criteria by

which it approves drugs. For example, propanolol, the first beta-blocking drug approved for

use in the United States, was approved by an advisory committee on the basis of all the evidence

presented to FDA, even though no one study was

found to be adequate and well controlled (21).

And in late 1981, timolol, another beta-blocker,

was approved for use in preventing death and recurrent heart attacks in patients who have survived initial heart attacks. This approval was

based on a foreign study—a 3-year Norwegian

study showing that the risk of death or a second

heart attack following a first heart attack was
. .

Ch. 6—issues and Options “ 51

reduced by about one-third when timolol therapy

began within 28 days and continued for up to 33

months (26). Although the study was Norwegian,

the results were accepted for publication by the

most prestigious medical journal in the United

States, the New England Journal of Medicine (57).

(Approval for another indication, high blood

pressure, was based on U.S. studies. )

Approval of timolol may also have been influenced by a similar study of propanolol in the

United States by the National Heart, Lung, and

Blood Institute (NHLBI). In the clinical trial of

propanolol, NHLBI’s Policy and Data Monitoring

Board took the unusual step of curtailing the trial

when data indicated that patients receiving propanolol experienced a 26 percent lower mortality from all causes than did a control group. According to the Beta-Blocker Heart Attack Study

Group (2):

The results . . . strengthen and extend the

conclusions of previous studies of beta-blockers

in survivors of acute myocardial infarction. This

large study of a noncardioselective agent is in accord with the results of the recent trial of timolol

maleate.

The criteria for FDA’s acceptance of timolol,

therefore, closely approximated the requirement

of two well-controlled clinical trials, notwithstanding the fact that one of these trials was performed in another country.

The approval of propanolol and timolol, however, do illustrate that FDA can grant exceptions

to its usual requirement of two well-controlled

U.S.-based clinical trials. In the case of timolol,

the validity of the Norwegian study was confirmed by its acceptance for publication in a prestigious U.S. medical journal, and even though approval was based on this one study, the results

of the NHLBI trial on propanolol, another betablocker, must surely have influenced the FDA

decision to approve timolol for prevention of

heart attacks. In the case of propanolol, the first

beta-blocker drug to be approved by FDA, approval was based on the preponderance of the

evidence as judged by an advisory committee.

In such a case, expert judgment relies on qualitative, not quantitative, criteria in approving a

drug, and such an approach falls outside the theoretical and experiential guidelines outlined above.

If FDA is to rely increasingly on such qualitative

criteria through the increased use of advisory

committees, it will be necessary for FDA to develop general guidelines to aid the advisory committees in their deliberations. Otherwise, in a caseby-case approach, evidence of the same quality

may lead to approval for one drug and nonapproval for another.

Issue 2:

Improving postmarketing surveillance

and its role in the drug approval process.

Controlled clinical trials, the most accepted scientific means of identifying and confirming a

drug’s effectiveness and safety, are used in drug

testing in the premarketing stage, but the evidence

they yield is necessarily limited because their sample sizes are small and the patients they test represent only a fraction of the kinds of patients who

will eventually use the drug. Other shortcomings

of small controlled clinical trials are that rare but

serious adverse effects or effects with a long latency will not be observed, and that average conditions of use are not duplicated. These limitations

of premarketing testing can only be addressed in

the wider use that comes with marketing the drug.

Thus, even if phase III testing were not curtailed

or eliminated, FDA’s powers in the postmarketing

period could be strengthened to enhance its surveillance role.

Generally, postmarketing surveillance “systems” that have been advocated are not systems

in the formal sense, but a series of related activities

oriented toward several purposes, with the regulatory approval process being only one use. The

activities most frequently mentioned include the

following three.

First is the building of a resource base through

training of additional experts and improving epidemiological tools such as methods for case-control and cohort studies. The concept of a national

Center for Drug Surveillance, advocated in the

report of the Joint Commission on Prescription

Drug Use, was one such attempt. Others believe,

in contrast, that the resources are already in hand.

According to Jick (40):
52 ● Postmarketing Surveillance of Prescription Drugs — — .

Contrary to the views stated in the report [of

the Joint Commission on Prescription Drug Use],

I believe that methods to efficiently perform

postmarketing surveillance are known and well

tested, and that a vast amount of data has

already been collected to evaluate drug toxicity.

Remington states (61):

IM]ethods for estimating characteristics of

large populations, although available since the

1940’s, have not been assimilated to any appreciable extent into the field of drug evaluation . . .

I think we must begin to apply modern mass

population methods to modern problems of drug

evaluation, both at the pre- and post-marketing

levels. Such methods, however, are particularly

appropriate to the evaluation of marketed drugs.

Second is strengthening voluntary reporting to

identify possible adverse drug reactions. Once

such reactions are suspected, clinical trials, casecontrol, and cohort studies could be used to determine whether an association with drug use in fact

exists. In this regard, FDA has come under criticism insofar as its adverse drug reaction reporting activities are concerned. For example, the activities listed in chapter 4 have been criticized as

being little more than a catalog, with no assessment of the relative values of the various activities

(80). Furthermore, in a recently released followup

to a study conducted in 1974, the U.S. General

Accounting Office concluded (29):

Many adverse reaction reports do not get to

the Division maintaining the system and many

others require a long time to get into the system.

Some of the missing or late reports involved serious reactions which were not discussed in the

drug labeling. Reporting by non-manufacturer

sources, such as hospitals or physicians, could

also be increased.

Third is developing an efficient method for

monitoring selected drugs after their release into

the market. The most frequently mentioned mechanism is formation of prospective cohorts of drug

users, utilizing existing data bases such as those

previously identified, i.e., Medicaid, Medicare,

the military health systems, and some health

maintenance organizations. In the opinion of one

expert, appropriate large-scale systems are available, but only drug companies currently use them

(41).

These components of a postmarketing surveillance “system,” and FDA’s role in supporting and

using them, are oversight issues.

There are also several legislative options that

could strengthen FDA’s powers in the postmarketing period. The following legislative options

are presented for congressional consideration.

Option 1: Give FDA the power to require

postmarketing studies.

Currently, FDA has no express power to require

a drug’s sponsor to conduct postmarketing studies

of the types summarized earlier under “phase IV”

testing. Drug companies have agreed to such requests in the past, however, because refusal might

mean nonapproval of the drug.

FDA is examining these studies to see if they

provided the kinds of information identified in its

objectives for “phase IV” testing. Additional questions are to determine when adverse reactions became specified on the package insert, and whether

the source of the identification of adverse reactions was spontaneous reports, the postmarketing

study, or both.

However, a broader analysis is needed, one that

does not focus only on these specific studies. It

would be helpful if FDA also assessed a sample

of drugs that have been marketed for several years

to see if significant additional adverse reactions

were later discovered that were not uncovered

during premarketing trials. Or a study could be

conducted on the significant adverse events that

were discovered during the postmarketing period.

In either of these latter types of studies, the assessment focus should be on whether the adverse effects could have been discovered through studies

of the kinds performed by the manufacturers at

FDA’s request. This assessment could provide additional information for deciding whether formal

postmarketing monitoring would be valuable.

The larger postmarketing studies carried out by

manufacturers at the request of FDA have cost

$1 million to $3 million each (11), and the industry

is certain to resist giving FDA explicit authority

to require them. Industry might be more willing

to conduct postmarketing studies if the drug approval process were shortened, however, since it
——. — — —

could obtain a quicker return on its investments.

In the absence of such a tradeoff, Congress could

consider increasing FDA’s appropriations to finance selected postmarketing studies on a drugby-drug basis.

A variation of this option is for FDA to use its

existing regulatory powers over advertising and

promotional practices to “certify” an industrysponsored postmarketing study. Although initially reluctant to conduct postmarketing studies, the

industry now sees them as part of its marketing

strategy. Physicians may cease to cooperate, however, if they feel they have been used to promote

a company’s product. FDA certification could be

used to distinguish between postmarketing monitoring and “product support studies” that are used

to interest physicians in a manufacturer’s products

and to defend a drug’s safety and therapeutic

value (69).

Option 2: Give FDA the power to restrict the

distribution, dispensing, and administration of a

drug.

FDA has considerable power in withholdir,g approval for a drug, but once a drug is approved,

there is a significant shift in the burden of proof

and in the amount of evidence required to rescind

approval. If FDA had the authority to restrict

drug marketing or less burden of proof in rescinding approval, it might give approval more freely

in the first place. Restrictions on drug use and a

lesser burden of proof for FDA to rescind approval would be particularly pertinent in the first several years of marketing, when adverse effects are

still quite likely to be identified. The therapeutictoxic ratio of some new drugs is so narrow that

it seems reasonable to provide the means whereby

FDA can restrict the use of certain prescription

drugs to groups of specially trained or experienced

physicians.

S. 1075, the bill introduced in 1979 and passed

by the Senate, would have given restrictive powers to FDA, provided that: 1) the drug presented

significant risks to patients or the public health;

2) a drug could not be determined to be safe unless

restrictions on distribution and dispensing were

imposed; 3) the restrictions could reasonably be

expected to reduce the risks while permitting its

use in appropriate patients; and 4) no other adCh. 6—Issues and Options ● 5 3 — —

ministrative or educational actions permissible

under the law could reasonably be expected to

reduce the risks. The bill also would have allowed

a drug to be restricted to practitioners with special

training or experience in its use or to practitioners

for use in certain facilities, but only if this were

necessary to determine drug safety; and no practitioners could be excluded solely on the basis that

they were not eligible for certification in a medical

specialty. The 1979 Senate bill also would have

required FDA to review any imposed restrictions

every 2 years.

The Medical Device Amendments of 1976 (Public Law 94-295) contains somewhat similar language in its section on “restricted devices. ” According to this amendment, a device could be restricted in its sale, distribution, or use if, “because

of its potentiality for harmful effect or the collateral measures necessary to its use, the Secretary

determines that there cannot otherwise be reasonable assurance of its safety and effectiveness. ” The

law also contains a prohibition against excluding

practitioners solely because of their ineligibility

for certification in a medical specialty (21 U. S. C.,

sec. 360j(e)).

In a limited or phased distribution, drugs could

be introduced into different geographic regions

rather than into the whole country at once. The

regions could be chosen with attention to the fact

that some drugs are used more in one part of the

country than another. Introduction of drugs on

a regional basis could also provide some insurance

against unexpected adverse effects in that less of

our population would be at risk, but different regions could be used for the first marketing of different drugs so that no one region would be the

“guinea pig. ” By specifying the regions well, comparable regions could be compared for reported

side effects (.5.5).

A variation of this option is to develop a parallel approval process for the use of a limited group

of drugs during phase III testing. This special

phase III testing would be considered only as a

relatively exceptional procedure restricted to drugs

of unusual need and promise. For drugs of apparent unusual therapeutic value compared with alternative therapies and with acceptable risk, a

limited number of physicians could be permitted
54 ● Postmarketing Surveillance of prescription Drugs

to use a drug without the fully detailed recordkeeping requirements of phase III (28).

Option 3: Change the standard for a drug’s removal from the market from “imminent hazard

to the public health” to “unreasonable risk of illness or injury to any segment of the population”

or some other less stringent standard.

Such a change was contained in the 1979 Senate

bill. However, under the present law, the “imminent hazard” standard is to be used only in cases

where a drug’s harmful effect would be so immediate and severe as to justify suspension of due

process until after the drug has been removed

from the market. The “imminent hazard” standard applies only to cases where FDA suspends approval of a drug first, then gives the drug sponsor prompt notice and an opportunity for an expedited hearing. FDA otherwise can remove a drug

from the market on the basis of new evidence on

safety or effectiveness or for other reasons such

as discovering that approval of the drug was based

on an untrue statement of a material fact. To take

such action, however, FDA must give due notice

and an opportunity for a hearing before it can proceed.

Substituting “unreasonable risk” for “imminent

hazard” in the standard would blur the present

distinction between those cases when due notice

and opportunity for a hearing should be required

before a drug could be taken off the market and

those cases when it would be justified to remove

a drug from the market prior to notice and an opportunity for a hearing. In other words, “unreasonable risk” is already the standard for those

cases when, in order to protect the drug sponsor’s

economic interests, FDA must give due notice and

an opportunity for a hearing before taking action.

If such a change in the standard were approved,

FDA would be able to remove a drug for any of

the currently accepted reasons to question safety

without first giving notice and an opportunity for

a hearing.

In the Medical Device Amendments of 1976,

no such “imminent hazard” standard is specified.

There is, however, a slight difference in the wording of the law. It states that, if a drug does not

represent an “imminent hazard, ” withdrawal of

the drug’s approval can proceed “after due notice

and opportunity for a hearing” (21 U. S. C., sec.

355(e)). For devices, withdrawal of approval can

proceed “after due notice and opportunity for informal hearing” (emphasis added) (21 U. S. C., sec.

360(e)).

In sum, efforts to shorten the drug approval

process in the premarketing period could take

place through reinterpreting the guidelines for assessing safety and efficacy. This report has provided theoretical and experiential criteria for evaluating how such changes could affect the detection capabilities of the current guidelines. It has

also discussed the desirability of guidelines for the

kinds of qualitative changes FDA is implementing

regarding the evidence required for drug approval.

These changes include accepting foreign data and

cumulative evidence (as opposed to the requirement of at least two well-controlled clinical trials).

Finally, the report has identified options relating

to FDA’s postmarketing surveillance. These options could be pursued independently of any revisions in the premarketing drug approval process,

but they could also be implemented to require

drug sponsors to maintain their level of drug evaluation responsibilities if there is a change in current premarketing approval requirements.
Appendixes
Appendix A.— Selected Excerpts From the

Statutes Governing Drugs and Medical Devices ——

Drugs

Grounds for refusing application; approval of application; “substantial evidence” defined (21 U. S. C., sec.

355(d)).

If the Secretary finds after due notice to the applicant in accordance with subsection (c) of this section

and giving him an opportunity for a hearing, in accordance with said subsection, that (1) the investigations, reports of which are required to be submitted

to the Secretary pursuant to subsection (b) of this section, do not include adequate tests by all methods reasonably applicable to show whether or not such drug

is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof;

(2) the results of such tests show that such drug is unsafe for use under such conditions or do not show that

such drug is safe for use under such conditions; (3) the

methods used in, and the facilities and controls used

for, the manufacture, processing, and packing of such

drug are inadequate to preserve its identity, strength,

quality, and purity; (4) upon the basis of the information submitted to him as part of the application,

or upon the basis of any other information before him

with respect to such drug, he has insufficient information to determine whether such drug is safe for use

under such conditions; (5) evaluated on the basis of

the information before him with respect to such drug,

there is a lack of substantial evidence that the drug will

have the effect it purports or is represented to have

under the conditions of use prescribed, recommended,

or suggested in the proposed labeling thereof; or

(6) based on a fair evaluation of all material facts, such

labeling is false or misleading in any particular; he shall

issue an order refusing to approve the application. If,

after such notice and opportunity for hearing, the Secretary finds that clauses (1) through (6) do not apply,

he shall issue an order approving the application. As

used in this subsection and subsection (e) of this section, the term “substantial evidence” means evidence

consisting of adequate and well-controlled investigations, including clinical investigations, by experts

qualified by scientific training and experience to

evaluate the effectiveness of the drug involved, on the

basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested

in the labeling or proposed labeling thereof.

Withdrawal of approval; grounds; immediate suspension upon finding imminent hazard to public health

(21 U. S. C., sec. 355(e)).

The Secretary shall, after due notice and opportunity for hearing to the applicant, withdraw approval of

an application with respect to any drug under this section if the Secretary finds (1) that clinical or other experience, tests, or other scientific data show that such

drug is unsafe for use under the conditions of use upon

the basis of which the application was approved;

(2) that new evidence of clinical experience, not contained in such application or not available to the

Secretary until after such application was approved,

or tests by new methods, or tests by methods not

deemed reasonably applicable when such application

was approved, evaluated together with the evidence

available to the Secretary when the application was

approved, shows that such drug is not shown to be

safe for use under the conditions of use upon the basis

of which the application was approved; or (3) on the

basis of new information before him with respect to

such drug, evaluated together with the evidence available to him when the application was approved, that

there is a lack of substantial evidence that the drug will

have the effect it purports or is represented to have

under the conditions of use prescribed, recommended, or suggested in the labeling thereof; or (4) that the

application contains any untrue statement of a material

fact: Provided, That if the Secretary (or in his absence

the officer acting as Secretary) finds that there is an

imminent hazard to the public health, he may suspend

the approval of such application immediately, and give

the applicant prompt notice of his action and afford

the applicant the opportunity for an expedited hearing under this subsection; but the authority conferred

by this proviso to suspend the approval of an application shall not be delegated. The Secretary may also,

after due notice and opportunity for hearing to the applicant, withdraw the approval of an application with

respect to any drug under this section if the Secretary

finds (1) that the applicant has failed to establish a

system for maintaining required records, or has repeatedly or deliberately failed to maintain such records

or to make required reports, in accordance- with a

regulation or order under subsection ( j ) of this section

or to comply with the notice requirements of section

360(j)(2) of this title, or the applicant has refused to

permit access to, or copying or verification of, such

records as required by paragraph (2) of such subsec57
58 ● Postmarketing Surveillance of Prescription Drugs ——— — — ——.— ——

tion; or (2) that on the basis of new information before

him, evaluated together with the evidence before him

when the application was approved, the methods used

in, or the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to assure and preserve its identity, strength,

quality, and purity and were not made adequate within a reasonable time after receipt of written notice from

the Secretary specifying the matter complained of; or

(3) that on the basis of new information before him,

evaluated together with the evidence before him when

the application was approved, the labeling of such

drug, based on a fair evaluation of all material facts,

is false or misleading in any particular and was not

corrected within a reasonable time after receipt of written notice from the Secretary specifying the matter

complained of. Any order under this subsection shall

state the findings upon which it is based.

Devices

Restricted devices (21 U. S. C., sec. 360j(e)).

The Secretary may by regulation require that a

device be restricted to sale, distribution, or use—

(A) only upon the written or oral authorization of

a practitioner licensed by law to administer or use such

devices, or

(B) upon such other conditions as the Secretary may

prescribe in such regulation, if, because of its potentiality for harmful effect or the collateral measures necessary to its use, the Secretary determines that there

cannot otherwise be reasonable assurance of its safety and effectiveness. No condition prescribed under

subparagraph (B) may restrict the use of a device to

persons with specific training or experience in its use

or to persons for use in certain facilities unless the

Secretary determines that such a restriction is required

for the safe and effective use of the device. No such

condition may exclude a person from using a device

solely because the person does not have the training

or experience to make him eligible for certification by

a certifying board recognized by the American Board

of Medical Specialties or has not been certified by such

a Board. A device subject to a regulation under this

subsection is a restricted device.

Withdrawal of approval of application for premarket

approval (21 U. S. C., sec. 360e(e)).

The Secretary shall, upon obtaining, where appropriate, advice on scientific matters from a panel or

panels under section 360c of this title, and after due

notice and opportunity for informal hearing to the

holder of an approved application for a device, issue

an order withdrawing approval of the application if

the Secretary finds—

(A) that such device is unsafe or ineffective under

the conditions of use prescribed, recommended, or suggested in the labeling thereof;

(B) on the basis of new information before him with

respect to such device, evaluated together with the

evidence available to him when the application was

approved, that there is a lack of a showing of reasonable assurance that the device is safe or effective under

the conditions of use prescribed, recommended, or suggested in the labeling thereof;

(C) that the application contained or was accompanied by an untrue statement of a material fact;

(D) that the application (i) has failed to establish a

system for maintaining records, or has repeatedly or

deliberatel y failed to maintain records or to make

reports, required by an applicable regulation under

section 360i(a) of this title, (ii) has refused to permit

access to, or copying or verification of, such records

as required by section 374 of this title, or (iii) has not

complied with the requirements of section 360 of this

title;

(E) on the basis of new information before him with

respect to such device, evaluated together with the

evidence before him when the application was approved, that the methods used in, or the facilities and

controls used for, the manufacture, processing, packing, or installation of such device do not conform with

the requirements of section 360j(f) of this title and were

not brought into conformity with such requirements

within a reasonable time after receipt of written notice

from the Secretary of nonconformity;

(F) on the basis of new information before him, evaluated together with the evidence before him when the

application was approved, that the labeling of such

device, based on a fair evaluation of all material facts,

is false or misleading in any particular and was not

corrected within a reasonable time after receipt of written notice from the Secretary of such fact; or

(G) on the basis of new information before him,

evaluated together with the evidence before him when

the application was approved, that such device is not

shown to conform in all respects to a performance

standard which is in effect under section 360d of this

title compliance with which was a condition of approval of the application and that there is a lack of

adequate information to justify the deviation from

such standard.
. —

Appendix B.— Conclusions and Recommendations of the

Joint Commission on Prescription Drug Use, Jan. 23,1980

1. Postmarketing surveillance (PMS) can be used to

develop information about prescription drugs that is

unavailable from premarketing studies but necessary

and, or useful for the clinical practice of medicine or

ongoing regulation of drugs. Existing postmarketing

surveillance programs should be coordinated with new

programs to form a comprehensive system.

2. The purpose of postmarketing surveillance is to

detect important drug effects earlier than would otherwise be possible. The surveillance, per se, or its results

will not and cannot be used to change the biological

properties or effects of drugs, but they can be used to

minimize the harmful consequences and maximize the

optimal use of drugs.

3. Certain risks posed by a PMS system must be recognized, accepted, and addressed, although they are

judged by the Commission to be far outweighed by

potential benefits.

4. Highest priority in a PMS system should be given

to surveillance of new chemical entity prescription

drugs, delayed or slowly developing drug effects,

commonly used drugs, populations in which drug effects are not well documented, certain important medical events (e. g., births, deaths, etc. ) and their relationship to drug use, and patterns of prescription drug

use. Other, but secondary, priorities should include

the study of: certain important non-prescription drugs,

the drug-taking practices of patients, the frequency of

given drug effects, dose-response relationships, the

characteristics of patients who experience certain effects as compared to those who do not, the relative

risks and benefits of individual drugs, changes in frequencies of drug effects over the course of time, and

the comparative efficacy and safety of different drugs

within the same class.

5. PMS must operate, to the maximum extent possible, in a setting of actual medical practice. In the majority of instances, PMS should be concerned primarily

with drugs marketed without special restrictions beyond those already enforced for drugs of certain

classes. Data collection for PMS should not interfere

with the normal delivery of health care.

6. A PMS system will require both an alerting (hypothesis-generating) mechanism and a confirming or

rejecting (hypothesis-testing) mechanism. Hypotheses

must be recognized as suggestions about cause-effect

relationships and not as established fact.

7. An hypothesis-generating mechanism should

ideally have access to all animal and clinical data about

a drug.

8. A great deal of selectivity will be required for

judicious decisions about which of the available hypotheses to test.

9. PMS must insure that great attention is paid to

research design and to the sequence of studies. Particular attention should be paid to the validity of the

methodology and to the sample size required. Possible types of study are prospective or retrospective, experimental or non-experimental, controlled or uncontrolled, cohort or case-control, studies of drugs or of

events, and studies of prophylactic, therapeutic, or

diagnostic drugs.

10. Development of new methodology for study of

drug effects must be a high priority for the PMS

system.

11. The drug effects requiring study will be expected

toxicity, unexpected toxicity, intended efficacy and unintended efficacy.

12. Currently available methodology can be used

to study expected or unexpected toxicity and unintended efficacy, successfully detecting events that occur with a frequency of at least one event per 1000 exposures. Less frequent events (e.g., one in 10,000 uses)

can be detected less reliably.

13. The Commission strongly recommends against

PMS that ignores the determination of intended efficacy and of long-term drug effects.

14. An intensive system of surveying the medical

literature should be established and particular attention given to a systematic review of data comparing

drug responses in various countries.

15. A PMS system should develop methods of seeking and receiving brief reports from large numbers of

health professionals.

16. Prospective, non-experimental cohorts that are

long-term and lifelong, if possible, should be established for PMS studies.

17. Liaison between the various components of a

PMS system will be necessary. This would require

development of a standardized terminology for describing PMS and for use in PMS.

18. Reports must be prepared, published and distributed to aIl parties involved in or affected by PMS.

Multiple types of reports will be necessary, tailored

to the differing needs and interests of the recipients.

19. For a prescription drug surveillance system to

59
60 Ž Postmarketing Surveillance of Prescription Drugs

be effective, it must have the confidence of the public

at large, including health care providers and patients.

This confidence must extend not only to the validity

of the information generated, but also to the manner

in which the information will be used.

20. In order to maintain trade secret protection for

manufacturers without prejudicing the PMS system’s

public and academic accountability, only the FDA

should have the power to require the disclosure of such

secrets. Because of this restriction, the FDA must

assume responsibility for reviewing this trade secret

data for any hints of drug effects in man that it may

contain.

21. In order to protect patient confidentiality, individually identifiable information should be kept

strictly confidential by any PMS system unless patients

specifically authorize release, with only the following

exceptions:

a.

b.

c.

Such information could be released to organizations engaged in similar research if an express

finding with supporting written statements is prepared documenting that such disclosure is necessary and identifying the individual receiving the

information. Such organizations must have comparable guarantees of confidentiality as the organization releasing the data. Redisclosure by the

receiving organization would be prohibited without written approval of the original organization.

Disclosure could be made to a properly identified

recipient pursuant to a bona fide medical emergency.

Both patient and provider must have access to

their own identifiable data and the ability to

make corrections or amendments.

22. Given the fact that the law is developing on the

issue of provider liability for disclosing patient identifiable medical records, the Commission recommends

that the organizations concerned with PMS review the

issue of liability as they begin to undertake PMS

functions.

23. In order to assure adequate security for data

gathered, a PMS organization should:

a. Maintain only that information which is relevant

and necessary to accomplish the purpose.

b. Maintain all records used in making any decisions

about an individual with such accuracy, relevance, timeliness, and completeness as is reasonably necessary to assure fairness to the individual

in the determination.

c. Establish administrative, technical, and physical

safeguards to insure the security and confidentiality of records.

24. The value for PMS of a limited shield law is recognized. Such a law would specify that identifiable information of the patient or provider submitted voluntarily to a PMS organization could not be admissible

as evidence in a medical or product liability action,

and might remove a deterrent to voluntary reporting.

Even without such a law however, the PMS functions

of the CDS [Center for Drug Surveillance] should commence and the results should be used to define whether

evidence needs to be gathered to support the need for

and formation of shield law in order to have an optimal PMS system.

25. A national Center for Drug Surveillance (CDS)

is necessary in the United States.

26. The objectives and functions of the CDS should

be to educate scientists, prescribers and the public, to

perform and encourage research into drug effects and

to promote cooperation among all existing PMS programs.

27. In using its resources, the CDS must be strictly

accountable for fairness, scientific accuracy, and

honesty.

28. The activities of the Center for Drug Surveillance (CDS) should not unnecessarily duplicate the

functions of other organizations engaged in PMS activities, whether public or private.

29. The CDS should be a private, non-profit, nonregulatory organization with a full-time staff and a

physical facility located in an environment that can

support and be supported by academic endeavors.

30. After five years, there should bean external review of the effectiveness of the CDS. If the projected

benefits from the CDS are not realized, the CDS

should be abandoned.

31. Support for the CDS should be in addition to,

not instead of, added support for other worthwhile

PMS activities,
—

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Walker, A. M., Sidney Farber Cancer Institute,

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Index
Index

abbreviated new drug application

adverse drug reactions (ADRs), 4,

37, 41, 42, 43, 45, 50, 51, 52

in Great Britain, 23-25, 38

in Japan, 23

international monitoring, 44

screening of (SOAR), 4 5

17

19, 24, 25, 33, 34/ 35,

American Academy of Dermatology, 42

authority for refusing application; approval of

application, 57-58

Beta-Blocker Heart Attack Study Group, 51

Birth Defects Monitoring Project (National Centers for

Disease Control), 43

Boston Collaborative Drug Surveillance Program, 41, 42

Boston University Medical Center Drug Epidemiology

Unit, 41, 42

case studies in drug evaluation, 36-38

Center for Drug Surveillance, 60

Children’s Hospital Medical Center (Boston, Mass.), 41,

42

cimetidine, 19, 37, 38, 42

Commission on Professional and Hospital Activities—

Professional Activity Study (Ann Arbor, Mich. ), 42

Commission on the Federal Drug Approval Process, 5,

27, 49

compassionate IND, 15

conclusions and recommendations of the Joint

Commission on Prescription Drug Use, 59-60

Congress:

acts of (see legislation)

House Committee on Energy and Commerce,

Subcommittee on Health and Environment, iii

House Committee on Science and Technology:

Subcommittee on Natural Resources, Agriculture

Research and Environment, 6, 27

Subcommittee on Investigations and Oversight,

6, 27

Senate Committee on Labor and Human Resources,

Subcommittee on Health, 5, 26

current activities that contribute to postmarketing

surveillance, 41-45

Department of Commerce, 5, 2 7

Department of Health, Education, and Welfare (now

DHHS), 5

Review Panel on New Drug Regulation, 26

Secretary of, 14, 57-58

diethylstilbestrol, 23, 33

Down’s syndrome, 36

drug approval process, 4-5, 13-19

drug classification, 16

Drug Enforcement Agency, 44

Dubin-Johnson syndrome, 36

Experimental Technology Incentives Program (ETIP),

5, 27

Food and Drug Administration (FDA) (Department of

Health and Human Services), 3, 4, 5, 6, 7, 8, 9, 10,

13, 14, 15, 16, 17, 18, 26, 27, 31, 37, 38, 41, 42,

43, 44, 45, 49, 50, 51, 52, 53, 54

authority, 3, 4, 26, 27, 28, 49, 51, 52, 53, 54

Bureau of Biologics, 6, 27

Bureau of Drugs, 6, 27

Current Drug Experience Literature, 45

Division of Drug Experience, 42, 44

National Center for Drugs and Biologics, 6, 27

New Drug Evaluation Division, 6, 27

monitoring questions, 45

refusing application, 57-58

removal of drugs, 53, 54

General Accounting Office (GAO), 45, 52

glossary of acronyms, ix

Great Britain:

adverse drug reactions, 23-25

oral contraceptives, 36

postmarketing surveillance, 23

practolol syndrome, 23

voluntary reporting system, 23

yellow card, 23, 24-25, 31, 36

Group Health Cooperative of Puget Sound, 41, 42

history and objectives of postmarketing surveillance,

23-28

Hoechst-Roussel Pharmaceuticals, 37

improving postmarketing surveillance, 9-10, 51-54

IND application process, 13

investigational new drug (IND), 4, 5, 14, 15, 16

clinical investigations:

Phase I: Clinical pharmacology, 4, 9, 13, 14, 15, 17

Phase II: Clinical investigations, 4, 6, 9, 13, 14, 15

27, 50

Phase III: Clinical trials, 4, 5, 6, 8, 9, 10, 15, 17,

18, 19, 27, 38, 49, 50, 53, 54

issues and options, 8-10, 49-54

Javits, Senator Jacob, 26

Joint Commission on Prescription Drug Use, 5, 26, 49,

51, 52

conclusions and recommendations, 59-60

Kennedy, Senator Edward, 5, 26

legislation:

Drug Regulation Reform Act of 1979 (S. 1075) (H. R.

4258), 5, 26

excerpts from statutes governing drugs and medical

devices, 57-58

69
70 ● Postmarketing Surveillance of Prescription Drugs

Food, Drug, Cosmetic Act, 5, 14, 26

Medical Device Amendments of 1976 (Public Law

94-295), 53, 54

Patent Term Restoration Act of 1981 (S. 255),

6, 27, 49

Senate Bill S. 1075, 5, 26, 53, 54

Medicaid, 32, 42, 43, 52

Medicaid Medical Information Systems, 4, 42

Medicare, 32, 52

methods of surveillance, 31-38

Monthly Index of Medical Specialties, 23

National Bureau of Standards (Department of

Commerce), 5, 27

National Cancer Institute, 13, 43

National Center for Drugs and Biologics, 14

Office of Drugs, 14, 15, 18, 19

National Center for Drug Science, 5, 26, 49

National Center for Health Statistics, 43

National Ambulatory Medical Care Survey, 43

National Heart, Lung, and Blood Institute (NHLBI), 51

National Institutes of Health, 45

National Institute on Drug Abuse, 44

National Registry of Drug-Induced Ocular

Side Effects, 42

new drug application process, 16

New England Journal of Medicine, 51

oral contraceptives, effects of 36, 37

in Great Britain, 36

in Sweden, 36

Pharmaceutical Manufacturers Association, 5, 26

practolol, 23

propanolol, 9, 19, 50, 51

Registry of Dermatological Reactions to Drugs, 42

Registry of Hepatic Toxicity to Drugs, 42

Registry of Patients Exposed to Radiopharmaceutical

Drugs, 42

Remington, R. D., 52

requirements following new drug approval, 18-19

Review Panel on New Drug Regulations, 5

revising premarketing tests, 8-9, 49-51

shortening the drug approval process, 8-9

Smith, Kline & French Laboratories, 37

Spontaneous Reaction Reporting Program, 4, 19

streptokinase, 19, 37, 42

surveillance:

abbreviated new drug application (ANDA), 17

background incidence, 8, 32, 34, 35

benefit/risk ratio, 17

clinical investigations (see investigational new drug)

evidence of efficacy and safety, 3, 6

grandfather drugs, 13

history, 5

imminent hazard to the public health, 3, 5, 10, 26,

54, 57

international monitoring, 44

manufacturer’s programs, 41, 42

methods, 6-8

case-control studies, 6, 7, 8, 9, 10, 31, 32, 33, 36, 51

cohort studies, 6, 7, 8, 9, 10, 31, 32, 33, 36, 51

controlled clinical trials, 6, 7, 8, 9, 10, 17, 31, 32,

33, 35, 36, 38, 51

voluntary reporting, 6, 7, 10, 31, 32, 33, 37, 42, 45

new drug application (NDA), 4, 5, 13, 14, 15, 16, 17,

18, 19

nonapprovable letter, 17

objectives, 5

postmarketing, 3, 5, 6, 7, 9, 10, 18, 23, 26, 27, 28,

31, 37, 38, 41, 45, 49, 50, 51, 52, 53, 54, 59-60

Phase IV, 18, 19, 42, 52

principal focus, 3

premarketing testing, 3, 4, 6, 8, 9, 13, 14, 18, 19, 26,

27, 28, 31, 37, 38, 49, 50, 52, 54

removal of drug from market, 3

sampling, 7, 8, 9, 33, 34, 35, 37, 38

sponsor of drug, 4, 5, 13, 14, 16, 17, 18, 26, 37, 52

substantial evidence, 13

timolol, 9, 50, 51

Norwegian study, 50-51

Temple, Robert, 15

thalidomide, 23

World Health Organization (WHO), 4, 19, 41

Program for International Monitoring of Adverse

Reactions, 44

yellow card (fig. 1), 24-25