Drug Labeling in Developing Countries

February 1993

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Recommended Citation:

U.S. Congress, Office of Technology Assessment, Drug Labeling in Developing

Countries, OTA-H-464 (Washington, DC: U.S. Government Printing Office,

February 1993).

For sale by the U.S. Government Printing Office

Superintendent of Documents. Mail Stop: SSOP, Washington, DC 20402-9328 

ISBN 0-16 -041628- 0
Foreword

P

harmaceuticals developed in the latter part of this century have caused

dramatic improvements in the quality of life for people around the globe.

U.S. pharmaceutical companies can take credit for the largest number of

new products and collectively maintain a share of the market larger than

that of any other country. With this prominence comes the responsibility of

informing the prescribers and consumers of pharmaceuticals of all the medically

important information known about each one. In developing countries, where

government resources to analyze and monitor drug labeling are severely constrained, companies operate with little oversight.

Prompted by the ethical imperative that U.S. pharmaceutical companies

provide accurate and complete information with their products, and evidence

from the past that they did not always do so, Congressman John Dingell,

Chairman of the House Committee on Energy and Commerce; Congressman

Henry Waxman, Chairman of its Subcommittee on Health and the Environment;

and Senator Edward M. Kennedy, then Ranking Minority Member and now

Chairman of the Senate Committee on Labor and Human Resources, asked OTA

to examine the status of drug labeling by U.S.-based multinational pharmaceutical companies in developing countries.

OTA developed a method for analyzing drug labeling, using a sample of

several hundred labels from four developing countries-Brazil, Kenya, Panama,

and Thailand. Unfortunately, serious problems were found. The policy options

identified by OTA present Congress with possible ways to improve the situation.

The success of this project depended on a great deal of assistance to

OTA. An Expert Working Group, which spent many days working with OTA

staff, was key to the analytic process. The advisory panel, chaired by Dr.

Bernard Mirkin, Professor of Pediatrics at Northwestern University Medical

School, helped to guide the project. The cooperation and interaction with OTA

of the 18 companies whose product labeling was evaluated was essential.

Numerous individuals and organizations also provided information and assistance, including meeting with project staff in Kenya and Thailand and reviewing

drafts of the report.

OTA is grateful for the contribution of each of these individuals and

groups. As with all OTA reports, the final responsibility for the content of the

assessment rests with OTA.

(7’$- -

Roger Herdman, Acting Director

. . .

Ill
Advisory Panel

Bernard Mirkin, Chair

Northwestern University Medical

School

Chicago, IL

Stewart A. Baker

Steptoe and Johnson

Washington, DC

Paul A. Belford

Association Executive Resources

Group

Arlington, VA

Joseph Cook

Program for Tropical Disease

Research

Edna McConnell Clark Foundation

New York, NY

Enrique Fefer

Essential Drugs Program

Pan American Health Organization

Washington, DC

Paula Fujiwara

New York City Dept. of Public

Health

New York, NY

Harris Gleckman

Centre on Translational Corps.

United Nations

New York, NY

Keith Johnson

United States Pharmacopoeia

Rockville, MD

Barry MacTaggartl

Pfizer International, Inc.

New York, NY

William S. Merkin

Strategic Policy, Inc.

Washington, DC

Mary Ellen Mortensen

Columbus Children’s Hospital

The Ohio State University

Columbus, OH

Robert Neimeth

Pfizer International, Inc.

New York, NY

Mark Novitch

The Upjohn Co.

Kalamazoo, MI

Johanna F. Perlmutter

Beth Israel Hospital

Brookline, MA

Michael Reich

Harvard School of Public Health

Boston, MA

Regina Rowan

Interfaith Center on Corporate

Responsibility

Medical Mission Sisters

Hyde Park, MA

Albert Wertheimer

Philadelphia College of Pharmacy

Philadelphia, PA

Sidney Wolfe

Public Citizen Health Research

Group

Washington, DC

1 Until July 1991.

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel

members. The panel does not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility for the report and the accuracy of its contents.

iv
Preject Staff

Hellen Gelband Robert S. McDonough

Project Co-Director Project Co-Director

Jacqueline C. Corrigan David Alberts

Senior Analyst Research Analyst2

Pamela Simerly Michelle M. Odom

Analyst 1 Research Assistant3

Roger C. Herdman ADMINISTRATIVE STAFF CONTRACTORS

Assistant Director, OTA, Health Beckie Erickson Philip M. Budashewitz

and Life Sciences Division Office Administrator Washington, DC

Clyde J. Behney Carolyn Martin Health Information

Health Program Manager Word Processing Specialist Designs, Inc.

Arlington, VA

Eileen Murphy

P.C. Specialist Janet M. Malcolm

McLean, VA

Alzinete O. Platts

UnionviIle, CT

Lynn Dee Silver

Oswaldo Cruz Foundation

Brazil

1 September 1987 to August 1989.

2 September 1987 to July 1988.

3 From November 1990.

v
Expert Review Group

Jay Bautz

George Washington University

Medical Center

Washington, DC

Madeline Feinberg

School of Pharmacy

University of Maryland

Baltimore, MD

Susan Garabedian-Ruffalo

DataMed Scientific

Communications

University of Southern California

School of Pharmacy

Larry Koran

Stanford University

Medical Center

Stanford, CA

Peter Lamy

School of Pharmacy

University of Maryland

Baltimore, MD

Mary Ellen Mortensen

Columbus Children’s Hospital

The Ohio State University

Columbus, OH

Philip Peirce

Georgetown University Hospital

Washington, DC

Johanna F. Perlmutter

Beth Israel Hospital

Boston, MA

Lynn Dee Silver

National School of Public Health

Oswaldo Cruz Foundation

Rio de Janeiro, Brazil

Albert Wertheimer

Philadelphia College of Pharmacy

Philadelphia, PA

Sidney Wolfe

Public Citizen Health Research

Group

Washington, DC

vi
1 Summary and Options, 1

The Request for This Assessment, 2

The OTA Drug Labeling Survey, 2

The U.S. Pharmaceutical Industry in Developing

Countries, 7

Regulation of Drug Labeling by the U.S. FDA, 9

Extraterritorial Jurisdiction Under U.S. Law, 12

Codes of Conduct and Pharmaceutical

Information, 15

International Programs To Improve pharmaceutical

Labeling, 18

Content of This Report, 21

Options for Congressional Action, 22

2 The OTA Survey and Evaluation

Process, 27

Sample Selection, 27

The Labeling Evaluation Process, 30

3 Results of the OTA Survey, 39

Qualitative Results: Addenda, 39

Quantitative Results, 40

Explanation of Addendum Tables 3-1

Through 3-6, 54

4 Drug Prescribing Information in the United

States and Other Countries, 91

U.S. Drug Labeling Laws and Regulations, 92

Differences in Drug Labeling Among Industrialized

Nations, 106

Company Development of International Product

Labeling, 107

Sources of Pharmaceutical Information in Developing

Countries, 109

contents

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vii
5 Multinational Pharmaceutical Corporations

and US. Extraterritorial Jurisdiction, 113

The Multinational Corporation, 113

International Law and Extraterritoriality, 116

Summary, 126

6 Codes of Conduct and Voluntary Guidelines

for Pharmaceutical Information, 127

Codes of Conduct and Guidelines Under

International Law, 128

IFPMA Code of Pharmaceutical Marketing

Practices, 135

summary, 139

7 Efforts to Improve Drug Information In

Developing Countries, 141

The World Health Organization, 141

The U.S. Food and Drug Administration, 147

The U.S. Agency For International Development, 148

Consumer Health Advocates, 149

summary, 153

A Major Studies of Pharmaceutical Labeling in

Developing Countries, 155

B Drug Registration and Labeling in Brazil,

Kenya, Panama, and Thailand, 163

C Acknowledgments, 169

REFERENCES, 175

INDEX, 187

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List of Abbreviations

ACE —angiotensin converting enzyme

AIDS —acquired immunodeficiency syndrome

—American Medical Association

APED —Action Program on Essential Drugs (WHO)

BUKO —Federal Congress of Development Action

Groups (Germany)

CIOMS —Council for International Organizations of

Medical Sciences

DDA —Division of Drug Analysis (Thailand)

DEAC —Drug Export Act country

DESI —Drug Efficacy Study Implementation

(FDA)

DHHS —Department of Health and Human Services

DIMED —Division of Drugs of the Ministry of Health

(Brazil)

DIPROD-Division of Products (Brazil)

DMP —Drug Management and Policies (WHO)

EAA —Export Administration Act

FCPA —Foreign Corrupt Practices Act

FDA —Food and Drug Administration (DHHS)

FDCA —Food, Drug and Cosmetic Act

FR —Federal Register

GAO -General Accounting Office (U.S. Congress)

GATT -General Agreement on Tariffs and Trade

GPO -Governmental Pharmaceutical

Organization (Thailand)

HAI —Health Action International

IAS —International Affairs Staff (FDA)

IBFAN —International Baby Food Action Network

ICI —Imperial Chemical Industries

ICJ —International Court of Justice (United

Nations)

IEEPA —International Emergency Economic Powers

Act

—Infant Food Manufacturers

IFPMA —International Federation of Pharmaceutical

Manufacturers Associations

ILO —International Labour Office (United Nations)

IMS —Index of Medical Specialties

—Investigational New Drug (FDA)

—international proprietary name

INRUD —International Network for the Rational Use

of Drugs

IOCU —International Organization of Consumers

Unions

—Institutional Review Board

MaLAM-Medical Lobby for Appropriate Marketing

MIMS —Monthly Index of Medical Specialties

MNC —multinational corporation

MOPH —Ministry of Public Health (Thailand)

NAS —National Academy of Sciences

NATO —North Atlantic Treaty Organization

NDA —New Drug Application (FDA)

NIFAC —Nestle Infant Formula Audit Commission

OECD -Organization of Economic Co-operation

and Development (United Nations)

OTA -Office of Technology Assessment

(U.S. Congress)

OTC -over-the-counter

PAHO —Pan American Health Organization

PDR —Physicians’ Desk Reference

PLM —Para los Medicos

PMA —Pharmaceutical Manufacturers Association

SEC -Securities and Exchange Commission

SMON —subacute myelo-optic neuropathy

SNVS —National Secretariat for Health Monitoring

(Brazil)

TFDA —Thai Food and Drug Administration

UNCTC —United Nations Centre on Translational

Corporations

UNICEF-United Nations Childrens Fund

USAID —United States Agency for International

Development

USP DI —United States Pharmacopoeia Drug

Information

WHO —World Health Organization (United Nations)

ix
Summary

and

Options

E

ffective pharmaceuticals have been directly responsible

for major gains in health around the world during the latter half of the 20th century. Continued growth in the international pharmacopoeia creates the potential for

greater improvement, but only if prescribers of products have the

information they need to use products safely and effectively.

While appropriate “labeling” is the norm in the United States, it

has not always been so in developing countries. Out of concern

for this issue, OTA was asked to examine the current labeling

practices of U.S.-based multinational corporations for the products they sell in the developing world.

OTA evaluated a sample of labeling by U.S. companies in

four developing countries. Half the products evaluated had labeling that was either entirely appropriate or had relatively small

problems. The other half diverged significantly and seriously

from the standard. Physicians relying on the information provided with those products could put patients at undue risk, provide

less-than-effective therapy, or both. This may happen whenever

physicians are not fully informed about specific dangers of the

drugs they are prescribing, or when they are given to believe that

the drug is effective for a condition when effectiveness has not 1’

been established. ●q

It should be emphasized that OTA examined only the labeling

s;?’%

.

of U.S.-based companies because it is those companies that are

of interest to Congress, and those companies that can be influ- i~

enced by U.S. law and policy. Previous studies in this area have

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found, uniformly, that U.S. companies provide at least as good

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or better information than do companies based elsewhere.

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1

Nothing in this report should be used to denigrate the operations 1

of U.S.-based companies in comparison with their international

competitors.

1
2 I Drug Labeling in Developing Countries

The results of the OTA survey set the stage for

exploring ways to improve drug labeling in developing countries. This report discusses the

pharmaceutical labeling requirements imposed

on U.S.-based companies by the laws of the

United States and the barriers to U.S. regulation

of their labeling in other countries. Concern

about prescribing information in developing

countries is demonstrated by activities of United

Nations agencies, particularly the World Health

Organization, and those of private industry and

consumer groups, which also are described in

this report. Options for the Congress to consider

are presented at the end of this chapter.

THE REQUEST FOR THIS ASSESSMENT

In debates preceding passage of the Drug

Export Act of 1986, concern surfaced about the

quality of drug labeling by U.S.-based multinational companies for the products they sell in deHospital pharmacy in Latin America.

veloping countries. The concern was prompted

particularly by a series of highly visible studies

that had uncovered seriously inadequate labeling

by multinational companies for a number of

products (see appendix A). As a result, Congressman John Dingell, Chairman of the House

Committee on Energy and Commerce, Congressman Henry Waxman, Chairman of its Subcommittee on Health and the Environment, and

Senator Edward Kennedy, then Ranking Minority Member of the Senate Committee on

Labor and Human Resources, asked OTA to undertake this assessment. They asked OTA to evaluate labeling by U.S.-based companies by:

comparing] the labeling of the drugs sold in

such country and the labeling approved for such

drugs under the Public Health Service Act of

the Federal Food, Drug and Cosmetic Act and

determine whether any labeling differences are

based on valid scientific evidence, including

clinical investigations.

THE OTA DRUG LABELING SURVEY

This study, the first on this topic sponsored by

a national government, began in 1987, and the labeling evaluated was current from about 1988 to

1990. Samples of labeling from Brazil, Kenya,

Panama, and Thailand were evaluated during this

time. The process involved recognized medical

experts recruited to an “Expert Review Group” in

addition to OTA staff. The participating companies were provided two successive opportunities

to respond to OTA’s evaluations of their labels

and to provide additional material to support

their cases when they disagreed with OTA.

The major research-based multinational pharmaceutical companies with headquarters in the

United States, 18 in all, were included in the survey. Their cooperation, in providing labeling material and reviewing two iterations of the product

evaluations, was essential to the completion of

this study.

The type of labeling information analyzed

varied according to what was available. In general, OTA tried to use the most complete source

that would be available readily to most physicians in the study countries. The preferred source

was a package insert and the associated information printed on drug containers. In some cases,

companies supplied package inserts pending approval by the foreign drug regulatory authority,
Summary and options 3

and in those cases, that was OTA’s source material. Since not all products are accompanied by inserts, “prescribing guide” entries were used for a

number of products. This was more prevalent for

products from Panama, as inserts are not required there. Prescribing guides-quick reference volumes—are ubiquitous in developing

countries, and are acknowledged to be the first

line information source for physicians in many

places.

There is no gold standard to apply as an objective comparator for drug labeling around the

world. Even the U.S. labeling, approved by the

Federal Food and Drug Administration (FDA), is

not the only or most authoritative source of prescribing information. Any standard that could be

adopted for this study incorporates an element of

subjectivity, leading to results that might differ

somewhat depending on who was making the

judgments. OTA adopted a standard of “medical

importance” for judging the information on sample labels. It was intended to identify definite

problems with labeling information that would

be subject to little or no variation in different

parts of the world. It would not be appropriate,

nor was it intended, as a standard for developing

new labeling. In practice, this means that OTA

initially questioned, and in the end identified as

problems, points of potential importance to physicians attempting to use the products in a safe

and effective manner. Both information judged

missing from the label and information present

but misleading in some way contributed to the

evaluations.

OTA did use the FDA-approved labeling as an

initial “screen” for the sample labels of products

that were available in the United States. If one

were to stop at that point, however, the result

would be a long list of “differences’’ -thousands

for the 241 products evaluated fully in the survey,

the meaning of which would be uncertain. OTA

used the “medical importance” standard to separate the important differences from trivial ones.

Only the important differences entered into the

further evaluation and analysis. A significant

point is that no labeling was held to a higher

standard than that set by the U.S. labeling.

The OTA survey captures a “snapshot” of developing country labeling in the late 1980s to

early 1990s-one point in a dynamic process.

All the companies that participated in the survey

are continually updating their labels all over the

world, so the problems identified by OTA might

be the result simply of a time lag between

changes made in the United States but not yet

completed in the study countries. This does not

appear to be the case: while some of OTA’s

queries concerned recent developments, e.g., the

need for warnings based on relatively new information, the vast majority did not.

 Survey Results

Of the 273 products in the survey, 241 were

evaluated fully. The remaining 32 were excluded

for a variety of reasons, most because they were

no longer being marketed at the time OTA evaluated them. The information for each product was

examined and scored in each of 8 categories

(based on the structure of the U.S. label, but

without regard to where the information appeared in the sample labels):

1.

2.

3.

4.

5.

6.

7.

8.

description and clinical pharmacology,

ingredients,

indications,

contraindications,

warnings and precautions,

adverse reactions,

dosage and administration, and

overdosage.

Scores for individual categories were based on

the amount and seriousness of divergence from

the medical importance standard, and ranged

from O (no significant divergence) to 2 (greatest

divergence). This can be taken as a measure of

the potential risk to patients from the labeling.

Overall product scores were calculated on the

basis of the category scores, and ranged from O to
4 I Drug Labeling in Developing Countries

3, with O signifying no important divergence and

3 signifying the greatest divergence. About half

the products had labels that were either completely in accord with OTA’s medical importance

standard, a score of O (using the FDA-labeling as

a ceiling), or diverged to a small but medically

important degree (score of 1). About 25 percent

scored 2, and about 25 percent scored 3 (see table

l-l).

Table l-l-Summary of Overall Scores

Overall score Number of products

o . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78( 32%)

1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40( 17%)

2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64( 27%)

3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59( 24%)

All fully evaluated . . . . . . . . . . . . . . . . . . . . . 241 (1OO%)

Not fully evaluated . . . . . . . . . . . . . . . . . . . . 32

Total in original sample ................ 273

Degree of divergence from medical Importance standard:

0- No divergence from medical importance standard

1 -At least one category score = 1; no score >1

2 -No more than one category score= 2; other categories may -0 or 1

3 -At least two category scores -2

NOTE: Sea text for details of scoring.

SOURCE: Office of Technology Assessment, 1993.

ANALYSIS BY CATEGORY OF INFORMATION

The results by category of information are

summarized below and in table 1-2. The numbers

and percentages reported in each section are

based on the 241 products that were evaluated

fully.

Description and Clinical Pharmacology

Problems were found in 51 (21 percent) of the

description and pharmacology sections of the labels, most of them (45) rated 1, and 6 rated 2. The

most frequent concerns were failure to identify

the drug class of the product and, more commonly, failure to include adequate pharmacokinetic

information (especially half-life, metabolism,

and route of elimination).

Ingredients

The ingredients section contributed to a divergence from OTA’s primary or secondary score in

only four cases. This does not include labeling

that failed to list inactive (inert) ingredients, except in cases where a particular inactive ingredient was known to cause an allergic reaction in a

substantial number of patients. Instead, lack of

inactive ingredient lists elicited a score of “R”

which was tracked separately from the rest of the

scores. (In the United States, FDA does not require that all inactive ingredients be listed in U.S.

labeling, but the companies do list them all routinely.) In all, 74 labels lacked lists of inactive ingredients.

Indications

Indications was one of the most problematic

sections. Sixty-three labels (26 percent) were divergent in this area, and 43 of those were rated 2,

representing the most serious problems. The reasons for these scores were mainly: 1) indications

Table 1-2-Summary of Category Scores

Category

score DCP ING IND cl WP AR DA OD

1 45 (19%) 1 ( o%) 20 ( 8%) 12 (5%) 49 (20%) 25 (10%) 17 (7%) 8 ( 3%)

2 6 ( 2%) 3 ( 1%) 43 (18%) 15 (6%) 79 (33%) 37 (15%) 11 (5%) 37 (15%)

R 74 (31%)

Categories: Category scores:

DCP - Description/Clinical Pharmacology 1 -at least one unresolved query in category with score -1

ING = Ingredients 2. at least one unresolved query in category with score -2

IND - Indications R - lack of inactive (inert) ingredient list

CI - Contraindications

WP - Warnings and Precautions

AR . Adverse Reactions

DA = Dosage and Administration

OD - Overdosage

NOTE: The percentage calculations use 241, the number of fully evaluated products, as the denominator. See text for details of scoring.

SOURCE: office of Technology Assessment, 1993.
Summary and Options 5

that did not appear in widely accepted drug compendia and for which inadequate evidence of efficacy was presented by the companies, 2) indications that were overly broad and vague, and 3)

failure to inform when the product was not considered first-line treatment for an indication.

Contraindications

Contraindications were found to diverge from

the medical importance standard for 27 labels(11

percent), including 15 rated 2, the most serious

score. Contraindications describe patients who

should not receive a drug because, for one reason

or another, the risks of taking it are likely to outweigh the benefits. The reasons include:

1.

2.

3.

4.

a medical condition that might interfere

with the metabolism or action of the particular drug in a dangerous way (e.g., kidney

or liver disease);

the patient is taking a drug that is known to

interact with the product in an unacceptable way;

the drug may harm a fetus in a pregnant

woman, or pass through a nursing mother’s

breast milk, potentially harming the child;

and

the drug should not be taken by children

(because of lack of evidence of safety or

because of a known unacceptable adverse

effect) or by frail elderly people.

Warnings and Precautions

More problems occurred in warnings and precautions than in any other section, and they included a high percentage of more serious divergences. Over half the labels evaluated (128)

deviated from the medical importance standard,

and 79 of those were rated 2. Warnings and precautions cover a broad range of information, so it

may not be surprising to find so many divergences there. The types of problem included:

1. failure to warn of relatively rare but potentially life-threatening effects;

2.

3.

4.

5.

6.

7.

8.

9.

10.

failure to warn of less serious but more

common effects;

providing too weak a warning in relation

to the risk;

failure to warn particular high-risk patients (e.g., with other chronic diseases);

failure to note interactions with other

drugs;

failure to note effects on laboratory test

results;

omission of instructions for monitoring

patients on the drug;

lack of specificity about possible adverse

effects;

lack of information about use of drug in

pregnancy, in nursing mothers, in pediatric patients, or in the elderly; and

lack of information on possible carcinogenicity.

Adverse Reactions

Widespread divergences were also noted in

adverse reactions sections of the labels. Just over

a quarter (62) had unresolved queries, of which

59 percent (37) were rated 2. Adverse reactions

omitted ranged from those that might be worrisome to patients though not medically serious

(e.g., discoloration of urine or other body fluids)

to some that are life threatening (e.g., agranulocytosis, the complete suppression of blood cell

production), but all were considered important

enough for physicians to be fully informed about

them. In some cases, an adverse reaction was listed on the sample label but its severity was understated.

Dosage and Administration (excluding Overdosage)

Most problems in dosage and administration

had to do with regimens that were either higher

or, in a few cases, lower doses than recommended in the comparison labeling or in drug compendia, and for which inadequate support existed in

the literature. The divergences occurred both in
6 I Drug Labeling in Developing Countries

daily doses and in the length of the regimen, and

often involved regimens specifically for infants

or children. In a few cases, the label failed to state

the maximurn length of time the drug should be

taken before either stopping or taking other measures. Twenty-eight (12 percent) of the labels

scored 1 (17) or 2 (11) in this area.

Overdosage

Failure to include information on the signs and

symptoms of overdosage, and on its management, was common. Forty-five (19 percent) of

products diverged from the medical importance

standard in this section, and most of those (37)

instances were placed in the most serious category (score of 2). Lack of this information was considered particularly important if there are specific

measures, as opposed to just general monitoring

and supportive measures, that should be recommended for treatment of overdose.

ANALYSIS BY COMPANY

The number of fully evaluated products per

company ranged from 4 to 25, roughly in proportion to the number of products each company offered for sale in the sample countries. OTA calculated average overall product scores for each

company (the scale for overall scores is O-3), and

these ranged from O to 2.22, but most fell between 1 and 2. Two were less than 1, and two

were more than 2. For several reasons, we do not

believe it is useful to try to rank companies by

their scores.

A major factor affecting company scores is the

mix of products in the OTA sample. Many company product lines tend to clump in particular

therapeutic categories, e.g., antihypertensive

medications or corticosteroid products. Certain

types of product, no matter how they are used,

are unlikely to have effects that are life threatening or even serious. Such products would almost

never be rated a 3 regardless of the labeling.

Products fitting this description do, in fact, dominate in the sample from the company with the

best (lowest) overall score and form varying proportions of other companies’ products.

In general, the samples by company are not

large enough to sustain rigorous statistical analysis. The wide range of company scores in different countries also suggests the need for caution in

generalizing at the company level.

ANALYSIS BY COUNTRY

The average overall product scores for the

sample countries ranged from 1.1 to 1.6 (out of

3), with the average of all scores at 1.4. Medically significant problems occurred in all countries and no clear distinctions can be made in a

country-by-country comparison. A sample of

four countries is too small to conclude that labeling in all developing countries is in need of improvement, but it does suggest it is not an isolated problem.

 Comparison of OTA Results for One

Company With Labeling From Other

Industrialized Countries

A number of survey companies criticized

OTA’s methodology for accepting a U.S. perspective on labeling, to the exclusion of established

standards in other industrialized countries. In

particular, they believed that labeling from the

exporting country for each product should be

given weight. Having heard this argument, OTA

asked the companies to indicate the country of

export for each sample product and to provide labeling from the exporting country so that a direct

comparison could be made. One company responded during the study process by comparing

OTA’s interim scores for their products against

labeling for the same or similar products in each

of the 21 countries named in the Drug Export Act

of 1986, and by providing the labeling from some

of those countries to document their analysis.

Sixteen other companies conducted a similar

analysis during their review of the final draft, but

did not provide the supporting materials for corroboration. Their results were reported to OTA
Summary and Options 7

by the Pharmaceutical Manufacturers Association (PMA) in summary form and are not included in this report. The single company analysis is described here.

The 21 countries included in the “composite

standard” are named in the Act as having regulatory systems adequate to allow the export to them

of drugs not yet approved in the United States,

provided they have already been approved in the

importing country. The company analysis took

each unsatisfied query that OTA had scored 1 or

2 and checked the labeling in each of the 21

countries to see whether they were similar to the

original survey country label on the point OTA

had questioned. If they found a correspondence

with at least 1 of the 21 countries, they considered OTA’s score invalid and rescored the query

as O. They then retallied the overall scores.

The company’s analysis demonstrates that labeling does differ among industrialized countries, and that if OTA had used a composite of all

industrialized country labels as a standard, the results of the survey would have been very different, and clearly more favorable to the companies.

Neither this company nor the PMA explains why

this composite standard is more appropriate than

OTA’s. It could be argued that a composite standard incorporating all the warnings, , precautions,

etc., of the foreign labels, and restricting indications only to those approved in all countries

would be appropriate, unless evidence suggested

otherwise.

 Comparison of OTA Results With WHO

Model Prescribing Information

OTA compared its final product evaluations

with recent WHO model prescribing information

monographs (280,282,283,284,288,289), which

are being prepared to cover all products on the

“Model List of Essential Drugs.” The monographs represent a consensus of WHO’s Expert

Advisory Panel on Drug Evaluation and are reviewed by selected members of Advisory Panels

in relevant areas of medicine and nongovernmental professional and business organizations (including those representing the pharmaceutical industry).

Twenty-three drugs in the OTA sample were

also included in one of six WHO model prescribing information monographs now available. OTA

compared the monograph entries with OTA’s

final evaluations of those products. This was

done by checking each of the unresolved queries

with the monographs to see if the monograph

“agreed” with OTA’s evaluation (e.g., if OTA’s

query was for lack of a warning in the sample

label, and the WHO monograph contained the

warning, the monograph agreed with OTA).

Excluding queries about listing inactive ingredients, there were 52 relevant queries. Of these,

the monographs agreed completely with OTA’s

evaluation in 40 cases. In five cases, the monographs were consistent with some, but not all, aspects of the query, and in seven cases, the monographs agreed with the sample label and not with

the OTA evaluation. This analysis suggests

strongly that the great majority of unresolved

queries in OTA’s product evaluations represent

significant problems in the content of the label,

when measured against another independent

standard. It provides validation of OTA’s method

and standard of evaluation.

THE U.S. PHARMACEUTICAL INDUSTRY

IN DEVELOPING COUNTRIES

U.S. pharmaceutical multinational corporations (NIFJCs) are leaders in the world market. In

1989, 8 of the top 15 pharmaceutical companies

worldwide, ranked by total sales, were U. S.-

based MNCS. Annual sales averaged $3.5 billion

(198). U.S. companies hold their leading position

by dominating the U.S. domestic market, but they

also have a significant presence in foreign markets. Foreign sales account for 30 to 50 percent or

more of total sales for most companies (178,

191). The largest foreign markets for U.S. pharmaceuticals are other industrialized countries, accounting for approximately 82 percent of foreign
8 I Drug Labeling in Developing Countries

sales in 1989 (177). Although only a minority of

MNC foreign sales are in developing countries,

the majority of drugs available in those countries

are imported, because indigenous pharmaceutical

industries are small (223,279).

With about 75 percent of the world’s population, developing countries consume about 21 percent of the world’s pharmaceuticals (by market

value), and well over half of that 21 percent goes

to just a few countries-India, Brazil, Mexico,

Argentina, Egypt, Iran, and South Korea (67,

279). (The percentage of market value probably

understates the percentage of the world’s drug

supply actually consumed in developing countries, but figures on consumption are not available. ) Approximately $30 billion per year is

spent by developing countries on pharmaceuticals, and this amount is expected to grow over the

next decade, both in absolute terms and as a percentage of the world market (242).

 Influences on Labeling Practices of

U.S. Multinational Pharmaceutical

Corporations

Drug labeling by pharmaceutical MNCs is influenced by the following factors:

1. Home country: the laws and policies of the

country in which the parent company is

headquartered (the United States, in the

case of U.S.-based MNCs);

2. Host country: the laws and policies of the

foreign country in which the MNC is manufacturing or importing;

3. International organizations: codes of conduct or guidelines developed by international organizations;

4. Self regulation: internal company policies,

and national and international codes of

conduct developed to standardize certain

practices worldwide; and

5. Public interest groups and consumer activists: political and media pressure.

These forces, and how they affect the issue of

drug labeling, are discussed in various chapters

of this report, and summarized briefly here.

THE MULTINATIONAL CORPORATION–

STRUCTURE AND LEGAL CONTROL

There is no single definition of a multinational

corporation (MNC), but the most obvious distinguishing characteristic of an MNC is that it has

direct investments in several different countries.

The MNC does not merely market its product in

foreign countries, but directly owns or controls

production or service facilities in those countries.

The foreign operations of a U.S. MNC may take

a variety of forms. In the pharmaceutical industry, foreign operations are usually carried out by

wholly or majority-owned foreign subsidiaries in

“host countries” (65). A U.S. pharmaceutical

MNC may have 50 or more foreign subsidiaries,

but perhaps only a dozen major foreign operations. The typical MNC owns a small number of

separate plants, each dedicated to manufacturing

active ingredients of a specific type. The active

ingredients are then shipped to local plants where

the final product is formulated and packaged

(205).

A parent corporation may exercise varying degrees of control over its foreign operations, from

control of its day-to-day operations to less centralized management of operations, involving exchange of technology, information, capital, and

personnel. Different subsidiaries of the same corporation may be subject to different degrees of

control depending on their type, size, and importance. The type of corporate structure linking the

parent company to a foreign subsidiary or other

foreign operation is important in determiningg the

degree of control an MNC has over the manner in

which its drugs are marketed in other countries.

Most pharmaceutical MNCs have majority equity

control over their foreign operations, but corporate headquarters do not necessarily exercise

close control over the management of those operations.
Summary and Options 9

MNCs consist of multiple legal entities operating in various countries. Domestic operations

of U.S. MNCs are subject to U.S. law, and with

respect to certain laws—tax and securities, for

example-a U.S.-based MNC must also account

for its foreign subsidiaries to the U.S. Government. Aside from that, by and large, foreign subsidiaries are regulated by the laws of the countries in which they are located. But the MNC

itself operates as a single business entity that may

adopt business and marketing strategies that take

into account the legal constraints and advantages

of each country in which it operates. As a result

of these and other complexities of MNC business, the United Nations and other international

governmental organizations have sought to develop standards to govern the operations of

MNCs in host countries. Pharmaceutical MNC

practices, including labeling, have been the object of scrutiny by public interest groups which

have attempted to change MNC behavior through

adverse publicity and direct appeals to the companies. The pharmaceutical industry has responded to the combined influences of legal requirements and public pressure by creating a

structure aimed at self-regulation. The International Pharmaceutical Manufacturers Association’s “Code of Pharmaceutical Marketing

Practices” sets out broad guidelines for the promotion of pharmaceutical products. Member

companies believe that this measure is appropriate and that further regulation is unnecessary, but

the effectiveness of the Code is a matter of dispute, particularly by consumer activists.

REGULATION OF DRUG LABELING

BY THE U.S. FDA

All the companies in the OTA survey are U. S.-

based corporations and all market products in the

United States under the stringent controls of the

Federal Food, Drug, and Cosmetic Act

(FDCA)(21 U.S.C. §§321 et. seq.). The FDCA is

implemented by the Federal Food and Drug

Administration (FDA), whose role is that of

health promoter and protector. One of FDA’s primary functions is to approve drugs for marketing

in the United States and to regulate the manner in

which they may be marketed.

The FDCA regulates only those pharmaceuticals sold in or exported from the United States;

its reach does not extend to pharmaceuticals that

are manufactured, repackaged, and/or sold by the

foreign subsidiaries of U.S. companies. Some

companies do, however, use the U.S. labeling as

a starting point for the development of labeling

for other countries.

 Labeling of Drugs in the United States

In approving new drugs, the FDA must also review and approve all labeling material. Labeling

includes the “label;’ which is the “display of any

Pharmaceutical formulation in Latin America.

written, printed, or graphic matter upon the immediate container” of the drug, as well as any

written, printed, or graphic matter that accompanies the drug, including package inserts, containers, and wrappers (21 U.S.C. § 321(k),(m)). It is

not necessary that the labeling accompany the

drug physically. The FDA has interpreted labeling to include brochures, reprints of scientific articles distributed by a manufacturer, index file
10 I Drug Labeling in Developing Countries

cards distributed to physicians with information

about a drug, and even press releases (170).

All prescription drugs in package form must

have labels that include (21 U.S.C. § 352; 21

C.F.R.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

$$201.22,201.50,201.100 and 21 1.137):

the name and place of business of the

manufacturer, packer, or distributor;

the name or names of the drug, both proprietary and official or commonly recognized names;

the names and quantities of active ingredients and, in certain cases, inactive ingredients;

route of administration;

a statement about the quantity of the container, such as weight, measure, or numerical count;

an identifying lot or control number;

a warning that “Federal law prohibits dispensing without a prescription;”

a warning that the product may be habit

forming, if applicable;

additional warnings, when appropriate,

for products containing certain ingredients, e.g., phenylalanine or sulfites;

a recommended dose, and the expiration

date; and

a statement to the pharmacist indicating

proper container.

If there is insufficient space on the package, certain information, such as dosage and route of administration, may appear only on the package insert (21 C.F.R. § 201.100).

The package insert contains most of the information that the practitioner needs to use a drug

safely and effectively in the care of patients (44

FR 37437). The following types of information

are included (21 C.F.R. $5201.56, 201.57):

1.

2.

3.

description of drug, including qualitative

and/or quantitative ingredient information;

clinical pharmacology;

indications and usage;

4.

5.

6.

7.

8.

9.

10.

11.

12.

The

contraindications;

warnings;

precautions;

adverse reactions;

warnings about drug abuse and dependence;

overdosage information;

proper dosage and administration;

how supplied; and

date of most recent revision.

content of the label is guided by a requirement that all indications be supported by substantial evidence based on adequate and well-controlled studies, and that warnings be placed on

the label if there is a reasonable association between a drug and a serious hazard (21 U.S.C. §

355(d); 44 FR 37434). Once the label for a prescription drug has been approved, all proposed

changes by the manufacturer must be reviewed

and approved by the FDA (21 C.F.R. § 314.70).

Consumers buy over-the-counter OTC) drugs

without the assistance of physicians or pharmacists, so labeling information must be directed to

consumers. This has required FDA to develop

regulations for OTC labeling that differ from

those for prescription drugs. The guiding principle for OTC labeling is that it must be “clear and

truthful in all respects, not false or misleading in

any particular, and understandable to the ordinary

citizen, including individuals of low comprehension, under customary conditions of purchase and

use” (51 FR 16259). The outside label of an OTC

drug must include the name of the manufacturer,

packer, or distributor; lot number; expiration

date; and any special warning required by the

FDA (e.g., presence of aspartame as inactive ingredient) (21 C.F.R. §§201.1, 201.17, 201.18,

201.20-21). Directions for adequate use, warnings, precautions, contraindications, dosage information, and other required information may

be found on a package insert, the outside label, or

both (21 C.F.R. §§ 201.1-201.20) (56).

Labeling for a number of OTC drugs is prescribed by FDA monographs (21 C.F.R. Part 330;
Summary and Options 11

51 FR 16258). Labeling information for an OTC

drug for which there is no monograph is reviewed by the FDA on a product-by-product

basis, the same as for prescription drugs (21

C.F.R. §§330.11,330.12, 330.13).

The FDA also regulates prescription drug advertising and, to a lesser extent, advertising of

OTC drugs (OTC drug advertising is regulated

primarily by the Federal Trade Commission) (15

U.S.C. §§45, 52, 55). Advertising material for

both prescription and OTC drugs must be based

on the approved labeling and must not contain

any exaggerated or misleading claims (21 U.S.C.

§ 352(n); 21 C.F.R. § 202.1; 44 FR 37437) (166).

The FDA reviews prescription drug advertising,

which must include a summary of the indications, contraindications, and side effects, consistent with the prescribing information contained

in the package insert (21 C.F.R. Part 202.l(e)).

The advertisement must present this information

in a balanced manner; the warnings may not be

minimized nor the effectiveness exaggerated (21

C.F.R. § 201.1).

EXPORT AND LABELING OF APPROVED DRUGS

All approved drugs may be exported freely

from the United States provided they are accompanied by FDA-approved labeling, The FDCA

prohibits export of pharmaceuticals in finished

form that do not include a U.S. label, with some

minor exceptions. Certain older drugs, those approved prior to 1938, may be exported without

U.S. labeling provided the labeling complies

with the importing country’s requirements (21

U.S.C. § 381(e)), and certain antibiotics may be

exported with labeling that differs from the U.S.

labeling (21 C.F.R. § 432.9).

The net result is that U.S. companies do not

export drugs approved after 1938 with a label

that differs from the U.S. labeling, even if the

drug regulatory authority in the importing country requires different labeling. Most pharmaceutical products exported from the United States,

however, are not in finished dosage form, but are

in bulk form for repackaging and labeling abroad

(178,243).

EXPORT OF UNAPPROVED DRUGS

For many years, drugs not approved in the

United States could not be exported at all. This

was changed in 1986, when Congress amended

the FDCA to allow for limited export of unapproved pharmaceuticals. To be eligible for export, the pharmaceutical must be in the clinical

trial stage of the drug approval process, and the

company must be in active pursuit of U.S. approval. An unapproved drug may be exported

only to an industrialized country named in the

legislation, and only after it has been approved

for sale in that country (21 U.S.C. § 382(b)

(l)(B)). The current list of countries that may import unapproved drugs from the United States includes all the European Community countries

(except Greece) plus Australia, Austria, Canada,

Finland, Japan, New Zealand, Norway, Sweden,

and Switzerland. These countries were selected

because they have well-developed drug regulatory systems.

To export an unapproved drug, the exporter

must submit an application to the FDA 90 days

before intending to export. Notice of the application, identifying the applicant, the product, and

the country to which the product will be exported, is published in the Federal Register. The exporter must certify that all other FDA requirements have been met and must obtain written

agreement from each importer stating that the

importer will not reexport the drug to a country

not included on the list of countries to which unapproved drugs may be exported from the United

States. The exporter must cease exporting if:

1.

2.

3.

the receiving country withdraws approval

of the drug or withdraws the drug from sale,

the drug is withdrawn from the U.S. approval process, or

the FDA rejects the drug for marketing in

the United States (21 U.S.C. §§ 382(c)(1)

(A)-(C)).
12 I Drug Labeling in Developing Countries

EXPORT OF TROPICAL DISEASE DRUGS

The FDA has special provisions to govern the

export of unapproved new pharmaceuticals intended primarily for treatment of tropical diseases. To be eligible for export, the Secretary of

Health and Human Services must find “credible

scientific evidence,” including human studies,

that the drug is safe and effective in the prevention or treatment of a tropical disease in the importing country (21 U.S.C. § 382(f)(l)(A)). The

procedural requirements for export of these drugs

Pharmacy in Latin America.

is similar to those required to export other unapproved drugs. The main difference between the

export of unapproved tropical disease drugs and

all other unapproved drugs is that the former are

exported primarily to developing countries, and

need not be in the U.S. approval pipeline.

EXTRATERRITORIAL JURISDICTION

UNDER U.S. LAW

The FDA’s authority over drug labeling stops

at the U.S. border. It has no authority to regulate

the labeling of pharmaceuticals that are produced

or finished, and subsequently marketed, by foreign subsidiaries of U.S. MNCs. And it is these

products, not those exported in finished form

from the United States, that constitute the overwhelming majority of U.S. products sold in other

countries, including developing countries. Pertinent to this assessment is the question of whether

the United States could regulate or otherwise influence the labeling of these products, an authority clearly beyond the reach of the FDCA as it

stands today. The question is one of U.S. extraterritorial jurisdiction, and the answer comes

from understanding the principles of international law.

INTERNATIONAL LAW

A decision to exercise extraterritorial jurisdiction is usually guided by two basic principles of

international law: the territorial principle and the

nationality principle. In addition, the United

States has asserted a third basis for exercising extraterritorial jurisdiction, the effects doctrine.

While this doctrine is generally accepted by the

United States, it is not well accepted by other

countries, and is the subject of debate (2,218).

The territorial principle is the primary doctrine

of international law, holding that each nation has

the exclusive right to regulate conduct within its

borders. A corollary is that one country does not

have the right to interfere in another country’s internal affairs. Under a strict interpretation, the

United States would never have the right to exercise jurisdiction over a foreign subsidiary of a

U.S. company. The territorial principle is not absolute, however. The nationality principle recognizes a nation’s interest in maintaining some degree of control over its citizens residing in other

countries. An example is a U.S. citizen’s obligation to pay U.S. income taxes even when residing
Summary and Options 13

abroad, or the ability of the United States to demand child support payments from U.S. fathers

or mothers residing abroad. The nationality principle also may be applied to corporations which

are, in legal terms, “persons” (though there is

some disagreement on how the nationality of a

corporation is determined).

The effects doctrine is a modification of the

territorial principle that is accepted by the United

States, but not by all other countries. Under this

doctrine, the United States claims the right to exercise jurisdiction over certain acts that occur

outside the United States but that have a substantial, direct effect in the United States, This doctrine has been applied generally to economic

laws.

By definition, the nationality principle and the

effects doctrine conflict with the territorial principle, because they give a country the right to exercise jurisdiction within another country’s borders. One framework for resolving these conflicts

can be found in the “rule of reason” adopted by

the American Law Institute in their Restatement

(Third) of the Foreign Relations Law of the

United States (6), a document influential in

defining the U.S. interpretation of international

law (but not necessarily reflecting international

law as accepted by the majority of nations or

even the U.S. Government).

Under the reasonableness approach, a country

should not exercise extraterntorial jurisdiction if

it would be an “unreasonable encroachment” on

another country’s sovereignty. Determining th e

reasonableness of a particular action requires balancing the competing interests of the countries

directly involved in the situation, and examining

the impact the decision will have on international

economic and social discourse (136). The Restatement instructs that a country may not exercise jurisdiction over a foreign subsidiary merely

on the basis that it is owned or controlled by citizens of the regulating state. But there are exceptions; for example, it allows countries to impose

regulations that apply to all MNC subsidiaries requiring uniform accounting standards, disclosure

of information to investors, and the preparation

of consolidated tax returns. These financial reporting requirements may be important to the

regulating nation and should not affect the internal affairs of the host country.

In exceptional cases, a nation might argue that

an exercise of extratemitorial jurisdiction is vital

to its national interests. Trade embargoes and export controls are typical extraterritorial actions

used to protect national interests, or, more aptly,

to further foreign policy objectives. In some

cases, the extraterritorial law may conflict with

the laws or policies of the foreign country. This

type of action has been at the heart of extraterritorial conflicts between the United States and

other countries (186),

U.S. LAWS ALLOWING EXTRATERRITORIAL ACTS

U.S. statutes authorizing extraterritorial actions include the Export Administration Act of

1977 (50 U.S.C. App. §§ 2401-2420) and the

International Emergency Economic Powers Act

of 1977 (50 U.S.C. App. §§ 1701-1706). Under

these statutes, the President may assert Limited

jurisdiction over foreign subsidiaries in times of

war, national emergency, or when foreign policy

considerations make such acts imperative. Other

countries have opposed this authority, contending

that the United States has overstepped the bounds

of international law (59).

In the case of trade embargoes and boycotts,

foreign subsidiaries are caught in a dispute between the United States and a foreign government. But the actions of the foreign subsidiary itself may also prompt action. The most pertinent

example of this is the Foreign Corrupt Practices

Act of 1978 (FCPA), passed to stop U.S. MNCs

from bribing foreign officials. The FCPA might

be seen as a precedent for regulation of drug labeling by foreign subsidiaries of U.S. pharmaceutical MNCs.

The Foreign Corrupt Practices Act

The FCPA was enacted after revelations of

widespread secret payments to foreign officials
14 I Drug Labeling in Developing Countries

by U.S. companies. Most of the transactions occurred outside the United States and, according

to some corporations, were necessary to compete

in those countries. Congress concluded, however,

that such bribery could lead to scandals with serious foreign policy implications, and that corporate bribery offended the moral expectations and

values of the American public and distorted the

competitive market. Revelation of these bribes

could lead to lawsuits, cancellation of contracts,

and even appropriation of company assets. These

consequences would affect U.S. investors and destroy investor confidence in U.S. industry. The

FCPA makes bribery of foreign officials by U.S.

citizens and corporations a criminal act.

Despite the fact that the FCPA has such broad

extraterritorial reach, it has encountered little international opposition. One reason may be that

the statute captured the sentiment of the time,

when the United Nations was considering a resolution condemning corrupt practices in international commerce, and the Organization for

Economic Cooperation and Development had issued voluntary guidelines for MNCs forbidding

bribery of public officials. There was international consensus that bribery of foreign officials by

MNCs should be controlled, even if most countries were unwilling to act unilaterally against

their own corporations,

EXTRATERRITORIAL REGULATIONS RELATING

TO THE HEALTH AND SAFETY OF

FOREIGN NATIONALS

The appropriateness of the FCPA as a precedent for extraterritorial regulation of pharmaceutical labeling should not be overstated. In

contrast to the foreign and domestic policy implications of bribery by U.S. corporations, pharmaceutical labeling is viewed primarily as a domestic health and safety issue by each country. The

Restatement of U.S. Foreign Relations Law

leaves activities that affect primarily the health,

safety, and welfare of the national population exclusively to national laws. Attempts to regulate

these domestic issues would impinge on the sovereignty of the host country to control activities

within its borders (6). There are few examples of

U.S. legislation that force foreign subsidiaries of

U.S. companies to comply with US. health, safety, and labor standards when operating abroad,

and those that do exist are designed to protect

U.S. citizens working for those companies (43,

293).

To justify an exercise of unilateral extraterritorial jurisdiction, the United States must have a

strong foreign policy interest that cannot be

served by any alternative action. Under the effects principle, the action the United States seeks

to regulate must have an adverse effect within the

United States. This is sometimes further limited

to foreign actions that violate criminal or civil

laws of countries with developed legal systems

(59,73). In the case of the FCPA, Congress recognized that bribery of foreign officials could lead

to scandals that, in turn, could both damage foreign relations and have domestic financial implications if investors lost faith in U.S. companies.

In addition, bribery is almost universally seen as

a crime.

The case for extraterritorial jurisdiction over

labeling by U.S. companies and foreign subsidiaries is not so strong. This study assumes that

U.S. corporations are, on the whole, in compliance with national laws and are providing at least

as good or better information than other companies. There is no evidence that U.S. companies

are violating laws or acting in a manner that

could lead to sanctions or other actions that could

erode investor confidence. The United States,

therefore, has virtually no authority to regulate

the subsidiaries under the effects principle. This

leaves the nationality principle; however, the

United States is virtually alone in its position that

its foreign subsidiaries incorporated in foreign

countries can be considered nationals of the

United States for purposes of U.S. laws.

The justification for exercising extraterritorial

jurisdiction over pharmaceutical labeling would

be a moral interest in having U.S. pharmaceutical

companies lead the way and provide the best and
Summary and Options 15

most informative labeling of all companies. This

does not reach the “major national interest” required by U.S. precedents and the Restatement.

In addition, the United States’ interest must be

weighed against the factors that do not support

U.S. jurisdiction, primarily the fact that developing countries have their own laws regulating

pharmaceutical labeling, and that the U.S. law

would primarily protect foreign citizens. These

countervailing factors do not necessarily preclude all forms of extraterritorial jurisdiction, but

they cannot be ignored.

This issue also raises practical considerations.

Whereas most countries condemn bribery and

agree generally on its definition, coming to

agreement on proper labeling of pharmaceuticals

would be more difficult. The fact that a developing country has limited labeling regulations or

enforcement does not necessarily mean that it

would welcome U.S. labeling, thought it might

see this as desirable.

CODES OF CONDUCT AND

PHARMACEUTICAL INFORMATION

International law is based on the consensus of

nations. Sometimes international law is expressed in binding agreements, such as treaties.

Treaties may address a single issue between two

nations or may address a multitude of economic

issues among many nations, as does the General

Agreement on Tariffs and Trade (GATT’), Binding agreements are not entered into lightly, however, and those affecting primarily domestic commerce are generally avoided. At the same time,

the increasingly international economy and the

cross-border operations of MNCs present issues

that cannot be addressed effectively by one nation’s legal system. One way to promote the necessary cooperation is through codes of conduct

and international guidelines,

Codes of conduct are voluntary agreements

between nations in which countries endorse certain general principles that they may—though

they are not required to-implement through national laws and other actions. Codes of conduct

contain policies that nations agree are desirable,

but do not force nations to uphold the embodied

principles through specific actions. As one legal

commentator explained, codes are “politicallyagreed behavior which cannot be directly legally

enforced but cannot either be legitimately infringed” (125),

Codes of conduct have been formulated by

both governmental and nongovernmental organizations, including the United Nations and its

agencies, the International Labour Office (ILO),

the Organization of Economic Co-operation and

Development (OECD), the International

Chamber of Commerce, and regional organizations. The codes range from broad pronouncements of principles which multinationals should

follow, such as the OECD Guidelines for Multinational Corporations, to specific guidelines for

corporate operations, such as the United Nations

Conference of Trade and Development Code of

Conduct on Restrictive Business Practices, or the

European Community’s Code of Conduct for

Companies Operating in South Africa (98).

Codes of conduct often address the operations

of MNCs; however, MNCs are not parties to the

agreements negotiated by international governmental organizations, such as the United Nations,

As a result, government-negotiated codes do not

bind MNCs to take any specific action unless the

code is implemented into national law. But

MNCs may feel pressure to comply with codes in

order to maintain good political relations, or they

may find it advantageous to comply so that the

host country is more likely to fulfill its obligations to the MNC. Most codes of conduct include

an implementing body that may provide interpretations of the code and assess its implementation.

This organization may also provide a forum for

further debate and may identify code violations

that can be addressed at a national level.

Currently, no single code addresses pharmaceutical labeling. A draft United Nations Code

for Translational Corporations, which has been

under negotiation for more than 12 years, gener-
16 I Drug Labeling in Developing Countries

ally addresses consumer issues, including the

provision of safety information for consumer

products. The language of the consumer protection provisions is very general and the Code, if

passed, may not have a significant impact on

drug labeling.

There is an International Code for the Marketing of Breast-Milk Substitutes (Breast-Milk

Substitutes Code), which was negotiated under

the auspices of WHO. This code addresses promotional practices of companies that sell infant

formula and other breast-milk substitutes. The

Breast-Milk Substitutes Code addresses a single

industry and focuses on preventing marketing

practices that have potentially harmful effects on

consumers. It has, therefore, been viewed as a

precedent for a pharmaceutical code.

WHO rejected a proposal to draft a pharmaceutical code in the 1980s when the pharmaceutical industry developed its own code of conduct

for promotional practices. Unlike a code adopted

by governments, industry’s code was adopted by

IFPMA member associations, so it is a self-imposed standard. WHO did, however, issue guidelines on advertising and promotion of pharmaceuticals. Although similar to the industry code,

WHO’s guidelines are more specific, and WHO

would like governments to implement them at the

national level.

INTERNATIONAL CODE OF MARKETING OF

BREAST-MILK SUBSTITUTES

The WHO International Code of Marketing of

Breast-Milk Substitutes was passed in 1981 in response to specific marketing practices of MNCs

and, at the time of drafting, it was seen as a possible precedent for a pharmaceutical marketing

code, The Breast-Milk Substitutes Code, which

sets forth standards for the promotion and labeling of infant formula, has been used by a number

of countries as a basis for national regulation or

national codes of conduct.

Consumer groups have used the Code to generate public pressure against companies that fail

to comply, and have educated governments and

health officials about the meaning of the Code

(281). Industry also has responded. The International Association of Infant Food Manufacturers (IFM), an industry group with 35 member

companies in 15 countries, has instituted a complaint procedure and is developing an arbitration

mechanism to address Code violations that cannot be dealt with by direct negotiations between

the company and the complainant (281). Finally,

the Code’s requirement that each country report

annually to WHO on the actions it has taken toward implementation has been instrumental in

keeping attention on the issue. It appears that the

more egregious promotional practices have

ceased since the Code came into existence,

though violations still are being reported (188,

281).

WHO’S ETHICAL CRITERIA FOR

MEDICINAL DRUG PROMOTION

In 1968, before interest became strong in a

pharmaceutical code of conduct, WHO adopted

“Ethical and Scientific Criteria for Pharmaceutical Advertising” (267). This document was

revised and expanded in 1988, The revised document, now called the “Ethical Criteria for Medicinal Drug Promotion” (referred to as the “Ethical

Criteria”), provides “guidelines” for a broad

range of “informational and persuasive activities

by manufacturers and distributors” (273).

Guidelines are weaker policy pronouncements

than are codes of conduct. The language of the

Ethical Criteria merely “urges Member States to

take into account the Ethical Criteria in developing their own appropriate measures” and

“appeals to pharmaceutical manufacturers and

distributors” to use these Criteria (264). The document also states that the Ethical Criteria “constitute general principles that could be adapted by

governments. . .as appropriate to their political,

economic, cultural, social, educational, scientific

and technical situation, their national laws and

regulation s.” They do not constitute legal obligations (264,265).
Summary and Options 17

The primary target of the Ethical Criteria is

advertising, but they also instruct companies to

comply with national laws with respect to other

information, and if no national laws pertain, or if

the laws are rudimentary, the company should

provide information consistent with that required

by another reliable drug authority. The Ethical

Criteria state that all text and illustrations on the

drug package and label should provide only reliable, truthful, informative, and current information, supported by scientific data. Companies are

instructed not to use information that is likely to

induce medically unjustifiable drug use or give

rise to undue risks (264).

The Ethical Criteria specify information required in advertisements as: the name and quantity per dosage of active ingredients, the brand

name of the drug, the name of other ingredients

that patients might be sensitive to, the approved

therapeutic use, the proper dosage, the side effects and major adverse drug reactions, precautions, contraindications, warnings. major drug interactions, name and address of manufacturer and

distributor, and references to scientific literature

as appropriate.

No formal body oversees the implementation

of the Ethical Criteria, and WHO recently found

that few developing countries have the capacity

to oversee advertising and promotion of pharmaceuticals. The International Federation of Pharmaceutical Manufacturers Associations (IFPMA),

an association of national pharmaceutical manufacturers associations, has not adopted the guidelines of the Ethical Criteria, but believes its own

code of conduct is consistent with them.

IFPMA CODE OF PHARMACEUTICAL

MARKETlNG PRACTICES

The IFPMA is an association of 50 pharmaceutical associations (e.g., the U.S. Pharmaceutical Manufacturers Association) from 51 countries. In 1981, the IFPMA adopted its Code of

Pharmaceutical Marketing Practices, industry’s

statement on promotional practices. The Code

addresses drug labeling only generally, stating

that all information provided with a pharmaceutical should be scientific and be presented with

“objectivity and good taste, with scrupulous regard for truth and with clear statements with respect to indications, contraindications, tolerance

and toxicity” (111). In addition, pharmaceutical

companies are expected to provide essential information on safety, contraindications, side effects, and toxic hazards of their products, “subject to the legal, regulatory and medical practices

of the country.”

The phrase, “subject to the legal, regulatory

and medical practices of the country,” has been

the source of controversy among consumer advocates. The IFPMA claims that decisions of national drug regulatory authorities on indications

and precautionary information take precedence

over decisions made by more sophisticated drug

regulatory agencies, such as the FDA (1 11). (As a

point of information, no evidence surfaced in the

OTA survey to suggest that opposition to U. S.-

type labeling by regulatory authorities in study

countries accounted for the divergences that were

found.) In addition, for products that have been

evaluated and registered by an established regulatory authority, the approval itself is accepted as

evidence that the drug is efficacious (9). Certain

consumer groups argue that the point of a code of

conduct is to set standards that are higher than the

legal minimum, and that deference to regulatory

bodies in developing countries, which the

IFPMA admits may be rudimentary, essentially

defeats the purpose of a code (9). Consumer

groups have also been critical of the IFPMA

Code because it uses very general language,

lending itself to varying interpretations.

Enforcement of the Code

Alleged violations of the Code maybe reported to IFPMA or to member associations that have

developed their own dispute resolution systems.

For complaints made to IFPMA, the local member organization where the company is located

will issue a decision on whether the company violated the Code. Over the past 10 years, the
18 I Drug Labeling in Developing Countries

IFPMA has reviewed 72 complaints, consisting

of 962 separate cases, of which 56 percent were

found to be violations of the Code.

The IFPMA cannot force a company to change

its advertising, but instead uses the threat of adverse publicity to encourage change. According

to the IFPMA, most companies take remedial action as soon as they are informed of a complaint.

A contentious issue in interpreting the Code

has been the definition of “reminder advertisements,” which require less information than must

be provided with full advertisements. According

to WHO’s Ethical Criteria, reminder advertisements must not make therapeutic claims for

Health workers examining essential drugs.

drugs. But the IFPMA Code defines reminder advertisements more loosely, so that some relatively long advertisements (more than 200 words)

have been classified as reminders, exempting

them from the more inclusive requirements of

full advertisements (130,196).

Over the past 2 years, the number of complaints brought to the IFPMA has dropped significantly. It is not known whether this drop signifies that pharmaceutical advertising is improving,

consumer groups are bringing a larger proportion

of complaints directly to national associations, or

if complaints are no longer being filed for other

reasons, such as frustration with earlier experience.

INTERNATIONAL PROGRAMS TO

IMPROVE PHARMACEUTICAL LABELING

The most effective way to insure that adequate

prescribing information is available in developing countries is to strengthen existing regulatory

systems within the countries. WHO is the primary international governmental agency providing

direct support to developing countries for all aspects of health care. One of WHO’s major initiatives is the Action Program on Essential Drugs

(APED), whose aim is to improve access to and

the rational use of pharmaceuticals. The provision of accurate prescribing information is a key

component. The majority of APED’s activities

are in the form of direct country support. However, the WHO’s Division of Drug Management

and Policies (DMP) is responsible for developing

standards and systems for drug safety, efficacy

and quality, as well as drug regulation. Relevant

WHO activities are reviewed briefly below and

are discussed more fully in chapter 7.

 Distribution of Prescribing Information

WHO’s Division of Drug Policies and Management (DMP) has developed training materials

designed to improve prescribing practices.

Among those relevant to drug labeling are: the

Model Guide to Good Prescribing, developed in

conjunction with the Groningen University in the

Netherlands, and designed to be used in undergraduate medical education (286); and the

Manual for Rural Health Workers: Diagnosis

and Treatment with Essential Drugs (47). In addition, APED distributes the The Essential Drugs

Monitor, a quarterly newspaper that discusses all

aspects of essential drug programs, to 28,000

subscribers worldwide (286).

DMP’s ongoing work includes a series of publications entitled WHO Model Prescribing

Information for drugs on the essential drugs list

and which are of particular interest to developing
Summary and Options 19

countries (280,282,283,284,288,289). Recognizing that prescribing guides from industrialized

countries provide useful information, WHO also

provides national drug regulatory authorities in

developing countries with official prescribing

guides from France, the United Kingdom, and

the United States (10,15 1,249).

I WHO Certification Scheme

Nearly all countries have a process for registering new drugs, and it is at the point of registration that labeling is reviewed and approved. For

pharmaceuticals imported into a country, the

WHO Certification Scheme on the Quality of

Pharmaceutical Products Moving in International

Commerce (Certification Scheme) provides developing countries with a mechanism for obtaining information on their quality, whether they are

approved for use in the country of export and, if

approved, what labeling is used there.

Under the Certification Scheme, an importing

country may request that the exporter provide a

WHO certificate for the product to be imported.

The exporter must ask the regulatory authority in

the country in which the drug is manufactured to

issue one of three certificates.

The most comprehensive is the certificate for a

pharmaceutical product, which may be used

when the importing country is deciding whether

to register the product for sale in the country, or

when administrative action is necessary to renew,

extend, or vary an existing license for import or

sale (285). The certificate includes the following:

a statement that the product was manufactured in

accordance with current good manufacturing

practices and information on when the plant was

last inspected, confirmation that the product is

approved for sale in the country in which it is

manufactured or an explanation of why it has not

been approved, and a copy of the labeling approved in the country of manufacture.

In lieu of a certificate for a pharmaceutical

product, a country may request the statement of

licensing status, a short certificate attesting that

the product is licensed for sale in the country of

export. This might be used when bidding on an

international contract to supply pharmaceuticals.

The third type of certificate is a batch certificate

to be issued by the manufacturer (except for vaccines, sera, and other biological products for

which governments issue batch certificates).

Batch certificates provide the importing country

with information on the expiration date and the

results of any analyses undertaken on the batch

(285).

Despite the fact almost all industrialized countries have agreed to participate in the scheme and

most exports to developing countries are from industrialized countries, the Certification Scheme

has apparently not been used extensively by developing countries. Expanding use of the Certification Scheme remains one of WHO’s priorities

and with financial support from the U.S. Agency

for International Development (USAID) and the

assistance of the U.S. FDA, the DMP will evaluate the Certification Scheme and make recommendations to improve its implementation (259,

286).

I Access to New Safety and Efficacy

Information

In both developing and industrialized countries, registration may be effective for defined periods (e.g., 5 years in Panama) or indefinitely (as

in the United States). Regardless of the registration period, most countries require pharmaceutical companies to amend their registration in response to new information on the safety and

efficacy of the drug. In industrialized countries,

this requirement often is supplemented by a

mandatory adverse drug reaction reporting system. Since most developing countries do not have

a surveillance system of this type, WHO attempts

to provide them with equivalent information.

WHO does this by gathering information from

around the world on restrictive regulatory decisions and voluntary actions taken by manufacturers in response to concerns about the safety of
20 I Drug Labeling in Developing Countries

their products. This information is distributed

monthly to the drug regulatory authorities of

member countries through the WHO Pharmaceutical Newsletter (285). WHO Drug Information, a quarterly journal, provides discursive

commentaries on the more important actions of

national drug regulatory bodies (258,285).

Finally, WHO has established collaborating centers in each of its five regions for the purpose of

information dissemination, training, and operational research (274). APED’s documentation

center distributes more than 20,000 publications

a year (286).

 International Activities of the U.S. FDA

The U.S. FDA is primarily a domestic agency,

but as the drug regulatory agency for the largest

pharmaceutical market in the world, it is often

called on for advice. FDA’s primary international

activity is disseminating information about its

own regulatory actions. FDA sends WHO and the

European Community monthly updates on important regulatory developments, which include:

proposed regulations and policies; reports of serious adverse reactions from pharmaceuticals; lists

of approvals for new drugs, medical devices, and

biologics; and other public information (95).

Information on important regulatory decisions is

sent on an as-needed basis to WHO and to 62 foreign embassies in Washington, DC (32). This information focuses on decisions that FDA believes

are important, and which may or may not be of

critical importance to developing countries. The

FDA also distributes its newsletter, Medical

Bulletin, to over 800 government and academic

organizations all over the world, mostly in industrialized countries, but also in developing countries. The Medical Bulletin also focuses on new

FDA policies and findings on particular drugs

and devices.

The FDA also hosts many international visitors. In the year ending September 1991, FDA

was visited by 603 representatives from 61 countries. In 1990, they were visited by 789 foreign

officials representing 65 countries and multinational organimations (168).

FDA cooperates with WHO in various activities. In 1980, the FDA and WHO cosponsored

the first International Conference of Drug Regulatory Authorities, which has continued biannually, bringing together regulatory authorities

from all over the world. FDA representatives

have provided advice and other assistance to various WHO programs (166), and FDA is a WHO

Collaborating Center for Monitoring of Adverse

Drug Reactions, providing WHO on a monthly

basis with an automated data processing tape of

all serious domestic adverse reaction reports

(168).

Most recently, the FDA agreed to assume a

small role in the collaborative effort of USAID

with WHO to evaluate the Certification Scheme.

The FDA will also assist WHO in its evaluation

of the “Guiding Principles for Small National

Authorities” (24,278). (The Guiding Principles

outline some of the key elements for establishing

a drug regulatory system.)

 The U.S. Agency for International

Development

USAID has recently begun assisting WHO

with evaluations of the Certification Scheme and

the “Guiding Principles for Small National

Authorities;’ and it also is collaborating on research projects to facilitate the rational use of

drugs in developing countries. The research will

be carried out by the International Network for

the Rational Use of Drugs (INRUD), a nonprofit

research organization.

USAID has a 5-year cooperative agreement

with the U. S. Pharmacopoeia to assess and facilitate the distribution of pharmaceutical information in developing countries, including information provided to both drug regulatory authorities

and health workers. Finally, USAID will be sponsoring a 5-year project to assist developing countries address the following pharmaceutical

issues: drug regulation and registration; ration-
Summary and Options 21

alization of procurement strategies; and the development of pharmaceutical information for

prescribers, consumers, and drug regulatory authorities (24).

 Consumer Groups

Consumer groups and academic researchers

have helped bring to the public’s attention the

problems of improper drug labeling in developing countries. Most consumer groups use public

opinion and pressure as instruments of change, so

distribution of newsletters, journals, and books

are key activities. Some of the major studies of

drug labeling supported by these groups are summarized in appendix A, and their ongoing activities are discussed in chapter 7.

A number of the individual health and consumer groups in developing and industrialized

countries are part of the larger international network, Health Action International (HAI), which

itself works closely with the International Organization of Consumers Unions, a large and active

umbrella group that helps promote consumer issues and consumer advocacy in many countries.

Consumer groups often confront pharmaceutical companies directly, demanding explanations

for behavior. One influential group is the Medical

Lobby for Appropriate Marketing (MaLAM), an

international network of physicians that acts as a

watchdog for pharmaceutical advertising (199)

(results of some of MaLAM’s work are discussed

in ch. 4 and ch. 6).

Finally, some groups function as research consultants to developing countries. One such group

in the United States is the International Network

for the Rational Use of Drugs (INRUD). INRUD

is a cooperative organization of health professionals, administrators, and researchers whose

aim is to devise and implement innovative programs to improve the use of pharmaceuticals in

developing countries. According to INRUD,

there has been little evaluation of a number of

strategies developing countries have tried to improve the rational use of drugs, including development of standard treatment protocols, provision of drug information and drug bulletins, implementation of changes in health training curricula, restriction of drug advertising, and use of

public education. These strategies are merely assumed to have a positive impact. However, studies in industrialized countries have revealed that

some of these same interventions have not been

very effective, and INRUD believes similar research needs to be done in developing countries

(127).

CONTENT OF THIS REPORT

The remainder of this chapter presents options

for Congress to consider that could improve the

state of drug labeling in developing countries.

Chapter 2 lays out OTA’s labeling survey and

evaluation process, and chapter 3 presents the

survey results, both in summary form and in a

table giving the details of each product evaluation. Chapter 4 contains a discussion of drug labeling and registration requirements in the United

States and, in less detail, in other countries. It

also talks about sources of prescribing information other than drug labeling. Basic information

about the structure and functioning of multinational pharmaceutical corporations within the international legal community is covered in chapter

5, along with a discussion of extraterritorial jurisdiction. Various types of international agreement,

focusing on codes of conduct and voluntary

guidelines, are explored in chapter 6. Chapter 7

reviews efforts being made to improve drug labeling in developing countries by WHO, consumer organizations, and other private groups. It

also discusses the role of the U.S. FDA and

USAID in these efforts.

Appendix A reviews the major studies of pharmaceutical labeling in developing countries that

were carried out in the 1970s and 1980s by academic researchers and consumer organizations.

These studies sparked interest in the issue of

pharmaceutical labeling by multinational corpo-
22 I Drug Labeling in Developing Countries

rations and, in part, congressional interest in this

assessment. Finally, appendix B provides summary information on drug regulations in the

countries that were studied, focusing on drug labeling requirements.

OPTIONS FOR CONGRESSIONAL ACTION

Option 1: Require that all pharmaceuticals

sold in developing countries by U.S. multinational corporations and their controlled

subsidiaries be accompanied by the FDAapproved label in an appropriate language.

Congress could extend the existing requirements for labeling of drugs exported from the

United States by making them applicable to all

pharmaceuticals approved in the United States

and sold in developing countries by U.S. pharmaceutical corporations or their foreign subsidiaries, regardless of where they are manufactured.

This requirement could be limited to countries

without well-developed drug regulatory systems.

Such a limitation would recognize that the intent

of the legislation would be to assist countries that

do not have adequate resources to evaluate and

regulate pharmaceutical labeling, and not to impose U.S. regulations on other nations. The law

could require that the labeling be in English only,

or in both English and the language required by

the laws of the country in which the drug is sold.

Exceptions to labeling requirements under this

option should be permitted when the regulatory

authority of the host country affirmatively rejects

the U.S. label. Deference to conflicting national

laws of the importing country would ensure that

this legislation would not interfere with the importing country’s national sovereignty.

Under this proposed legislation, penalties

would apply only to the offending U.S. corporation and not to its foreign subsidiaries, which

usually are considered “citizens” of the host

country. It would have to be established initially

that the U.S. corporation had “control” over the

labeling of pharmaceutical products sold by the

foreign subsidiary that had “mislabeled” a product. In the case of a corporation, control over the

labeling standards could be presumed if there is a

corporate policy that requires the foreign subsidiary to obtain approval for labeling from the

parent corporation, or if there is evidence of corporate control as demonstrated by a majority equity ownership of the subsidiary, a shared Board

of Directors, or some other indicator,

However, even indirect regulation of the actions of foreign subsidiaries may be seen as an

encroachment on the sovereign right of developing nations to regulate the labeling of pharmaceuticals marketed within their borders, especially

since most developing countries already exercise

jurisdiction over pharmaceutical labeling. To address this concern, a company would be exempt

from this law if it is affirmatively required to follow contrary national laws of the importing country.

The legislation may require a company that

uses this exemption to provide evidence that it

was required to follow contrary national laws.

This might, however, put U.S. companies at a

disadvantage when competing for pharmaceutical contracts in developing countries because the

company would need a ruling on the issue by the

developing country before it is able to submit a

contract bid. The U.S. State Department would

consult with developing countries before legislation is enacted and provide them with the option

of being included in the legislation. This would

also provide Congress with feedback on whether

developing countries favored the legislation.

This legislation would, in some ways, be analogous to the Foreign Corrupt Practices Act

(FCPA), which, with respect to bribery, requires

that foreign operations of U.S. multinational corporations comply with the same standards for

corporate behavior that govern domestic companies.

One significant difference between this legislation and the FCPA is that it would apply only to

corporations and not to individuals. Penalties

under the FCPA apply to U.S. citizens as well as
Summary and Options 23

U.S. corporations. However, the rationale for applying civil or criminal penalties to citizens is

more compelling under the FCPA than it would

be under a drug labeling statute, because bribery

is an act that may be perpetrated by one or several individuals. By contrast, labeling of pharmaceutical products is generally a matter of corporate policy, and it is unlikely that a single

individual would be responsible for product labeling.

Another significant difference between this

legislation and the FCPA is that under the FCPA,

the United States is essentially assisting in the

enforcement of antibribery acts, which already

exist in most other countries. The labeling legislation, however, would require U.S. MNCs to include information beyond the minimum required

by the local drug labeling authorities.

The agency charged with monitoring and enforcement of this legislation would logically be

the FDA, or possibly the Federal Trade Commission, which has responsibilities in other areas of

international regulation. A surveillance mechanism could be established by the responsible

agency to review samples of labeling periodically. The legislation might also permit a private reporting mechanism (i.e., by private citizens, including public interest groups) to supplement

agency efforts.

It might be argued that the cost of compliance

with this legislation could put U.S. pharmaceutical manufacturers at a competitive disadvantage

relative to other manufacturers. Any new requirement is likely to necessitate an internal review of

current labeling, and companies would have to

bear the cost of this review. Most companies

would also have to print new packages and labels. These costs could be minimized by allowing a grace period for compliance.

Option 2: Endorse a voluntary international

code of conduct for pharmaceutical labeling

and press for adoption of the draft United

Nations Code of Conduct for Translational

Corporations.

Codes of conduct are voluntary agreements

among nations, associations, or other entities to

comply with certain standards of behavior. Codes

of conduct among nations often address the behavior of MNCs as well, although MNCs are not

legally bound by the codes because technically

they are not parties to the agreements. Nevertheless, the codes can be used by host countries

and consumer groups to pressure multinationals

into voluntary compliance. In addition, codes of

conduct may become the basis for national laws.

In the late 1970s and early 1980s, a WHO

code of conduct for labeling of pharmaceuticals

was debated in the World Health Assembly. By

1983, it was no longer on WHO’s agenda, in part

because of opposition by the U.S. Government to

codes of conduct by WHO to control specific industries. Interest in a code maybe renewed, however. In addition to promoting expansion of the

Ethical Criteria, the United States could take an

active role in revitalizing the move toward an international code.

An international code of conduct would provide a universal standard for pharmaceutical labeling that would apply to manufacturers from

every country and could be adopted into national

legislation. Endorsement of a pharmaceutical

code could be coupled with U.S. assistance to

WHO or directly to developing countries to establish and maintain administrative and legal

mechanisms to implement the scheme.

The code could also establish an international

entity to provide interpretations of the code and

to monitor its implementation. Such an entity

would provide a locus for the exchange of information and debate between signatories. The entity could also serve as a place for public interest

groups to report violations and exert pressure for

change. It could also arbitrate between companies and those that allege violations of the code.

As experience with the Breast-Milk Substitutes

Marketing Code suggests, implementation of a

labeling code could lead to education of officials,

adoption of country-specific codes of conduct,

330-065 0 – 93 – 2 QL 3
24 Drug Labeling in Developing Countries

adoption of legislation implementing provisions

of the code, and public education on the issue.

This code of conduct would be the result of an

agreement among nations, and would differ from

the International Federation of Pharmaceutical

Manufacturers Associations’ (IFPMA) Code,

which was established by agreement among the

manufacturers associations themselves. Under

the IFPMA Code, the IFPMA itself determines

whether a violation has occurred.

Codes of conduct are usually very crude tools

for addressing technical areas. A code might set

general parameters for labeling, such as the categories of information to be included, but is unlikely to provide specific standards for judging

the adequacy of information for each product.

The amount of opposition mounted against making the Ethical Criteria stronger and more specific suggests that successful negotiation of a very

specific code is unlikely.

The United States could press for adoption of

the U.N. Code of Conduct for Translational

Corporations (UNCCTC). This draft code instructs MNCs to go beyond the requirements of

national law by disclosing complete information

on product risks, through accurate and honest

promotion of products, and through active participation in the development of consumer protection policies. If the UNCCTC is passed by the

U.N. General Assembly, it could be used to pressure MNCs to properly label and promote their

drugs sold in developing countries. The UNCCTC provides much less specific labeling standards than would a code that directly addresses

drug labeling.

Option 3: Endorse strengthening and expanding WHO’s “Ethical Criteria for Medicinal

Drug Promotion” to set standards for pharmaceutical labeling.

In 1968, WHO adopted the “Ethical Criteria

for Pharmaceutical Advertising.” This document

was revised and significantly expanded in 1988,

and currently covers a number of areas of pharmaceutical promotion, including drug labeling.

The new “Ethical Criteria for Medicinal Drug

Promotion” (the Ethical Criteria) provide general

guidelines for package inserts and drug labels, requiring that they comply with national laws, and

if national laws are rudimentary, that they provide information consistent with that required by

a more developed drug authority.

The Ethical Criteria also require that all text

and illustrations on the drug package and label

provide only reliable, truthful, informative, and

current information, supported by scientific data.

Pharmaceutical companies are instructed to refrain from using information that is likely to induce medically unjustifiable drug use or give rise

to undue risks.

Guidelines are a weaker pronouncement of

policy than codes of conduct and, to date, it appears that few developing countries have implemented the Ethical Criteria. At the 1992 World

Health Assembly, WHO member countries

agreed to endorse a collaborative meeting of

WHO and the Council for International Organizations of Medical Sciences (CIOMS) to discuss

strategies for further advancing the Ethical

Criteria. The United States could support activities that could help developing countries implement the Ethical Criteria. In addition, more specific labeling guidelines could be supported.

Option 4: Continue to support and expand direct assistance to developing countries for

projects to improve pharmaceutical regulation, and provide additional information on

pharmaceuticals to regulatory authorities.

The FDA and USAID now provide some assistance to developing countries for improving

pharmaceutical regulation and for other related

activities. FDA currently provides limited information about its regulatory actions to developing

countries. These efforts could be systematized

and expanded.

The FDA could be required to provide drug

regulatory authorities in developing countries

with information about the pharmaceuticals approved by their agency, including information on
Summary and Options 125

the safety and efficacy of approved drugs, and the

approved U.S. labeling. This would apply to

newly approved products and to products with

amended labels. However, providing information

alone may not be sufficient to improve pharmaceutical regulation in developing countries.

Efforts must be made to improve the legal and

technical drug regulatory infrastructure in developing countries so that the information provided

can be used effectively.

Option 5: Mandate ongoing surveys of pharmaceutical labeling in developing countries.

Congress could designate an agency to conduct periodic surveys of pharmaceutical labeling

in developing countries. The results of these surveys would be presented to Congress and could

serve as a basis for further investigation and action. In addition, the results could be made public

and would serve as a source of information about

the status of drug labeling by U.S. pharmaceutical manufacturers in developing countries.

This option does not necessarily require that

Congress charge a Federal agency with the responsibility for monitoring the pharmaceutical

labeling situation in developing countries. Congress could require that a joint public-private

commission, comprising pharmacists, FDA representatives, academics, consumers, and industry

representatives, be appointed to conduct the surveys. By appointing a commission with diverse

membership, the survey could give a measure of

impartiality that may not be achieved by similar

surveys conducted by consumer activist groups

or by industry. The design of the surveys could be

similar to that employed in this OTA study, with

the selection of several countries for review, the

selection of a sample of products, and an assessment of the adequacy of their labeling. Advertising and promotional material could also be

studied.

Industry may object to the adverse publicity

that is generated about U.S. manufacturers,

which may place them at a disadvantage in international markets. To address this concern, the

survey could also include an evaluation of the labeling of products manufactured by multinational pharmaceutical corporations of other countries

and by domestic manufacturers in developing

counties. However, such a survey could also be

politically sensitive as other countries may oppose a U.S. Government sponsored audit of their

pharmaceutical companies’ labeling.

The difference between this option and previously listed options is that compliance with the

labeling standards that are established is purely

voluntarily, i.e., no criminal or civil penalties

would attach to manufacturers whose products

were found to have inadequate labeling. Motivation for improvement among manufacturers

would be based on their concern about the safety

of consumers, about adverse publicity that would

arise from inadequacies in labeling that are discovered, and about the threat of further regulation, should Congress find this necessary.

One advantage of this option is that it avoids

possible objections of the international community to the extraterritorial application of laws and

resultant threats to national sovereignty. In addition, this option has no provision for criminal or

civil penalties, so the burden of the judicial proceedings and trial-type administrative procedures

that arise from enforcement of criminal or civil

penalties would be avoided.
T h e

T

his study took a “snapshot” of drug labeling current between 1988 and 1990 and evaluated its medical appropriateness. Unlike previous drug labeling studies, which

had approached the task by documenting problems with

specific product labeling, OTA took a broader perspective and

developed new methodology. This chapter describes the methods that were developed to select sample products, gather labeling material, and evaluate the information content of the labeling. The results of the analyses are presented in chapter 3.

SAMPLE SELECTION

 Selection of Countries

The congressional requesters of this study stipulated that 8

countries be included from the 15 listed in their letter to OTA.

OTA considered it important to represent different geographic

areas and, to the extent possible, other country characteristics

(e.g., level of development, cultural background). Panama and

Brazil were selected for a pilot study based on OTA’s judgment

that they would be accessible for field visits and represented sizable markets for the products of U.S.-based pharmaceutical

companies. As it turned out, it was not possible to arrange official visits to either country during the time of the pilot study.

Product labeling was obtained from those countries, however, and

procedures for evaluating the information were developed and

tested.

In order to gauge the importance of field work to the project

(visits to study countries were required by the request), a third

country, Kenya, was chosen. Arrangements were made quickly

for project staff to travel to Kenya in March 1988 for discussions

with government, industry, and health sector representatives,

and to collect labeling directly.

27

OTA Survey

and

Evaluation 

Process 2

.
28 I Drug Labeling in Developing Countries

Experience with the evaluation process and

the field visit made it clear that it would not be

possible to carry out a thorough study in eight

countries. The evaluation process is time-consuming and exacting of medical knowledge, both

for OTA staff and for outside reviewers. Field

visits require extensive planning and are expensive both in staff time and money. OTA therefore

proposed to limit the study to four countries, including those already begun, adding one other in

Southeast Asia, the other major market area. For

reasons of market size and for the ease of conducting field work, Thailand was chosen. OTA

staff visited Thailand in November 1989 to conduct interviews and collect labeling for a sample

of products.

 Identifying Relevant Companies

OTA identified the U.S.-based companies selling products in the study countries through the

Pharmaceutical Manufacturers’ Association

(PMA). PMA was approached for this purpose

after it had been determined that it was not possible to identify U.S.-based multinational pharmaceutical companies from any U.S. Government

source, including the FDA and the Department of

Commerce. In all, 19 companies were included.

All are PMA members and are major researchbased fins. Although it is possible that some

companies were missed, based on examining

prescribing guides and on scanning pharmacies

for products, these 19 companies do account for

the vast majority of U.S.-based pharmaceutical

business in the study countries.

 Selection of Sample Products

Over the course of the study, OTA asked each

company to supply a complete list of their products marketed in Brazil, Kenya, Panama, and

Thailand. Sampling of products for each country

was carried out independently, and within each

country, independent samples were drawn for

each company. In total, 273 products were selected. The same sampling procedure was used for

Panama and Brazil, and a slightly different one

for Kenya and Thailand. Both procedures were

designed to produce unbiased samples.

For Panama and Brazil, each company’s complete list of products was first grouped by therapeutic category. The products within each category were alphabetized and numbered. Samples

of between 20 and 25 percent of each company’s

products were selected by number within each

therapeutic category using a random number

generator.

For Kenya and Thailand, the lists of products

were used as sampling frames in the order they

were received from the companies. Again, samples of 20 to 25 percent were taken, using a “systematic sample.” For each company, every fourth

or fifth product listed was included. The companies had organized the lists in different ways, and

OTA had specified no special order for them, so

the systematic approach should not have introduced any bias.

No adjustments were made to the random or

systematic samples to include or exclude specific

products for any reason. No attempt was made to

include “problem” products.

Throughout the course of the study and in this

report, OTA has maintained as confidential the

names of the sample products and the details of

the evaluations. Only the Expert Review Group,

OTA staff, and the companies themselves (each

for their own products only) were privy to all the

details. This was not done because the study involved privileged information, but because the

particular products studied by OTA are a representative sample and do not themselves represent

an important set of drugs.

OBTAINING PRODUCT LABELS

Early in the study, OTA asked the companies

to send all labeling material (including packaging, package inserts, advertising, and promotional material) for all their products marketed in

Panama and Brazil. This elicited a large volume

of information, which was used to determine
——. —

The OTA Survey and Evaluation Process 29

what a reasonable sample size would be, and to

examine the various types of material for their

general content. Since there was no opportunity

for field collection in Panama and Brazil, labels

for the sampled products came directly from material submitted by the companies. Labeling material (packaging and inserts) for products in the

Thailand and Kenya samples was obtained from

pharmacies in those countries.

The original labeling sources were supplemented by the companies in response to queries

sent to them after the original material (for

Panama and Brazil, material provided by companies, and for Kenya and Thailand, the field-collected material) had been examined by the

Expert Review Group (see below). Various updated inserts, inserts pending approval, and prescribing guide entries were submitted to OTA

and these were used in subsequent analyses providing they were in circulation or had been submitted to the country regulatory authority for approval at the time the Expert Review Group

reviewed them. New labels initiated after the relevant Expert Review Group workshop were not

accepted for later review. This restriction was

necessary because many changes were initiated

by companies as a result of OTA’S initial queries.

In a number of cases, companies sent their international product circulars, but these were not acceptable for the purposes of this study, as they

would not be available routinely to practicing

physicians.

OTA always evaluated the most comprehensive piece of labeling material that would be

readily available to practicing physicians for

each product in each country. Table 2-1 lists the

information sources that were accepted for

analysis, and each one is described briefly below.

Package Insert

Package inserts—fliers enclosed with each

company-packaged bottle or box of product—

generally contain more detailed information than

other sources of labeling. In the United States,

package inserts are virtually always included

with over-the-counter (OTC) and prescription

drugs. (See ch. 4 for the detailed requirements.)

Their format is dictated by the U.S. Code of

Federal Regulations, and their content must be

approved by the FDA. Brazil, Kenya, and Thailand also require some type of package insert, but

they are optional in Panama. In Thailand, many

products contain both a Thai language and an

English language insert, and others have English

Table 2-l—Sources of Labeling Material for OTA Analysis

Source Description

Package insert pending approval Insert submitted to local regulatory agency but not yet approved.

Contains, on average, more complete information than insert then

in current use.

Package insert Fliers enclosed with each company-packaged bottle or box of

product. Generally contains the most detailed information (when

no new insert is pending approval).

Product label only The composite of information printed on packages and bottle

labels. Used only when no package insert was available.

Prescribing guide A periodic publication distributed to physicians designed as a

quick reference for availability y and prescribing information for

pharmaceuticals. Used when no package insert was available.

Product datasheet Also known as international product documents. This detailed

source of product information is distributed to physicians and

pharmacists by drug company representatives and is also

available on request from the company.

SOURCE: Office of Technology Assessment, 1993.
30! Drug Labeling in Developing Countries

or Thai inserts only. The Thai language inserts

are often abridged compared with the English

ones, so, when available, English inserts were

used for analysis.

In some cases, companies informed OTA that

they had submitted a request to the national drug

regulatory authority for approval of updated labeling. In those cases, OTA asked the companies

to document their claims, and when it was provided, the inserts pending approval were used for

the analysis. In two instances, product documents

were evaluated.1

Prescribing Guide Entries

Prescribing guides are periodic publications

distributed to physicians in many countries, and

often are the most readily available pharmaceutical reference. They are specific to individual

countries or regions, and exist for each of the

countries included in this study. The purpose of

prescribing guides is stated by their publishers as

being a quick reference to find out which drugs

are available in a country or region and to provide

brief prescribing information.

In most prescribing guides, general information about a class of drugs is given, followed by

brief entries for each product in the class. A typical entry contains the trade name and generic

name of the product, the manufacturer, a brief review of indications, contraindications, warnings,

precautions, and dosing information, and a description of how the product is presented and

packaged. The product-specific information is

submitted to the publisher by the companies, but

the publisher has editorial control, and may

abridge the entry considerably. In this study, prescribing guide entries were used for just under

half of the products from Panama and were also

used as supplementary information when provided for drugs from Thailand and Brazil.

Package Labels and Boxes

When nothing else was available, the composite of information printed on packages and on

bottle labels was used for analysis.

TRANSLATION OF FOREIGN LANGUAGE LABELING

All labeling to be evaluated from Panama and

Brazil was translated into English by independent technical translators of Spanish and Portuguese, respectively, on contract to OTA. Labels

from Kenya were all in English. Labels in Thai

language were translated for OTA by a Thai pharmacy graduate student with English fluency. In a

few cases, OTA asked the companies to provide

translations from Thai.

THE LABELING EVALUATION PROCESS

The heart of the evaluation process was a review of the labels for “medically important” information by a group of outside experts. The

sample drugs were discussed during the course of

three 2-day meetings of this Expert Review

Group. The “medical importance standard” was

not applied by simply cataloging differences between the foreign labels and FDA-approved labels or some other standard. Each label was

reviewed to determine whether it contained appropriate and sufficient information-essential

medical information-for a physician to rely on

to use the product safely and effectively. The

process is described fully in the sections that follow.

Although details of each product evaluation

are given in chapter 3, the products are not

named, nor are the responsible companies or

countries of sale. This presentation is meant to illustrate the nature of OTA’s evaluation and rating

system. Summary data from the sample are also

presented in chapter 3.

1 At the beginning of the study, OTA agreed to evaluate the company product documents for two products that did not have package insert.% Later, however, OTA decided not to accept company product documents as a source of labeling for analysis be-cause product documents

are not universally available to the physicians who use the product (they are often only available by request to the company or sometimes distributed by company detail men to physicians and pharmacists). Because OTA had previously agreed to evaluate the two product documents

referred to, they remain in the analysis.
The OTA Survey and Evaluation Process 31

I OTA Preliminary Screen of Labels

OTA screened each label before the meeting at

which it was to be discussed, as an aid to the

Expert Review Group. The screen consisted of a

section by section comparison of the sample

label with some recognized standard, and the differences were listed on a summary form. Information is often organized differently on labels

from different companies and in different counties, so the summaries were also useful in standardizing information groupings, regardless of

where the information appeared on the foreign

label. Labels were not considered divergent from

the medical importance standard simply because

information was organized differently, however.

The sources of comparison for screening are

listed in table 2-2. For brandname products (or

their components) available in the United States

(or products with the same active ingredients),

the Physicians’ Desk Reference (PDR) (151) or

the Physicians’ Desk Reference for Nonprescription Drugs (152) was used as the reference.

These annual volumes contain the complete

FDA-approved labeling for most products sold in

the United States; however, it is not mandatory

that all products be included in the PDR volumes.

One or a combination of other sources were used

for products not included in the PDR, either because they are not sold in the United States or because entries for them did not appear in the PDR.

The screening summaries for each product

were distributed to the Expert Review Group,

along with the actual label (or translation) and a

notation of the source used for the screen (less

readily available sources, e.g., specific journal articles, were enclosed for the convenience of the

members).

 The Expert Review Group: First Review

The Expert Review Group consisted of academic and practicing physicians and pharmacologists and one physician consumer advocate

(members are listed in the front of this report).

All were highly qualified technically to make

medical judgments on pharmaceutical information. It was OTA’s intention to include technically

qualified industry representatives in the group as

well, but for legal reasons, this proved problematic for industry, so they chose not to be represented. The members listed all attended at least one

meeting; about eight were present at each meeting.

Three 2-day meetings were held between 1988

and 1990 to review the sample labels. About 50

Table 2-2—References Used for Comparison With Sample Labeling

Source Use in sample

Physicians’ Desk Reference Prescription drugs sold in the United States

(151)

Physicians’ Desk Reference for OTC products sold in the United States

Nonprescription Drugs (152)

Martingale: The Extra Pharmacopoeia Drugs that are not approved for sale in the United

(184) States

USP DI (U.S. Pharmacopeial Convention) Commonly used generic products Iacking full prescrib-

(247) ing information in PDR.

American Hospital Formulary Service Generic products and products not available in the

(8) United States

Goodman and Gilman’s The Pharmaco- Basic pharmacologic information.

logical Basis of Threrapeutics (75)

Search of medical literature Products with no other source of reference.

SOURCE: Office of Technology Assessment, 1993.
32 I Drug Labeling in Developing Countries

products were reviewed each day. OTA’s screening summaries were used as a guide, but discussion was not limited to the points mentioned in

them, and the sources of comparison used by

OTA were not considered “gold standards.”

Other references, from standard pharmacology

textbooks (75) to specific journal articles, were

referred to regularly during these meetings.

The standard of evaluation was “medical importance.” The question OTA posed to the group

was:

Is the information provided on this label accurate and is it sufficient to allow a physician to

use the product safely and effectively, given

what we know about the drug from U.S. labeling and other sources?

The result was a focus on essential medical information, rather than a laundry list of all the “differences” between the foreign labels and either

the U.S.-approved label or another comparison.

In addition, each medically important deviation

was given a relative importance ranking, which

eventually was translated by OTA into a numerical ranking.

When the FDA-approved labeling was the

screening source, there was general agreement

that the indications listed were probably well

supported, given FDA’s strict standards of evidence. However, lack of an indication on the

FDA-approved label was not taken as sufficient

evidence that an additional indication on the sample label was inappropriate. Other references

were often consulted to determine the evidence

for and medical acceptability of “unlabeled indications” (see discussion in ch. 4). Most commonly used were the USP DI (247), AMA’s Drug

Evaluations (7), and Drug Facts and Comparisons (46), each of which routinely lists both

labeled and unlabeled indications that are accepted by medical experts in the United States.

Expert Review Group members were the final arbiters.

It was recognized by the Review Group and

OTA that FDA-approved labeling contains a

large number of warnings and precautions that

represent rare cases, and may be of limited medical importance. When these were absent from

foreign labels, they were not necessarily considered violations of the medical importance standard. Important divergences in warnings and precautions were identified only when the Review

Group believed that their absence would hinder a

physician’s safe and effective use of the product,

and might place a patient at undue risk.

After products were reviewed, each instance

of a divergence from the medical importance

standard, as determined jointly by the Expert

Review Group and OTA staff, was formulated

into a query to the manufacturer.

 Queries to Companies

A summary query sheet was prepared for each

product evaluated. If there were no divergences

from the medical importance standard, a sheet

was still prepared conveying that information,

but not requiring a response. For the labels with

divergences, queries were organized by category

of labeling information. Companies were asked

to provide justification or medical evidence to

support the adequacy of the labeling as it existed,

in relation to each query. The type of information

to be submitted was left to the discretion of the

companies.

It had been explained in correspondence with

the companies that, except for issues requiring

clarification, the request for information on the

queries would not be reopened, so their responses

should be as complete as possible. (OTA was to

recant on this and allow further submissions late

in the process. This is discussed later in this

chapter.)

 OTA Evaluation of Company Responses

Companies responded with varying degrees of

completeness and with different types of infor-
mation (the types of responses received are described in table 2-3). The responses fell into two

broad groupings: “evidence” and “explanations.”

Although some type of response was given for

most queries, one company chose to respond to

queries for only a “sample” of their products.

Another company sent a list of general responses,

and answered the queries with a numbered list of

the general responses that applied in each case.

OTA evaluated each response using the criteria

given in table 2-3. If the response provided sufficient justification for the existing labeling, or if

the company indicated that a revised label had already been prepared that covered the point raised

by OTA, the query was considered satisfied. (At

the time of the first review for each product, OTA

did not require documentary evidence that a revised label had been submitted to the foreign regulatory authority, but this was required later in

the process, as discussed below.)

Many of the queries had referred to indications

not appearing in the major references used by

OTA, and which were considered inappropriate

or questionable by the Expert Review Group. The

issue in some cases was that the indications were

overly broad or vague and might lead to inappropriate use of the product. In general, OTA required evidence from at least one adequately controlled, well-designed clinical trial as support for

these additional indications. Submission of articles (or abstracts during the initial round of information seeking) or citations to articles describing

the clinical trials were necessary for OTA to evaluate the studies and judge their acceptability as

evidence. In some cases, however, companies

stated that they had an application pending with

the FDA to include the questioned indication on

the U.S. labeling. OTA accepted those statements

as adequate, as companies were deemed unlikely

to go through the long and expensive application

process without having carried out the necessary

studies. Some of those applications would undoubtedly be approved, and some might be denied. OTA gave the benefit of the doubt to the

The OTA Survey and Evaluation Process 33

companies that they did have evidence, and did

not attempt to review submissions to FDA.

In many instances, companies stated that the

questioned labeling had already been changed or

that the changes were pending approval by the

foreign drug authority. In some cases, companies

Table 2-3-Categories of Company Responses

to OTA Queries

Explanations

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

Product is no longer sold by this manufacturer.

Other manufacturers have similar labeling for this product.

OTA has misinterpreted information on the label.

Inclusion of the requested information will be misleading or

confusing to patients or practitioners.

The local regulatory agency will not allow the requested

information to be included on the label.

This information is presented in datasheets that are distributed separate from the product, is included in a drug manual

or prescribing guide, or is sent to physicians who request it.

The information omitted is common medical knowledge.

The questioned information appears in the label.

OTA has not correctly translated the label or insert.

The company will make or consider making the requested

changes.

The local regulatory agency has approved the labeling.

The labeling complies with local practice customs.

Regulatory agencies from sophisticated countries have

approved the questioned labeling.

The requested information has been approved for labeling

for the same or a similar product marketed in the United

States.

The requested changes are pending with the local regulatory agency.

The requested information is included in the current product

insert (which supersedes the one reviewed by OTA).

The requested changes are unnecessary for reasons other

than noted above.

Evidence

●

●

●

●

●

●

●

●

●

The questioned indication or lack of warning/adverse

reaction/contraindication/precaution is supported by the

data.

The company cited U.S. FDA application materials for this

indication.

The company submitted results from controlled clinical trials

as support for an indication.

The company claimed that certain labeling was supported

by studies in uncited literature.

The company cited anecdotal evidence as support for an

indication.

The company provided support for indications with opinions

of medical experts.

The company provided abstracts of relevant studies as

evidence.

The company provided support with in vivo and in vitro

experiments in animal models.

The foreign labeling includes “unlabeled” indications that

are widely accepted in the U.S. but the manufacturer has

not obtained formal FDA approval. . .

SOURCE: Office of Technology Asssessment, 1993.
34 I Drug Labeling in Developing Countries

enclosed the revised labeling, but in many cases,

they did not. If the changes had been made or

were in process at the time the Expert Review

Group had evaluated the particular product, OTA

accepted these statements as sufficient evidence

to dismiss the query, even if documentation was

not included. Documentation for these instances

was later sought, however (see below, Provision

of Scoring Sheets to Companies).

 OTA Scoring of Labels

After all company submissions had been evaluated, those queries that had been justified by

data or explanations were eliminated from further consideration. The remaining unsatisfied

queries formed the basis for calculating a “score”

for each product. The scoring system was threetiered: first, each individual unresolved query

was assigned a score based on its seriousness;

second, each information category was assigned

a score; and third, an overall score for the product

was calculated. All aspects of scoring are discussed here and shown in table 2-4.

Table 2-4-Scoring OTA Survey Drugs

Category scores (derived from scores for Individual

queries)

score

code Definition

N/A Not applicable (drug excluded from consideration)

— No queries in category

o All queries in category resolved

1 At least one query rated 1; no query rated 2

2 At least one query rated 2

R Score of R (or 1) in “INGREDIENT’ category

specifically for failure to list inactive ingredients

Overall scores (derived from category scores)

score

code Definition

N/A Not applicable (drug excluded from consideration)

o No queries or all queries resolved

O/R INGREDIENT Score = R; all other category

scores = O

1 Score of 1 in one or more category; no category with

score of 2

2 Score of 2 in one category only

3 Score of 2 in two or more categories

SOURCE: Offices of Technology Assessment, 1993.

Individual queries were assigned scores of “l”

or “2,” representing lesser or greater divergence

from the medical importance standard. A score of

2 was generally defined as one for which there

was:

a substantial likelihood that a practitioner relying on the information would use the drug in a

manner that could result in nontrivial harm to a

substantial proportion of users or severe harm or

death to some users.

All unsatisfied queries not fulfilling the criteria for a score of 2 were assigned a score of 1.

Overall scores were calculated byexamining the

individual query scores by category of labeling

information.

For clarity, it should be noted that more than

one divergence from the standard in a single category (e.g., two medically important adverse reactions missing) did not carry more weight than

would one divergence in that category. This allowed OTA somewhat more freedom in stating

the queries in the most concise manner. In some

cases, similar divergences were grouped together

within a category to avoid repeating the same

phrase for each one. Whether these would be

considered one or several divergences in the scoring was not important because scoring took into

account the entire category, rather than the individual queries within each category.

PROVISION OF SCORING SHEETS TO COMPANIES

OTA sent each company the score sheets for

their own products. These sheets included all the

original queries, with a summary of OTA’s evaluation of the evidence that had been submitted on

each point. Scores for each remaining unsatisfied

query and the overall scores were indicated.

OTA had informed the companies originally

that there would not be a second opportunity to

respond to the queries, and the scoring sheets

were being provided for their information only. A

number of companies and members of the

Advisory Panel urged OTA to consider additional

information submitted by the companies; for a
variety of reasons, complete information had not

been submitted during the initial rounds.

In the interest of fairness and completeness,

OTA invited the companies to submit additional

information on the queries still remaining.

Companies were asked to limit their submissions

to information available at the time of the Expert

Review Group meeting at which the particular

product labeling was evaluated (e.g., a labeling

change that had been made after OTA’s initial review would not be accepted to satisfy the query).

OTA also took the opportunity to request documentation for certain statements made in the

companies’ original responses. Table 2-5 lists the

The OTA Survey and Evaluation Process 35

items for which documentation was requested,

and the type of material that would be accepted.

This request to the companies also allowed

OTA to gather information for an analysis recommended by the Advisory Panel and certain companies. There was some concern that OTA’s standard (the “medical importance” standard) was an

inappropriate one for products shipped to developing countries from developed countries, mainly European countries, other than the United

States. The general feeling was that OTA should

take into account the fact that labels rated deficient by OTA’s standards might well be identical

Table 2-5-Responses for Which Documentation was Requested

Company response Requested documentation

The company has applied for changes in

labeling with the relevant regulatory authority.

The questioned information appears in

the labeling pending approval.

More complete labeling superseded the

labeling that OTA reviewed.

The questioned information appears in

the superseding labeling.

The questioned information appears in

the labeling that OTA reviewed.

A claim that the local regulatory authority

has not required certain labeling.

Particular labeling is approved in the

developed country that the product is

exported from.

Any questioned indications.

Must be accompanied by dated documentary evidence.

Official correspondence with the regulatory authority is

acceptable.

The pending labeling must be submitted.

Must be accompanied by a dated copy of that labeling, The

label must be dated before the evaluation date indicated on

the product evaluation sheets.

The superseding labeling must be submitted.

Must be accompanied by a copy of the labeling.

This is sufficient justification for a deficiency if the manufacturer documents that the regulatory authority rejected more

appropriate language. If the local regulatory authorities

have devised standard package inserts for certain products, documentation must be provided that these standard

inserts are mandated by local health authorities.

Must be accompanied by the foreign label from that country

accompanied by translation if the original is not in English.

(OTA evaluation will still be based on the medical importance standard, however.)

OTA will accept indications supported by adequately

controlled clinical trials (excepting only a disease with a

well known natural history, where there is evidence that a

therapy consistently alters the natural history of that

disease).

NOTE: If documentation was not provided, OTA relied on the label reviewed originally. OTA requested that copies of

all studies cited for support be submitted, non-English studies translated into English, FDA submissions cited

for support provided in summary form, and unpublished data include a clear statement of the study design and

a summary of the findings.

SOURCE: Office of Technology Assessment, 1993.
36 I Drug Labeling in Developing Countries

to the approved labels in the developed countries

of export.

It was agreed that a subsidiary analysis would

be carried out on this point. OTA, therefore,

asked companies to submit the approved labeling

from the exporting countries for products in the

sample. (In the end, this analysis was not carried

out because companies did not submit the material, though one did a different subsidiary analysis, which is discussed in ch. 3.)

The new material submitted by the companies

was evaluated using the same standards described earlier, and scores adjusted as appropriate. It was only possible for scores to improve

based on new information, except in cases where

companies failed to document previous statements.

 Review of OTA Scoring by Expert

Review Group

OTA did not routinely seek the advice of the

Expert Review Group in evaluating evidence

submitted by the companies. In most cases, the

evidence either clearly did or did not respond adequately to the queries. The experts were consulted on an ad hoc basis, according to OTA’s needs.

Initially, therefore, they did not review OTA’s

scoring.

At the urging of the companies and members

of the Advisory Panel, a subgroup of the Expert

Review Group met to review the criteria for scoring and the scores themselves, based on the first

submissions of the companies. The four members

of the Expert Review Group who also served on

the Advisory Panel constituted the subgroup, and

they were joined by the Advisory Panel chairman, who had not been present at previous

Expert Review Group meetings.

In nearly all cases, the Subgroup affirmed

OTA’s judgments. However, they believed OTA

to have been lenient in its judgments, giving the

benefit of the doubt to the companies in many

more cases than they themselves were willing to

do. Consequently, they recommended some

changes in the original scoring. The changes

were due to the Subgroup rating the absence of

certain types of information (mainly adverse reactions) as more medically serious than had

OTA. Of the 66 products to which OTA had given

an overall score of 3 (greatest divergence from

standard), it was recommended that 3 be considered less serious, lowering the scores to 2. Of the

66 originally scored as 2, they recommended

lowering scores for 3 to less serious categories

and raising 11 products to 3s. Of the 61 initially

rated as 1, they recommended lowering 1 to a less

serious category and raising 13 to a more serious

one. Of the 39 products OTA rated as O initially,

no changes were proposed. (The final figures reported in ch. 3 are different from these because

they reflect the company’s “additional responses.”

In the end, 59 products, rather than 74, were rated

3.)

By the time of the Subgroup meeting, OTA

had already sent the companies evaluation sheets

for their additional responses. In the cases where

scores had been raised for individual queries

from O (OTA’s original evaluation) to 1 or 2 based

on the Subgroup evaluation, revised evaluations

were sent to the companies.

 Provision of Summary Sheets to

Companies for Additional Responses

In November 1991, the updated summary

sheets were provided to the companies for their

additional responses, which were received over

the next several months. A massive amount of information was submitted by the companies overall, responding much more fully to the queries

than they had originally. OTA staff analyzed the

new information and rescored all the products.

As a whole, the scores improved as a result of the

additional responses. In a few cases they were

worse, mainly because companies had originally

stated that labels had been changed, or that applications for changes had been filed with the country regulatory authority, but the company failed

to document these claims in the additional re-
sponse period. Table 2-6 shows the distribution

of interim and revised overall scores.

 Analysis of Final Results

The results of the evaluation process are presented in chapter 3. All discussion and presentation of scores, both for individual points and

products overall refer to the final evaluations,

after the material submitted by the companies

during both rounds of review had been evaluated

and queries were either resolved or not.

The OTA Survey and Evaluation Process 37

Table 2-6—Distribution of Interim and Final Scores

Overall score Interim score count Final score count

o 59 78

1 61 42

2 59 63

3 63 59

Not evaluated 31 31

Total 273 273

NOTE: Interim versus final scares were not cross tabulated, so this

table cannot be used to determine how many scores changed

during the process.

SOURCE: Office of Technology Assessment, 1993.
Results

of the

OTA

Survey 3

T

he results presented here emerged from the process described in chapter 2. Quantitative results based on the

product scores give a general picture of the quality of information found, but the detail behind the scores brings

them into clearer focus. Detailed tables (addenda 3-1 to 3-6) at

the end of this chapter catalogue every divergence from the medical importance standard that OTA scored for each of the products, but does so using only the type of drug as an identifier, and

not the name. The rest of this chapter describes the types of

problem encountered and gives quantitative results by section of

the label, by overall scores, by company, and by country. Also

included is an analysis provided by one of the survey companies,

pitting OTA’s evaluation against labeling in other industrialized

countries; and an OTA analysis comparing our own evaluation

against the information included in World Health Organization

(WHO) monographs of drug prescribing information.

QUALITATIVE RESULTS: ADDENDA

The particular products evaluated in the survey are not listed

by name in this report. These drugs constitute a representative

sample and were not singled out as being potentially problematic; by themselves, they do not constitute a meaningful universe

for action. It was realized, however, that with no detail on the

types of divergences from OTA’s standard that contributed to the

scores and the results in general, it would be difficult to judge

the fairness and consistency of the OTA process. To remedy this,

the addenda to this chapter consist of tables listing each product,

identified by therapeutic class and type of drug (where appropriate), and the divergences that contributed to its score. Illustrations are drawn from the addenda in the discussion that fol39
40 I Drug Labeling in Developing Countries

lows, but readers are encouraged to delve into the

tables themselves to understand the nature of the

OTA analysis, which cannot be judged adequately on the basis of numeric scores and averages.

QUANTITATIVE RESULTS

 Overall Analysis

Of the 273 products in the survey, 241 were

evaluated fully. The remaining 32 were excluded

for a variety of reasons, most because they were

no longer being marketed at the time OTA evaluated them. The rest were scored, as described in

chapter 2, taking into account all the information

the companies sent in response to OTA queries.

The scale for overall scores ranges from O to

3, with O signifying no important divergence

from OTA’s medical importance standard, and 3

Table 3-l-Summary of Overall Scores

Overall score Number of products (%)

o . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 ( 32%)

1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 ( 17%)

2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 ( 27%)

3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59( 24%)

All fully evaluated . . . . . . . . . . . . . . . . . . . . . 241 (1 00%)

Not fully evaluated . . . . . . . . . . . . . . . . . . . . 32

Total in original sample ................ 273

Degree of divergence from medical importance standard:

O: No divergence from medical importance standard

1: At least one category score = 1; no score >1

2: No more than one category score= 2; other categories may= O or 1

3: At least two category scores. 2

NOTE: See text for details of scoring.

SOURCE: Office of Technology Assessment, 1993.

signifying the greatest divergence. Labeling was

assigned an overall score of 3 if two or more sections of labeling information were found to have

the most medically serious divergence scores.

(The scoring system is explained in detail in ch.

2.) The overall scores use the FDA-approved labeling as a ceiling. This means that labels were

never held to a higher standard than what is required by FDA in U.S. labels.

In this analysis, about half the products had labels that were either completely in accord with

OTA’s medical importance standard, a score of O,

or diverged to a small but medically important

degree (score of 1). About 25 percent scored 2,

and about 25 percent scored 3 (see table 3-l).

 Analysis by Category of Labeling

Information

INTRODUCTION

The sections listed below, which OTA used to

categorize divergences from the medical importance standard, were adopted from the U.S. label

format as a matter of convenience. Labels from

other countries, developed and developing, are

organized differently, and OTA did not require

that specific items of information appear in the

sample labels in sections of the same name. The

labels were evaluated as whole entities, and the

appearance of the appropriate information, as

judged against the medical importance standard,

was all that was required, regardless of the label’s organization.

The scale for category scores ranges from O

(no divergence) to 2 (the most serious category

of divergence). The numbers and percentages reported in each section, below, and in table 3-2,

are based on the 241 products that were evaluated fully.

DESCRIPTION AND CLINICAL PHARMACOLOGY

Problems were found in 51 (21 percent) of the

description and clinical pharmacology sections

of the labels, most of them (45) rated 1, and 6

rated 2. The most common concerns were failure

to identify the drug class of the product and,

more commonly, failure to include adequate

pharmacokinetic information (especially halflife, metabolism, and route of elimination).

For example, a manufacturer of an antihistamine did not provide information about the halflife of the product, even though the half-life was

particularly long (l-2 weeks).

INGREDIENTS

The ingredients section contributed to a divergence in the final scores in only four cases. This
Results of the OTA Survey 41

contrasts markedly with OTA’s interim scores, in

which the lack of an inert (inactive) ingredient

list was scored as an unsatisfied query. In the

final analysis, lack of an inert ingredient list did

not contribute to overall divergent scores, except

in the few cases where a particular inert ingredient was known to be particularly sensitizing. A

specific exception is failure to note alcohol as an

ingredient of drugs that might be given to children, in whom even small amounts may cause serious adverse reactions, including central nervous system depression and seizures. For all the

rest, lack of inert ingredient lists elicited a score

of “R,” which was tracked separate from the rest

of the scores. In all, 17 of the products with a primary score of O lacked inert ingredient lists

(scored “R”), as did 57 (24%) of those with

scores of 1, 2, or 3. The “R” itself did not contribute to the score, however.

OTA and the Expert Review Group did consider it medically important to include a list of

inert ingredients, and, in fact, all manufacturers

in the OTA survey list them voluntarily on U.S.

labels. By regulation, they are required to list

inert ingredients only for injectable products, and

to note the presence of only a small number of

specific ingredients in oral products. In the past,

countries of the European Community have not

required a complete listing, but this is changing

with the new harmonization efforts, and inert ingredient lists will be required. Japan first required inert ingredient disclosure for injectable

drugs and those applied to mucous membranes in

1988. For drugs for internal use, however, listing

is required only for particular ingredients. An independent drug bulletin in Japan has, however,

assembled a database of all inert ingredients for

about 6,000 products. Sales of the database are

reported to be good (18).

These developments suggest that it is medically important for physicians to know what nonpharmacologic ingredients are in the preparations they prescribe. Nearly one-third of the

labels evaluated by OTA lacked this information.

INDICATIONS

Indications was one of the most problematic

sections. Sixty-three labels (26 percent) were divergent in this area, and 43 of those were rated 2,

representing the most serious problems. These

scores resulted from:

1.

2.

3.

indications that did not appear in the U.S.

label or in widely accepted drug compendia and for which inadequate evidence of

efficacy was presented by the companies,

indications that were overly broad and

vague, and

failure to inform when the product was not

considered first-line treatment for an indication.

Table 3-2—Summary of Category Scores

Category

score DCP ING IND CI WP AR DA OD

1 45 (19%) 1 ( O%) 20 ( 8%) 12 (5%) 49 (20%) 25 (10%) 17 (7%) 8 ( 3%)

2 6 ( 2°/0) 3 ( 1%) 43 (18%) 15 (6°/0) 79 (33$40) 37 (15%) 11 (5%) 37 (15%)

R 74 (31 %)

Categories: Category scores:

DCP = Description/Clinical Pharmacology 1: at least one unresolved query in category with score= 1

ING = Ingredients 2: at least one unresolved query in category with score -2

IND - Indications R: lack of inactive (inert) ingredient list

- Contraindications

WP - Warnings and Precautions

AR = Adverse Reactions

DA = Dosage and Administration

OD . Overdosage

NOTE: The percentage calculations use 241, the number of fully evaluated products, as the denominator. See text for details of scoring.

SOURCE: Office of Technology Assessment, 1993.
42 Drug Labeling in Developing Countries

In the first situation, the Expert Review Group

and OTA recognized that products are used and

effective for some indications other than those

approved by FDA, so the mere fact that an indication did not appear on the FDA-approved label

did not automatically call it into question. For example, OTA accepted the indication of a betablocker for prophylaxis of migraine headache,

even though it is not an indication on the FDAapproved label. OTA did not however, accept the

indication of an androgenic steroid in frigidity

therapy, in menopause, as therapy for benign

mammary disturbances, or in suppression of lactation.

The second situation, vague or general indications, is illustrated by an injectable corticosteroid

indicated for “arthritis in general” and “dermatitis in general” with no qualification.

The third type of divergence was failure to

note that the product, although effective for a

specific indication, was not the drug of choice.

For example, an antidiarrheal combination with

an aminoglycoside antibiotic did not note that

oral dehydration therapy is considered first-line

treatment for childhood diarrhea. This information is particularly important for drugs with relatively more common or more severe adverse effects compared with other choices, or which are

less effective than alternatives, In general, labeling was considered deficient if it failed to note

when a product was not first-line therapy. However, if the manufacturer provided some justification and supporting evidence for first-line use, it

was accepted, even if it did not agree with U.S.

labeling or other reference information.

CONTRAINDICATIONS

Contraindications diverged from the medical

importance standard for 27 labels (11 percent),

including 15 rated 2, the most serious category.

Contraindications describe situations in which a

drug should not be used because, for one reason

or another, the risks of taking it are likely to outweigh the benefits. The reasons include:

1.

2.

3.

4.

5.

the patient has another medical condition

that could be made worse by the drug (e.g.,

failure to contraindicate an anthelminthic

known to induce seizures in patients with

epilepsy);

the patient is taking another drug known to

interact with the product in an unacceptable way (e.g., failure to contraindicate the

use of a monoamine oxidase inhibitor with

the antidepressant fluoxetine);

the drug may harm a fetus in a pregnant

woman (e.g., failure to contraindicate use

of an androgenic steroid in pregnancy) or

pass through a nursing mother’s breast

milk, potentially harming the child;

the drug should not be taken by children

(because of lack of evidence of safety or

because of a known unacceptable adverse

effect) or by frail elderly people; and

the patient has known sensitivity to the

drug itself or related products.

There is some disagreement about the last

point, the need to contraindicate a drug specifically for hypersensitivity to the drug itself or to

the class of drugs. Some people consider this

self-evident. Silverman, Lydecker, and Lee, in

their recent book, Bad Medicine: The

Prescription Drug Industry in the Third World

(212), comment:

No attention is paid hereto statements that a

particular agent is contraindicated in patients

who may be allergic or hypersensitive to that

product or related substances—advice that

would be as useless and irritating as a warning

that “this drug should not be used by a patient

who should not use it. ”

This view is not held universally, however. The

WHO monographs of prescribing information,

which are relatively brief, and were developed by

a consensual process, do contain these statements, where appropriate.

In OTA’s survey, five of the divergence scores

in contraindications were for failure to mention
Results of the OTA Survey 43

hypersensitivity to the product itself (in two

cases, this was the only problem in contraindications, and in three, there was at least one other);

and in two cases, the score was given for failure

to contraindicate for hypersensitivity to the drug

class (in one case, this was the only problem; in

the other, it was one of several). Five labels had

unresolved queries for having no contraindication section at all, and presumably, some of those

might have specified hypersensitivity as a problem.

WARNINGS AND PRECAUTIONS

The greatest number of problems, and the

greatest number rating a 2, was found in warnings and precautions sections. More than half the

labels (128) evaluated deviated from the medical

importance standard, and 79 of those were rated

2. warnings and precautions cover a broad range

of information, so it may not be surprising that

divergences were common there. The types of

problem included:

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

failure to warn of relatively rare but potentially life-threatening effects;

failure to warn of less serious but more

common effects;

providing too weak a warning in relation

to the risk;

failure to warn about particular high-risk

patients (e.g., with other chronic diseases);

failure to note interactions with other

drugs;

failure to note effects on laboratory test

results;

omission of instructions for monitoring

patients on the drug;

lack of specificity about possible effects;

lack of information about use of drug in

pregnancy, in nursing mothers, in pediatric patients, or in the elderly; and

lack of information on possible carcinogenicity.

Specific problems in warnings and precautions

include:

an antiepileptic that failed to warn about the

increased risk of fatal hepatotoxicity in children under 2 years of age;

a magnesium-containing antacid indicated

for infant feedings “to prevent milk from

souring and forming curds in the stomach”

that did not warn about the risk of hypermagnesemia in infants from chronic administration;

an antihypertensive that stated that hypotension is an “infrequent secondary reaction,”

whereas in the United States, hypotension is

not considered infrequent, and potentially

serious consequences of hypotension are

noted in the labeling;

an antihypertensive known to increase blood

sugar levels that did not include information

about appropriate use in diabetic patients; and

an antihypertensive that failed to warn about

interactions with other drugs, most notably

other antihypertensive medications, which

may lead to additive or synergistic effects in

decreasing blood pressure.

ADVERSE REACTIONS

Widespread divergences were also noted in

adverse reactions sections of the labels. Just over

a quarter (62) had unresolved queries, of which

37 (59 percent) were rated 2, the most serious

category. Adverse reactions noted as absent

ranged from some that are possibly worrisome to

patients though not medically serious (e.g., discoloration of urine or other body fluids) to life

threatening (e.g., agranulocytosis, the complete

absence of a type of blood cell; and StevensJohnson syndrome, an extremely severe skin manifestation), but all were considered important

enough for physicians to be fully informed about

them.

In some cases, an adverse reaction was listed

on the sample label, but the seriousness of it was

not conveyed. In one case, for example, granulo-
44 I Drug Labeling in Developing Countries

cytopenia-low numbers of blood cells known as

granulocytes-was listed, but the product had, in

rare cases, caused agranulocytosis, the complete

absence of these cells, a potentially fatal condition. The company argued that the distinction

was not essential, as physicians know the relationship between the two conditions. OTA, however, scored this and other similar instances as divergences, either a score or 1 or 2, depending on

the seriousness of the reaction.

DOSAGE AND ADMINISTRATION (EXCLUDING

OVERDOSAGE)

Most problems in dosage and administration

had to do with regimens that included either

higher or in a few cases, lower doses than recommended in the comparison labeling or in drug

compendia, and for which inadequate support existed in the literature and other material supplied

by the companies. The divergences occurred both

in daily doses and in the length of the regimen,

and often involved regimens specifically for infants or children. In a few cases, the label failed

to state the maximum length of time the drug

should be taken before either stopping or taking

other measures. Twenty-eight (12 percent) of the

labels scored 1 (17) or 2 (11) in this area.

OVERDOSAGE

Failure to include information on the signs and

symptoms of overdosage, and for its management was common. Forty-five (19 percent) products diverged from the medical importance standard in this section, and most of those (37)

instances were placed in the most serious category (score of 2). Lack of this information was considered particularly important (score of 2) if there

were specific measures, as opposed to just general monitoring and supportive measures, recommended for treatment of the overdose. An

example was a combination phenothiazine antipsy chotic and tricyclic antidepressant that did

not include detailed information on the symptoms and management of overdose.

I Analysis by Company and Country

ANALYSIS BY COMPANY

The number of fully evaluated products (out of

241) per company ranged from 4 to 25, reflecting

in part the number of products each company

sells in the sample countries, and also the varying

number of products not evaluated. OTA calculated average overall scores for each company (the

scale for overall scores is O-3), and these ranged

from O to 2.22, but most fell between 1 and 2.

Two were less than 1, including one with a score

of O, and two were more than 2. For the reasons

discussed below, it was not considered appropriate to rank companies by their scores.

In general, the samples sizes for individual

companies are not large enough to sustain rigorous statistical manipulation, particularly because

most of the scores fall into a relatively small

range.

A major factor affecting company scores is the

mix of products in the OTA sample. Many companies emphasize products for one or several

clinical conditions, so their products tend to

clump in particular therapeutic categories. Certain types of product, no matter how they are

used, are unlikely to have effects that are life

threatening or even serious. Such products would

almost never berated as 3, diverging greatly from

the medical importance standard, regardless of

the labeling. Products fitting this description do,

in fact, dominate in the sample from the company

with the lowest overall score and form varying

proportions of other company’s products.

ANALYSIS BY COUNTRY

The average overall scores for the four sample

countries ranged from 1.1 to 1.6 (out of 3), with

the average of all scores at 1.4. Medically significant problems occurred in all countries, and no

clear distinctions can be made in a country-bycountry comparison. A sample of four countries

is too small to conclude that labeling in all developing countries is in need of improvement, but it

does suggest it is not an isolated problem.
Results of the OTA Survey 45

 Comparison With Other Industrialized

Countries

Several survey companies criticized OTA’s

medical importance standard for adopting a U.S.

perspective on labeling, to the exclusion of established standards in other industrialized countries.

This is true in that FDA-approved labeling was

used as a guide for evaluating sample labeling

and that labels were not held to a standard higher

than FDA requirements, OTA also required evidence of efficacy from formal clinical trials for

questioned indications and documentation to justify the omission of warnings, adverse reactions,

etc., that do appear in U.S. labels, so in this sense,

the medical importance standard borrows from

FDA standards of evidence.

Some companies believed the OTA standard to

be particularly inappropriate when the sample

label was based directly on labeling from the

country of export. They stated their belief that it

is important to consider European country labeling because former colonies have often patterned

their drug regulatory systems after their colonizers. Some companies noted that, from a business

perspective, it may be most practical to include

the export country’s label.

OTA recognizes that labels in other industrialized countries often contain different information

from their U.S. equivalents. Some of the reasons

for these differences are discussed in chapter 4,

having to do with the history of drug regulation

in different countries. In view of these concerns,

OTA asked the companies to indicate the country

of export for each sample product and to provide

sample labeling from the exporting country so

that a direct comparison could be made. No company responded systematically to this request.

One company did respond, however, by comparing OTA’s interim evaluations against labeling

for the same or similar products in each of the 21

countries named in the Drug Export Act of 1986

(see ch. 4 for a discussion of the Act) and documenting the labeling from those countries. During the final draft review, 16 other companies

conducted similar analyses, which they provided

to the Pharmaceutical Manufacturers Association

(PMA) and which were included in PMA’s comments to OTA. The PMA comments contained

only the companies summaries of the comparison, and not the corroborating labeling from the

other countries, so it was not possible for OTA to

fully evaluate those analyses. These latter results

are not discussed in this report, but the analysis

of the first company is presented in detail in table

3-3 and summarized below.

The 21 countries included in the one company’s “composite standard” are cited in the Drug

Export Act as having regulatory systems adequate to allow the export to them of drugs not yet

approved in the United States. The company

takes this a step further, reasoning that Congress

should then accept labeling from any of those

countries as being adequate in developing countries (although his conclusion is not supported by

the legislative history of the Act).

The company analysis took each unsatisfied

query that OTA had scored 1 or 2 and checked

the labeling of the 21 Drug Export Act countries

(DEACs) to see whether they were similar to the

original survey country label on the point OTA

had questioned. If they found a correspondence

in at least one of the 21 countries, they considered OTA’s score invalid and rescored the query

as O. They then retallied the overall scores.1

Nineteen of the company’s products had been

included in the survey and of those, 10 received

interim overall scores of 1, 2, or 3; the rest scored

O (no medically important divergences from the

OTA standard). The company conducted their

analysis on these 10 products. For two of them,

1 The company was working with OTA’S imen”rn evaluations. The material they submitted during their second opportunity to supply information resulted in cbanges reflected in OTA’S fmat scores. These instances are noted in table 3-3. The changes made by OTA occurred

only in response to medical evidence supporting the original label, not the mere correspondence of the sample label to a label in a third

country.
Table 3-3-Company Comparison of OTA Evaluation With Labeling in DEAC Countries

OTA Interim evaluation:

Product type divergence from standard Company reevaluation OTA final evacuation

Nonsteroidal indication for pain and fever associated with indication accepted in Finland and Japan Company provided insufficient medical evianti-Inf lammatory acute respiratory tract inflammation. (IQS = 2) and for “competitor products” in several dence to support efficacy for this indication.

drug other countries. (CQS = O) (FQS = 2)

Labeling recommends a higher dosage than Higher dosage approved in 16 other coun- Company documented safety and efficacy of

approved in U.S.(IQS = 2) tries. (CQS = O) higher dose. (FQS = O)

Overall scorn OTA Interim score = 3 Company rescore = O OTA final score= 2

Nonsteroidal Overly broad indication for conditions “requir- **Company stated that all labeling for this Specific conditions are given in the nature of

anti-inflammatory ing anti-inflammatory and/or analgesic activity, product contains specific indication state- examples, not delimiting the appropriate use

drug such as rheumatoid arthritis. . .“ ‘(IQS= 2) ‘rents. Because specific conditions are men- of the-product. (FQS =2)

Labeling recommends a higher

approved in U.S. (IQS =2)

Overall score OTA interim score = 3

tioned, indication cannot be considered overiy broad. (CQS = O)

dosage than Higher dosage is approved in 17 other Company documented safety and efficacy of

countries. (CQS = O) higher dose. (FQS = O)

Company rescore = O OTA final score= 3t

Asthma drug No information on signs and treatment of information not included in labeling in 2 This information is not required by FDA.

overdosage. (IQS = 2*) comparison countries in which drug is mar- (FQS = O)

keted. (CQS = O)

Overall Score OTA interim score = 2 Company rescore = O OTA final score= O

Oral hypoglycemic Labeling does not state that product is considagent ered second-line treatment for one indication.

(IQS = 1)

No contraindication in patients with history of

hypersensitivity. (IQS = 1)

No warning about increased cardiovascular

mortality associated with this type of drug.

(IQS = 2)

No information about use during pregnancy or

by nursing mothers. (IQS = 1)

No warning about possible loss of blood

glucose control when used with certain other

drugs. (IQS = 2)

information not included in 10 of 17 countries

in which drug is marketed. (CQS = O)

Company agreed with this evaluation.

(CQS = 1)

Labels in 15 other countries do not have this

warning. (CQS = O)

Company agreed with this evaluation,

(CQS = 1)

Company agreed with part of this evacuation,

but not with mention of one specific drug.

(CQS = 2)

The company provided no medical evidence

to modify this evaluation. (FQS = 1)

No change in OTA evaluation. (FQS . 1)

OTA accepted company’s additional argument that the study on which this warning is

based is controversial and its results not

widely accepted. (FQS. O)

No change in OTA evaluation. (FQS = 1)

No change in OTA evacuation. (FQS = 2)
No advice about dosages for patients with Company agreed with this evaluation. No change in OTA evaluation. (FQS = 2)

impaired hepatic or renal function. (IQS = 2) (CQS = 2)

No information about safety and efficacy of Company agreed with this evaluation. No change in OTA evaluation. (FQS = 1)

another drug when used with this product. (CQS = 1)

(IQS = 1 )

Overall score OTA interim score = 2 Company rescore = 2 OTA final score= 2

Antibiotic No susceptibility testing information. (IQS = 1 ) Information not included in 9 of 12 countries OTA accepted company’s additional contenin which drug is marketed. (CQS = O) tion that sufficient information is included in

label. (FQS = O)

Overall score OTA interim score = 1 Company rescore = O OTA final score= O

Antinausea No rationale for the combination. (IQS = 1)

antihistamine

combination

product

Indication for pyloric spasm and infant colic.

(IQS = 2)

Indication for all types of vertigo, including

vertigo of vestibular origin. (IQS = 1 )

No warning about use of product: a) with

alcohol orb) by children under 12 years.

(IQS = 2)

No warning that antihistamines can cause

excitability in children. (IQS = 1)

Dosage recommendations for children (OTA

requested evidence of safety and efficacy).

(IQS = 2)

No information on signs and treatment of

overdose. (IQS = 2*)

Overall score OTA interim score = 3

Product not marketed in U.S. or other

DE-ACs. Company states that “comparable

products” with similar labeling are available

in 5 countries. (CQS = O)

● *Company agreed with OTA evaluation but

not with score of 2. (CQS = 1)

Indication appears in labeling for 1 component in 1 DEAC. (CQS = O)

Labels in one DEAC and in other countries

for “comparable products” do not include

these warnings. (CQS = O)

Labels in one DEAC and in other countries

for’’comparable products” do not include this

warning. (CQS = O)

Dosage recommendations for children are

similar to those in some DEACs. (CQS = O)

● *Company pointed out that FDA-approved

labeling does not include this information.

(CQS = O)

Company rescore = 1

Company provided no medical evidence that

combination was more effective than any

single ingredient. (FQS = 1)

Company provided some evidence of efficacy in infant colic, but not for pyloric spasm.

(FQS = 2)

Company provided evidence of efficacy in

vertigo of vestibular origin. (FQS = O)

Company provided no medical rationale for

not including these warnings. (FQS = 2)

Company provided no medical rationale for

not including this warning. (FQS = 1 )

OTA found that dosages for children were

significantly higher than in other countries,

according to material supplied by company.

However, this was rescored to O because it

addresses the same concern as the warning

about use in children under 12, above.

(FQS = O)

This information is not required by FDA.

(FQS = O)

OTA final score= 3

(Cent/nued on next page)

o

sm

o

s
Table 3-3-Company Comparison of OTA Evaluation With Labeling in DEAC Countries-(Continued)

Corticosterold No information about drug interactions.

(IQS = 1)

No information on monitoring long-term therapy. (IQS = I*)

No information on risk of dermal and subdermal atrophy. (IQS = 1“)

No specification of maximum prescribing limits, pediatric doses, or doses for intra-articular

administration. (IQS = 1)

No description of procedure for intra-articular

administration. (IQS = 1•)

Overall score OTA interim score = 1

Company agreed with this evaluation

(cm =1)

This information does not appear in labeling

for “comparable products” in DEACs.

(CQS = o)

This information does not appear in labeling

for “comparable products” in DEACs.

(cm = o)

This information does not appear in labeling

for “comparable products” in DEACs.

(CQS = o)

This information does not appear in labeling

for “comparable products” in DEACs.

(CQS = O)

Company rescore = 1

No change in OTA evaluation. (FQS = 1)

This information is not required by FDA.

(FQS = O)

This information is not required by FDA.

(FQS = O)

No change in OTA evaluation. (FQS = 1)

This information is not required by FDA.

(FQS = O)

. . OTA final score= 1

Antibiotic No description of allergic reaction to sodium ● *FDA-approved labeling at time of OTA Company documented discontinuation of prodformaldehyde sulfoxylate (an antioxidant). (IQS review did not contain this warning. Product uct during second review. (FQS. NA)

= 2*) was discontinued in survey country 1 year

before OTA review. (CQS = O)

Overall score OTA interim scorn = 2 Company rescore = O OTA final score = NA

“* Denotes company response based on rationale other than labeling in other countries.

1• and 2*:A single asterisk denotes a query that deals with information not required by FDA. All such queries were rescored to O in the final evaluation, so no label was held to a standard higher

than that of FDA-approved labeling.

tThree additional queries concerning warnings and precautions with interim scores of O had final scores of 1 (one case) or 2 (two cases) because the company failed to document statements

made in their first responses to the effect that they had initiated changes in the labeling before the OTA review. The final score remained a 3.

ABBREVIATIONS:

IQS=Interim Query Score (OTA)

CQS. Company Query Score (Company)

FQS - Final Query Score (OTA)

DEAC - Drug Export Act Country (i.e., the 21 countries named in the Drug Export Act of 1986)

NA = Not applicable (product was dropped from analysis because it has been withdrawn from market before OTA review).

SOURCE: Office of Technology Assessment, 1993.
Results of the OTA Survey 49

the only outstanding query concerned a listing of

inactive ingredients. OTA’s final scoring excludes

consideration of inert ingredients (see ch. 2),

leaving eight of the company’s products with

queries of other types.

Using the company’s “DEAC” standard, five

products had overall scores of O, two had scores

of 1, and one had a score of 2. After taking into

account additional material submitted by the

company during the second round of review,

OTA final scores were two scores of O, two

scores of 1, two scores of 2, and two scores of 3.

 Comparison of OTA Evaluation With

WHO Prescribing Information

OTA compared its final product evaluations

with an independent standard, WHO model prescribing information monographs. These monographs are being prepared as part of WHO’s revised drug strategy, adopted by the World Health

Assembly in 1986 to complement their “Model

List of Essential Drugs.” The monographs represent a consensus of WHO’s Expert Advisory

Panel on Drug Evaluation and are reviewed by

selected members of Advisory Panels representing relevant areas of medicine and nongovernmental professional and business organizations

with official relations with WHO (including the

International Federation of Pharmaceutical

Manufacturers Associations, the International

Pharmaceutical Federation, the International

Union of Pharmacology, and the World Federation of Proprietary Medicine Manufacturers)

(282).

Six monographs, organized by area of medicine, were available as of mid-1992. The entries

for individual drugs are relatively short compared

to FDA-approved labeling, and are intended to

contain only essential medical information. For

all drugs in the OTA sample that also were in the

monograph, OTA compared the monograph entries with OTA’s final evaluations of those products. This was done by checking each of the

problems identified by OTA (“unresolved

queries”) with the monographs to see if the

monograph agreed with OTA’s evaluation.

“Agreement” with OTA’s evaluation in this case

means that the monograph contained information

OTA queried as missing from the sample label or

did not include information OTA queried as not

belonging in the label (mainly indications).

Details of the comparisons are given in table 3-4

and Summarized here.

Twenty-three products in OTA’s sample are included in the six WHO monographs. Excluding

queries about inactive ingredients,2 there were 52

queries relevant to this analysis. Of these, the

monographs “agreed” with OTA’s evaluation in

40 cases. In 5 cases, the monographs were consistent with some, but not all, aspects of the

query, and in 7 cases, the monographs agreed

with the sample label and not with the OTA evaluation. This analysis suggests strongly that the

majority of unresolved queries in OTA’S product

evaluations represent significant problems in the

content of the label, as measured against an independent standard.

 Summary of Comparisons

The composite standard used by the participating company in its reanalysis resulted in great

discrepancies with OTA scoring. The “DEAC

standard,” however, does not represent a particular set of guiding principles, so the meaning of

the results is difficult to interpret. It could be seen

as a “least common denominator”—labeling

pieced together from the least rigorous points of

each of 21 labels would be acceptable under this

standard.

OTA’s evaluations are generally consistent

with the judgments of WHO for those products

included in model prescribing information mono2 Inactive ingredients vary among product formulations and, therefore, are not listed in these monographs dealing largely with generic

products.
ul

o

Table 3-4-Comparison of OTA Evaluations With WHO Model Prescribing Information

WHO monograph WHO monograph agrees with OTA evaluation WHO monograph does not agree with OTA evaluation

Drugs Used in Anesthesia (280)

Product 1: No information on clinical pharmacology. (query score = 1)

Barbiturate

anesthetic No contraindication for patients hypersensitive to barbiturates, in

status asthmatics, or with porphyria. (query score =2)

No recommendation for special care in patients with advanced

cardiac disease, asthma, and endocrine insufficiency.

(query score =2)

No information about use in pregnancy and nursing mothers.

(query score =1)

No mention of following adverse reactions: respiratory depression, myocardial depression, prolonged somnolence, hypersensitivity reactions. (query score = 2)

Too Iittle information on use of product (advises physicians to

consult the literature). (query score = 2)

No information about management of overdose. (query score= 2)

No contraindication for patients without suitable veins for iv.

administration. This was part of the overall query on contraindications, so had no individual query score.

No recommendation for special care in patients with increased

intracranial pressure. This was part of the overall query on patients

requiring special care, so had no individual query score.

No mention of the following adverse reaction: bronchospasm during

recovery. This was part of the overall query on adverse reactions,

so had no individual query score.

No information about preparation of solutions and incompatibility

of product with compounds that may acidify the solution.

(query score = 1)

Product 2: No warning about allergic reactions to product. (query score= 1)

Analgesic

No information about symptoms and management of overdose.

(query score =2)

Product 3: inadequate data about safe use of product in pregnancy. No information about several aspects of clinical pharmacology,

Anesthetic (query score =1) including biotransformations, elimination, and half-life.

(query score. 1)

No discussion of psychological manifestations during emergence

and their avoidance. (query score = 1)

Drugs Used In Epilepsy (288)

Product 1: No warning about use in children under 2 years.

Antiepileptlc (query score. 2)

No mention that acute pancreatitis associated with this antiepilep

tic may be fatal. (query score= 2)

Product 2: No mention that acute pancreatitis associated with this antiepilep

Antieplieptlc tic may be fatal. (query score= 2)
Product 3: No warning that sudden withdrawal of this drug can precipitate

Antieplileptic absence (petit mat) status. (query score = 2)

No information on Stevens-Johnson syndrome, a serious adverse

reaction. (query score = 2)

Product 4: No information on clinical pharmacology. (query score= 1)

Antieplieptic

No information on indications and usage. (query score= 2)

No information on contraindications. (query score = 2)

No information on warnings and precautions. (query score =2)

No information on drug interactions. (query score =2)

No information on adverse reactions. (query score =2)

Specific doses for initiation and maintenance not given.

(query score =2)

Product 5: No information on clinical pharmacology. (query score = 1)

Antieplieptic No precaution to discontinue drug if serious forms of dermatitis

(bullous, exfoliative, or purpuric), Iupus erythematosus, orStevensJohnson syndrome are suspected. (query score =2)

No information on drug interactions. (query score =2)

No information on symptoms and management of overdose.

(query score =1)

Drugs Used in Parklnsonlsm (283)

Product 1: No mention of interaction with tricyclic antidepressants.

Antiparkinsonism drug (query score =1)

Product 2: No information on symptoms and management of overdose.

Antiparkinsonism drug (query score = 2)

Drugs Used In Mycobacterial Diseases (284)

Product 1: No statement that this drug should not be used as monotherapy in

Antituberculosis drug light of rapid development of resistance. (query score = 2)

Product 2: No warning about fatalities associated with hepatic dysfunction. No warning about increased incidence of hepatomas in mice

Antltuberculosis drug’ (query score =2) exposed to this drug. This was part of the warning about hepatic

dysfunction, so had no separate query score.

No mention that this drug may induce elevations of BUN and serum

uric acid. (query score = 1 )

(Continued on next page)

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z

U

Table 3-4-Comparison of OTA Evaluations With WHO Model Prescribing Information-(Continued)

WHO monograph WHO monograph agrees with OTA evaluation WHO monograph does not agree with OTA evacuation

No mention of a number of CNS effects (drowsiness, fatigue, ataxia,

dizziness, mental confusion, inability to concentrate, pains in

extremities, and generalized numbness). (query score = 1 )

No detailed description of hypersensitivity reaction.

(query score =2)

Product 3: No discussion of the syndrome of CNS depression in infants who

Antituberculosis drug receive this drug. (query score = 2)

Drugs Used in Parasitic Diseases (282)2

Product 1: No statement that other drugs are preferred for dracontiasis and no

Anthelmintic drug qualification of effectiveness in trichinosis. (query score= 1 )

incomplete information on carcinogenesis and mutagenesis.

(query score =1)

No information on pharmacokinetics. (query score = 1 )

Product 2: No specific warning about potential neurotoxicity of drug, especially No information on certain precautions (e.g., appropriate caution

Anthelmintic drug in children. (query score = 2) should be exercised for use in patients with severe malnutrition or

anemia). This was part of the overall query on precautions, so had

Nonformation on certain precautions (e.g., discontinue use if CNS, no individual query score.

gastrointestinai, or hypersensitivit y reactions occur).

(query score =2)

No information on adverse reactions. (query score = 2)

No statement that maximum cure rate is usually obtained with

multiple-dose regimen. (query score =2)

Product 3: No information on clinical pharmacology. (query score = 1 )

Anthelmintic drug

No contraindication for patients with epilepsy.

(query score =2)

No information on side effects, including transient neurological

effects and urticarial reactions, (query score = 2)

-.

3

No information on toxicity. (query score= 2)
Drugs Used in Superficial Fungal Infections (289)3

Product 1: No microbiology data. (query score= 1)

Topical antifungal drug

No warning about possible irritation or allergic contact dermatitis.

(query score =1)

No precaution against contact with eyes. (query score = 1)

Product 2: No statement that this drug is not indicated for trivial infections.

Topical antifungal drug (query score =2)

No warning regarding prophylactic use, tumorigenicity, use in

pregnancy, teratogenicity, and suppression of spermatogenesis.

(query score =2) (WHO monograph includes all except warning

about suppression of spermatogenesis.)

1 he of OTAI~ ~uefies, ~elat~ t. “~ of this drug for i~~ations other than my~bacterial diseas~, W= not address~ in the M&K) monograph. That query is not included in this table.

2Four pr~ucts in OTAIS ~mple were indu~ in this monograph: 1 had a final overall score of O. Only the remaining 3, w“th unresolved qUW’i6S, are included in this table.

3Six pr~~~ in OTAIS ~mple were indu~ in th~ monogra~: 4 had final overall ~r~ of (). only the remaining 2, with unresolved queries, are included in this table.

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54 I Drug Labeling in Developing Countries

graphs. The monographs contain relatively short

entries for products, containing only the most essential information. This analysis provides validation of OTA’s method and evaluation standard.

EXPLANATION OF ADDENDUM

TABLES 3-1 THROUGH 3-6

Addenda tables 3-1 through 3-6 detail the results of drug labeling analyses for each product

in OTA’s sample. The products are arranged in

six tables based on their overall scores, and are

arranged alphabetically by type of drug within

each table. Products with labeling that was not

fully evaluated are designated by the overall

score “NA.”

The column labeled Type of drug” gives a

brief description of each drug, rather than the

specific generic or brand name. (OTA agreed

early on in the study that it would not include the

specific generic or brand names of drugs in this

report.)

The third column, labeled “Source,” describes

the source of labeling information that was evaluated. In most cases, the package insert was evaluated (indicated by the abbreviation pi). In other

instances, the package insert pending approval by

the local regulatory agency was evaluated (abbreviated pipa). Where package inserts were not

available, other sources of information were

used, including prescribing guide entries (pg) and

package labels (pl), and in two instances, product

documents (pals) were evaluated.34

The fourth column, labeled “Category,” lists

the category of labeling information in which

each of the unresolved queries falls. Categories

of information include: description and clinical

pharmacology (abbreviated “dcp”), ingredients

(ing), indications (ind), contraindications (ci),

warnings and precautions (wp), adverse reactions

(ar), dosage and administration (da), and overdose information (od).

A description of each unresolved query appears in the fifth column, labeled “Nature of

problem.” The queries are listed by the category

of information to which they refer. Where several

queries for a product fall in the same category of

information, they are listed in succession.

The sixth column, “Query score;’ lists the

medical importance score assigned to each unresolved query.

3 At~~- of & s~y, OTA am to evdu~ tie comp8ny prod@ _ntsfor hvo ptiucu~M ‘t‘Ve pubge b

serts. Later, however, OTA decided not to review company product documents because they are not universally available to the physicians

who use the product (they are often only available by request to the company or sometimes are distributed by company detail men to physiChKIS and pharmacists). However, because OTA had previously agreed to evaluate the documents for these two products, these evaluations

appear in the sample.

4 In several instances, the package insert for a product did not include some medicaIly important information that was included in the product’s prescribing guide entry. In these instances, indicated “pi, pg,” credit was given both for medically important information included only

in the prescribing guide entry and for information appearing in the package insert.
Results of the OTA Survey] 55

Addendum 3-l—Products With Adequate Labeling (Overall Score = O)

Type of drug Source Type of drug Source

Absorbable hemostatic sponge

Adrenergic decongestant for ocular administration

Aminocyclitol antibiotic

Aminoglycoside for ophthalmic administration

Antacid

Antibiotic

Antiestrogenic drug

Antifungal agent

Antifungal polyene antibiotic suspension

Antihistamine

Antihistamine

Antihistamine, barbiturate, and methylxanthine

combination

Antineoplastic

Cephalosporin antibiotic

Cephalosporin antibiotic

Cephalosporin antibiotic

Cephalosporin antibiotic

Cholinergic agonist for urologic indications

Combination analgesic, antihistamine, and

adrenergic decongestant

Combination antifungal and antiprotozoal

antibiotic

Combination aspirin, antihistamine, caffeine, and

adrenergic decongestant

Combination sulfa antibiotic and corticosteroid for

ophthalmic administration

Combination sulfa antibiotic and corticosteroid for

ophthalmic administration

Combination topical anesthetic and antacid

Combination topical decongestant and analgesic

for otic administration

Combination xanthine-derivative bronchodilator

and expectorant

Dopamine antagonist antiemetic

Electrolyte dehydration solution

pi

pi

pi

pi

pi

pi

pg

pi

pg

pg

pi

pi

pi

pi

pi

pi

pi

pi

pi

pg

pi

pi

pi

pi

pi

pg

pi

pi

Emollient dental paste

Folic acid antagonist antineoplastic

Hair growth stimulant

Injectable corticosteroid with anesthetic

Injectable postmenopausal estrogen

Insulin preparation

Ion exchange resin

Monotropic cardiac drug

Macrolide antibiotic

Nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drug in

suppository form

Oral contraceptive

Penicillin-derivative antibiotic

Penicillin-derivative antibiotic

Progestin used for oncologic indications

Pyrimidine analogue antineoplastic

Quinolone antibiotic

Quinolone antibiotic

Selective alpha-ad renergic blocking agent

Sulfonylurea oral hypoglycemic

Sympathomimetic decongestant

Systemic corticosteroid

Systemic corticosteroid

Tetracycline antibiotic

Tetracycline antibiotic

Tetracycline antibiotic

Thioxanthene-derivative antipsychotic

Thyroid hormone synthesis inhibitor

Topical antifungal and steroid combination

Topical nonsteroidal anti-inflammatory drug

Tricydic antidepressant

pi

pi

pi

pipa

pi

pi

pi

pi

pipa

pi

pipa

pi

pg

pi

pi, pg

pi

pi

pi

pi

pi

pg

pi

pi

pi

pi

pi

pi

pi

pi

pi

pi

pi

pi

SOURCE KEY: pi - package insert; pg - prescribing guide entry; pipa - package insert pending approval.

330-065 0 - 93 - 3 QL 3
Addendum 3-2-Products With an Overall Score of 1

overall Query

score Type of drug Source Category Nature of problem score

1 Aminoglycoside antibiotic pi wp

1 Aminoglycoside antibiotic pi wp

1 Antihistamine pi wp

1 Antihistamine indicated for pi dcp

appetite stimulation ing

1 Antiparasitic drug pi dcp

ind

1 Antiparkinsonian agent

1 Beta blocker

pi

pi

1 Combination analgesic, pi

antihistamine, opioid, and

methylxanthine

1 Combination antacid pi

1 Combination antihistamine and pg

adrenergic decongestant

1 Combination antihistamine, pg

adrenergic decongestant, and

antitussive

1 Combination centrally acting pipa

antiadrenergic agent and

thiazide diuretic

wp

ing

ind

ar

dcp

dcp

da

a

od

dcp

ind

Labeling does not have information about some drug-laboratory test interactions.

Insert has no information about carcinogenesis.

Insert has no information about use of this product in patients with liver disease.

Insert omits information on pharmacokinetics and metabolism.

Insert does not list inactive ingredients.

Insert does not include information about pharmacokinetics.

Insert does not state that niridazole and metronidazole are preferred treatments for

dracontiasis; insert does not adequately qualify effectiveness of this drug in trichinosis (the

drug is not effective in altering the course of the infection once established, i.e., once the

infection has reached the invasive stage).

Insert omits interaction with tricyclic antidepressants (resulting in hypertension, dyskinesia).

Insert does not list inactive ingredients.

Product broadly indicated for symptomatic treatment of hyperthyroidism (rather than for

adjunctive therapy for thyrotoxicosis).

Insert does not list among adverse reactions depression, hailuanations, visual disturbances, and emotional lability.

Manufacturer did not provide adequate rationale for this drug combination.

Insert contains promotional language (e.g., “the preferred dosage”).

Insert does not include the maximum daily dosage.

Entry Iacks a specific contraindication for children under 2 years of age. Product should be

contraindicated in infants, who may have unpredictable reactions-e. g., central nervous

excitation rather than sedation.

Entry does not include information about overdose management.

Manufacturer did not provide data demonstrating the additive therapeutic actions and

minimal potential for toxicity of this combination.

Insert has no warning that this fixed combination drug is not indicated for initial therapy for

hypertension.

1

1

1

1

R

1

1

1

R

1

1

1

1

1

1

1

1

1
1 Combination mettiylxanthine pi

bronchodilator, barbiturate, and

adrenergic agonist

1 Folic acid analogue pi

1 H-2 receptor antagonist pipa

1 Long-acting nitrate vasodilator pi, pg

1 Macrolide antibiotic pl, pg

1 Multivitamin and multimineral pi

1 Multivitamin with iron pi

1 Non-barbiturate anesthetic pi

ing

ci

dcp

wp

da

wp

ci

wp

ing

ind

ar

ing

ind

ing

da

dcp

ing

wp

Insert does not list inert ingredients.

Insert has no contraindication for patients with prostatic hypertrophy.

Insert does not have section describing clinical pharmacology,

Insert does not have information about drug interactions (with neuroleptics).

Insert does not specifically advise monitoring methotrexate levels to ensure that the dose

of this folic acid analogue is adequate for rescue.

Labeling omits mention of the pharmacologic interaction of this H-2 receptor antagonist

and some other drugs, such as propranoloi, tricydic antidepressants, and lidocahe.

insert does not include contraindication for hypersensitivity or idiosyncrasy to other

nitrates or nitrites.

Insert has no warning about the following: risks inherent in concurrent with calcium

channel blockers; risk of paroxysmal bradycardia; risk of aggravation of angina.

Insert has no information about use in pregnancy, use in nursing mothers, or pediatric use.

Entry does not list inactive ingredients.

Entry indicates this macrolideantibiotic for treatment of Giardia/ambliaf C/ost?kfiumiefanii,

and L&@asma urealyficurn.

Entry does not note that rare reports of pseudomembranous enterocolitis have been

reported with therapy with this antibiotic; entry does not list adverse reactions for which a

cause and effect relationship has not been established, including isolated reports of

central nervous system side effects, cardiovascular symptoms, and, in persons with renal

insufficiency and/or who are receiving high doses of this antibiotic, reversible hearing loss,

Insert does not list inactive ingredients.

Product indicated for “undernourishment.”

Insert does not list inactive ingredients.

Insert does not have appropriate dosage information for infants less than one year of age.

Insert does not provide information about several aspects of clinical pharmacology,

including biotransformation, elimination, and half-life.

Insert does not list inactive ingredients.

Manufacturer provided inadequate data about safe use of this product in pregnancy (this

product may induce uterine contractions during the first trimester of pregnancy),

Insert does not have a detailed discussion about psychological manifestations during

emergence and its avoidance.

R

1

1

1

1

1

1

1

1

R

1

1

R

1

R

1

1

R

1

1

Continued on next page
Addendum 3-2—Products With an Overall Score of l-Continued

overall Query

score Type of drug Source Category Nature of problem score

1

1

1

1

1

1

1

1

1

Nonsteroidal anti-inflammatory

drug

Nonsteroidal anti-inflammatory

drug

Ophthalmic aminoglycoside

antibiotic

Ophthalmic tetracycline

analogue antibiotic

Opioid-derivative antidiarrheal

Oral contraceptive

Oral contraceptive

Penicillin-derivative antibiotic

Potassium-sparing diuretic

1 Substituted benzamide

antipsychotic

pi

pi

pg

pi

pi

pi

pi, pg

pi, pg

pg

pi

dcp

ing

ing

wp

ind

ind

ind

ind

ind

wp

dcp

ing

ind

wp

da

ing

ar

Insert does not have clinical pharmacology information, including half-life, onset and

duration of action, and route of elimination.

Insert does not list inactive ingredients.

Insert does not list inactive ingredients.

Insert does not contain a precaution regarding NSAID-induced aseptic meningitis.

Manufacturer did not provide data supporting efficacy against certain strains of

mycoplasma

Insert does not limit indications to ophthalmic infections that are superficial.

Labeling does not note that pediatric use for treating chronic diarrhea has not been

established.

Insert indicates product for menstrual irregularities in general without specifying causes.

Insert indicates product for correction of certain menstrual irregularities, without specifying

causes.

Insert does not warn about possible development of pseudomembranous colitis (merely

warns about the possibility of superinfection).

Entry does not describe chemical properties or pharmacokinetics.

Entry does not list inactive ingredients.

Entry does not state that the product is not first-line therapy for congestive heart failure.

Entry includes indications for “idiopathic edema,” myasthenia gratis, and malignant

hypertension.

Indication for malignant hypertension contradicts the contraindication in acute renal

dysfunction.

Entry has no warnings about drug interactions with indomethacin and captopril.

Entry does not recommend adding another diuretic if adequate response is not obtained

with the product alone.

Insert does not list inactive ingredients.

Insert does not caution about use in patients with cardiovascular disease, CNS

depression, blood dyscrasias, hepatic impairment, and in comatose patients.

Insert does not warn about the following adverse reactions: blurred vision, pigmentary

retinopathy, difficulty with urination, photosensitivity, rash.

1

R

R

1

1

1

1

1

1

1

1

R

1

1

1

1

1

R

1

1
1 Substituted benzamide

antipsychotic

1 Systemic corticosteroid

1 Systemic corticosteroid

1 Systemic corticosteroid

1 Systemic corticosteroid

1 Topical analgesic

1 Topical antifungal

1 Topical bacteriostatic agent

1 Topical combination corticosteroid and 8-hydroxyquinolone

antibiotic

1 Topical corticosteroid

pi

pi

pi

pds

pi

pg

pi

pi

pg

pi

wp

ing

wp

da

ing

od

wp

wp

ind

dcp

wp

ind

wp

ing

wp

dcp

wp

Insert does not include a precaution about the potentiating effect of alcohol.

Insert omits precautions about use in patients with respiratory disease or cardiovascular

disease; no warning about use in patients with liver dysfunction or a history of jaundice.

Insert does not have information about drug-lab test interactions.

Insert does not list inert ingredients.

Insert has no information about drug interactions.

insert does not give pediatric dosages.

Insert does not list inactive ingredients.

Insert does not have information on overdose.

Insert does not warn that this drug may prolong coma in cerebral malaria.

Insert does not warn about enhanced effect of steroids in patients with hypothyroidism or

cirrhosis.

Indications not appropriately limited to minor wounds.

Insert does not provide microbiology data.

Insert does not warn about possibility of irritation or allergic contact dermatitis.

Insert does not have precaution against contact with eyes.

Product is indicated for cleansing of infants in certain circumstances.

Insert does not note that detectable blood levels of this topical bacteriostatic agent have

been found after repeated cleansings.

Insert provides no information on use in nursing mothers or about carcinogenesis and

impairment of fertility,

Entry does not list inactive ingredients.

There are no precautions about interference with thyroid function tests and interference

with laboratory assays for phenylketonuria.

Entry does not note potential for adrenal suppression with substantial systemic absorption

and other adverse effects of systemically absorbed steroids.

Insert has no information about pharmacokinetics of topically absorbed corticosteroids.

Insert does not note that patients receiving large doses of a potent topical steroid applied

to a large surface area should be evaluated periodically for evidence of HPA axis

suppression by using the urinary free cortisol and ACTH stimulation tests.

1

1

1

R

1

1

R

1

1

1

1

1

1

1

1

1

1

R

1

1

1

1

Continued on next page

0

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Addendum 3-2—Products With an Overall Score of l-Continued

overall Query

score Type of drug Source Category Nature of problem score

1 Tricydic antidepressant pi ing Insert does not list inert ingredients. R

wp Insert does not warn about cross sensitivity with other tricyclic antidepressants. 1

Insert does not warn about the following: concurrent use with antithyoid agents may 1

increase the risk of agranulocytosis; delirium has been reported with concurrent

administration of the tricyclic antidepressant and disulfiram.

Insert does not warn that paralytic ileus may occur in patients taking tricyclic antidepres- 1

sants with anticholinergics; schizophrenic patients may have increased symptoms of

psychosis; patients with paranoid symptoms may have an exaggeration of such

symptoms.

Insert does not note that withdrawal symptoms of nausea headache, and malaise may 1

occur with abrupt cessation of therapy.

ar The following adverse reactions are not listed: drowsiness, dizziness, and neuroleptic 1

malignant syndrome.

1 Urinary tract antiseptic pi wp Insert does not state that urine pH should be monitored to maintain urine acidity. 1

SOURCE KEY: pi= package insert; pg - prescribing guide entry; pipa. package insert pending approval; pI= package label; pds - product document.

CATEGORY KEY: dcp= description/clinical pharmacology; ing. ingredients; ind - indications; ci - contraindications; wp= warnings and precaution; ar= adverse reactions; da. dosage and

administration; od = overdose information.
Addendum 3-3-Products With an Overall Score of 2

overall Query

score Type of drug Source Category Nature of problem score

2 Aminocyclitol antibiotic pi dcp

wp

2 Aminoglycoside antibiotic pi, pg

2 Aminoglycoside antibiotic

2 Analgesic

2 Anesthetic for ophthalmic

administration

2 Antacid

2 Antacid combination

ind

wp

pi dcp

wp

pi ing

wp

od

pi dcp

ing

wp

pi

ar

ing

wp

wp

Insert does not mention need for susceptibility y testing of isolates associated with treatment

failure.

Insert does not have warning about the benzyl alcohol content of the product’s diluent.

Insert does not include precautions regarding development of resistance to Neisseria

gonorrhoeae.

Insert has no warning about risk of anaphylaxis or anaphylactoid reactions.

Insert indicates product for methicillin-resistant S. aureus and gonococcal infections

without noting that this aminoglycoside antibiotic is not drug of choice for these infections.

Although labeling states that safety of this aminoglycoside antibiotic during pregnancy has

not been established, the insert fails to warn specifically about the risk of total irreversible

bilateral congenital deafness to children whose mothers receive aminoglycosides during

pregnancy.

Insert states that this aminoglycoside antibiotic is effective in vitro against Neisseria

meningitidis, Neisseria gonorrhoeae, and Streptococcus pyogenes.

Insert does not include a discussion of the syndrome of CNS depression in infants who

receive this aminoglycoside antibiotic.

Insert does not list inactive ingredients.

Insert does not warn about allergic reactions to this product.

Insert does not have information about the symptoms and management of overdose.

Insert does not describe clinical pharmacology.

Insert does not list inactive ingredients.

Insert does not warn about risk of corneal opacification with prolonged use.

Insert does not warn about risk of systemic toxicity.

Insert does not caution that the patient should protect eyes from irritants during the period

of anesthesia.

Insert does not list among adverse reactions systemic hypersensitivity, pupillary dilatation,

or cycloplegic effects.

Insert does not list inactive ingredients.

Insert fails to warn about risk of hypermagnesemia in patients with renal disease.

Insert omits information about the interaction of aluminum in this antacid with tetracycline.

Label omits warning concerning use in patients with renal dysfunction.

Label omits warning about known drug interaction with tetracycline.

1

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1

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2

1

1

2

R

1

2

1

R

2

1

2

1

R

2

2

2

1 —

Continued on next page OJ
a) IQ

G

Addendum 3-3-Products With an Overall Score of 2-Continued z

m

overall Query rDa

score Type of drug Source Category Nature of problem score g

2 Antidiarrheal combination with pi ind

aminoglycoside antibiotic

2 Antidopanergic antiemetic and

gastrokinetic

2 Antiepileptic drug

2 Antiepileptic drug

2 Antihistamine

2 Antiparkinsonian agent

2 Antituberculosis drug

pi

ci

ind

wp

da

pg ar

pg dcp

wp

pi

pipa

pi

ing

ar

od

od

ind

Product is broadly indicated for “bacterial diarrhea” (rather than specifically for preoperative suppression of intestinal bacteria and treatment of diarrhea due to enteropathogenic

Escherichia coli).

Insert does not note that oral dehydration therapy is considered first-line treatment for

childhood diarrhea.

Insert does not contraindicate use in children.

Product is indicated broadly for gastrointestinal motility disturbances (rather than for

symptomatic gastroesophageal reflux, diabetic gastroparesis, prevention of nausea and

vomiting associated with cancer chemotherapy, and small bowel incubation).

Insert has weak warning about tardive dyskinesia.

Insert does not include information about admixture compatibilities of intravenous solution.

Entry does not note that acute pancreatitis associated with use of this antiepileptic drug

may be fatal.

Entry does not include information about clinical pharmacology.

Entry does not include precaution to discontinue this antiepileptic if more serious forms of

dermatitis (bullous, exfoliative, or purpuric dermatitis), or if lupus erythematosus or

Stevens-Johnson syndrome are suspected.

Entry does not have information about drug interactions, including drugs which may

increase Ievels of this antiepileptic (e.g., chloramphenicol, acute alcohol intake, estrogens,

sulfonamides, cimetidine); drugs which may decrease levels of this antiepileptic (e.g.,

chronic alcohol abuse, reserpine, antacids containing calcium); drugs which may either

increase or decrease serum levels of this antiepileptic (phenobarbital, valproic acid,

sodium valproate); and drugs whose efficacy is impaired by this antiepileptic (corticosteroids, quinidine, digitoxin, rifampin, doxycydine, estrogens).

Insert does not list inactive ingredients.

Insert does not mention among adverse reactions the following: nervousness, weakness,

appetite increase, cough, angioedema, hypotension, photosensitivity, seizures, prolonged

QT interval on EKG, and ventricular arrhythmias.

Entry does not have information on symptoms and management of overdose.

Insert does not include information on signs and management of overdose.

Insert does not state that this antituberculosis drug should not be used as monotherapy in

light of rapid development of resistance.

2

1

1

2

1

1

2

1

2

2

R

2

1

2

2
2 Benzodiazepine

2 Benzodiazepine hypnotic

pg

pi

dcp

ci

wp

od

ing

2 Cephalosporin antibiotic pg

ar

ind

2 Cephalosporin antibiotic

2 Combination “hepatic

protector”

pi

pg

ind

dcp

ind

wp

ar

Company provided no adequate rationale for description of this product as a “tranquilizer.”

Entry does not include a contraindication against use by patients with hypersensitivity to

this product.

Entry does not include warnings against use in psychotic states and psychiatric disorders

in which anxiety is not a prominent feature; no warning about use in addiction-prone

patients, such as drug addicts and alcoholics; no information about withdrawal symptoms.

Entry does not include information on drug interactions.

Entry does not note the need for frequent patient reassessment; insert does not warn

about use in depressed patients in case of suicidal tendencies; does not warn that this

benzodiazepine may increase depression; no evidence of safety and efficacy of this

benzodiazepine in patients below age 18; no information on long-term use.

Entry does not have information on treatment of overdose.

Insert does not list inactive ingredients.

Insert claims that this benzodiazepine hypnotic has no withdrawal effects (omits mention

of daytime anxiety and rebound insomnia).

Insert does not state that fetal damage may occur if drug is used in the first trimester (insert

merely states that the safety of drug during pregnancy has not been established).

Insert does not warn that hypnotics can increase depression in patients who are already

depressed, and may therefore increase risk of attempted suicide.

Insert does not mention common (greater than 4 percent incidence) adverse reactions,

including nervousness, nausea and vomiting.

No adequate support for indication for use in treatment of endocarditis.

Entry does not have information about potential for superinfection with prolonged use of

this antibiotic.

No adequate support for indication for use in treatment of endocarditis.

Entry does not have description and information about clinical pharmacology.

Company did not provide adequate justification for this drug combination and the ratio of

its components.

Product is indicated for treatment of “hepatobiliary dysfunction” but also includes a

warning about use in persons with jaundice.

Entry omits precautions for an amino acid component of this combination (nausea and

vomiting; may precipitate hepatic encephalopathy in patients with established liver

disease; concurrent use with MAO inhibitors could superimpose symptoms of intoxication,

such as delirium, visual hallucinations, ataxia, speech disturbances, increased salivation,

and hyperhidrosis).

Entry omits adverse effects associated with one component of this combination (nausea,

vomiting, gastrointestinal discomfort and diarrhea, incontinence, depression, and an

unpleasant fishy odor).

1

1

2

1

2

1

R

2

1

1

1

2

1

2

1

2

1

1

1

Continued on next page a

a
Addendum 3-3-Products With an Overall Score of 2-Continued

.

s

1-

Overan Query g

score Type of drug Source Category Nature of problem score 5

s

2

2

2

2

2

Combination analgesic and centrally acting muscle relaxant

Combination antiflatulent and

antacid

Combination antihistamine and

adrenergic decongestant

Combination antihistamine,

analgesic, and adrenergic

decongestant

Combination antihistamine,

antitussive, and adrenergic

decongestant

2 Combination aspirin with

antacid

pi ing

dcp

ind

wp

pg wp

da

pl ing

wp

ar

pi ing

pi, pg ing

ind

wp

ar

od

pi ing

od

insert does not list inactive ingredients.

Insert does not describe chemical properties of this combination.

Insert does not describe the clinical pharmacology of this combination.

Company failed to provide evidence of efficacy and safety of this centrally acting muscle

relaxant in humans.

Insert has no warning about cross-sensitivity with aspirin.

Insert has no information about carcinogenesis, mutagenesis, or impairment of fertility.

Entry omits mention of a drug interaction with tetracycline.

Entry omits maximum dosage.

Label does not list inactive ingredients.

Label provides no warning about use in patients with cardiac disease, diabetes, or asthma.

Label has no information about use in pregnancy.

Label has no warning about use with MAO inhibitors or with antihypertensive drugs.

Labeling does not warn about sleeplessness, dizziness, and nervousness.

Insert does not include alcohol content of product.

Insert does not list inactive ingredients.

No evidence that components of this product are effective as expectorants.

Insert does not caution about using antihistamines inpatients with narrow angle glaucoma,

stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy,

bladder neck obstruction, and ventricular tachycardia.

Insert does not note adverse effects associated with antihistamines (such as dry mouth,

dizziness, disturbed coordination, confusion, epigastic distress, thickening of bronchial

secretions), adrenergic decongestants (such as tachycardia palpitations, headache,

nervousness, tremor), and the antitussive in this preparation (such as confusion,

nervousness, or irritability).

No information is provided about overdose.

Label does not list inactive ingredients.

No information about management of overdose.

R

1

1

2

1

1

2

1

R

2

1

1

1

2

R

1

1

2

1

R

2
2 Combination bismuth, anesthetic

and corticosteroid for topical

administration

2 Combination cortcosteroid,

antifungal polyene antibiotic,

and aminoglycoside antibiotic

for topical administration

2 Combination urinary tract antiseptic and analgesic

2 Combination xanthine

bronchodilator, barbiturate, and

adrenergic agonist

pi ing

wp

ar

da

pg wp

ar

da

pi wp

od

pi ing

wp

da

Insert does not list inert ingredients.

Insert does not have a precaution concerning systemic absorption and development of

HPA axis suppression and the need for monitoring; use over large areas; caution against

ophthalmic contact; and warning to discontinue use if irritation develops.

Insert does not warn against using tight-fitting diapers or plastic pants on children being

treated in the diaper area (these garments may constitute occlusive dressings).

Insert has no information on use in nursing mothers.

Insert does not list the following adverse reactions: skin atrophy, itching, irritation, dryness,

folliculitis, hypertrichosis, acneform eruptions, hypopigmentation, perioral dermatitis,

allergic contact dermatitis, maceration of skin, secondary infections, and striae.

Insert does not provide information on duration of therapy.

Entry contains no warning against ophthalmic use.

Entry Contains no warning about the following: nephrotoxicity and ototoxicity of aminoglycoside antibiotic, risk of HPA axis suppression and Cushing’s syndrome with systemic

absorption of topical corticosteroids, and risk of overgrowth of nonsusceptible organisms.

Entry contains no recommendation to perform appropriate microbiological studies if there

is a lack of therapeutic response.

Entry has no information about carcinogenesis, mutagenesis, and impairment of fertility.

Entry does not mention precautions about the following: use in pediatric patients, use in

pregnancy, use in nursing mothers, risk of systemic absorption of topical carticosteroids,

and types of conditions that augment systemic absorption.

Entry does not mention the following adverse effects: ototoxicity, nephrotoxicity, burning,

itching, dryness, folliculitis, hypertrichosis, acneform eruptions, hyperpigmentation,

perioral dermatitis, allergic contact dermatitis, maceration of skin, secondary infection, skin

atrophy, and striae.

Entry does not advise against use of this product under occlusive dressings.

Insert omits precaution against use in prepubertal children and pregnant women just prior

to labor.

Insert omits overdose treatment information for this combination.

Insert does not list inactive ingredients.

Insert does not state that acute or severe asthma attacks may necessitate supplemental

therapy with other inhaled or parenterally administered drugs.

Dosages are not adjusted for the weight of the patient.

Insert recommends dosing three times a day rather than every eight hours.

R

1

2

1

1

1

1

2

2

1

2

1

1

1

2

R

2

1

1 m

c

Continued on next page z

s
s

Addendum 3-3-Products With an Overall Score of 2 G

overall Query z

score Type of drug Source Category

m

Nature of problem score ~

2 Corticosteroid for ophthalmic pi ing

and otic administration ind

wp

ar

2 Direct-acting arterial

vasodilator

2 Hypolipidemic drug

2 Injectable progestin

2 Lincosamide antibiotic

pg wp

pi ind

ci

pi

wp

a

wp

pi ind

Insert does not list inactive ingredients.

Insert indicates this topical corticosteroid for treatment of herpes zoster ophthalmia,

without noting that other topical steroid preparations are preferred.

Insert indicates this topical corticosteroid for neovascularization, keratoconjunctivitis

(without qualification), phiyctenularkeratitis (other references recommend a combination

topical corticosteroid-antibiotic combination).

Insert lacks information about use in pregnancy, in pediatric patients, and in geriatric

patients.

Insert does not list the following adverse reactions: globe perforation, exacerbation of

glaucoma or ocular hypertension, Posterior subcapsular cataracts, and burning or stinging

of ears.

Weak warning about hypotension (listed as an “infrequent” serious secondary reaction).

Entry omits precaution that product is for use in closely monitored settings, such as in the

hospital.

Insert does not note that diet is the initial therapy of choice for hyperlipidemias, and that

drug therapy should not be used for routine treatment.

Labeling does not include a contraindication for patients with preexisting gallbladder

disease and for patients with hypersensitivity to this drug.

No warning that this drug maybe associated with cholelithiasis.

insert does not state that adequate studies on caranogenicity have not been done in

humans, and that hepatic carcinomas have been found in rats that have been exposed to

this drug.

Insert does not include the following precautions: insert does not state that treatment

should be discontinued if response is inadequate after 3 months; labeling omits rare

hematologic changes; no information on impairment of fertility (based on animal studies);

labeling has no statement about pediatric use.

Insert does not contraindicate use in carcinoma of the breast and missed abortions.

Insert states that “[n]o teratogenic effects were observed in mice and rats” although

progestins have been shown to have teratogenic effects in animals and humans.

Insert does not address evidence of development of mammary nodules in monkeys.

Insert indicates antibiotic for use in upper respiratory infections, although most upper

respiratory infections are non-bacterial.

Insert has weak warning about association between antibiotic use and the development

of pseudomembranous colitis.

Insert does not warn that this antibiotic should not be used for treatment of meningitis (due

to poor penetration of the blood-brain barrier).

R

2

2

1

1

2

2

1

1

1

2

1

1

2

1

1

1

2
2 Macrolide antibiotic

ar

pi ind

2 Multivitamin with calcium and pg wp

iron

od

2 Multivitamin with iron pg ing

ind

wp

2 Multivitamin with minerals pi ing

ci

wp

ar

da

od

2 Multivitamin with protein and pg

minerals

2 Nitrosourea antineoplastic pi

ing

wp

wp

da

Insert does not note that eosinophilia, agranulocytosis, and thrombocytopenia have

occurred with use of this antibiotic.

Insert includes indication for respiratory tract infections due to staphylococci, streptococci,

and haemophilus.

Insert does not limit the treatment of Staphylococcus aureus with this antibiotic to skin and

soft tissue infections.

Entry does not note that iron absorption is inhibited by the concurrent ingestion of eggs and

milk.

Entry does not mention interactions with other drugs, including antacids, tetracycline, and

Ievodopa

Entry does not include information about the signs, symptoms, and management of

overdose.

Entry does not list inactive ingredients.

Product is indicated as an appetite stimulant.

Entry does not have recommendation for pregnant women and nursing mothers to seek

medical advice before using this product.

Insert does not list inactive ingredients.

Insert does not have contraindication for patients with hemochromatosis.

Insert does not warn that the presence of pernicious anemia should be excluded before

initiating therapy because folic acid may mask symptoms of pernicious anemia, allowing

untreated necrologic deficits arising from vitamin B-1 2 deficiency to progress.

Insert does not have the following precautions: calcium content should be considered

before prescribing for patients with kidney stones, do not exceed recommended dosage,

need for periodic hematologic tests to monitor therapy.

Insert does not list adverse reactions such as allergic reactions, skin rashes, gastrointestinal disturbances, nausea vomiting, diarrhea, constipation, generalized flushing and

feeling of warmth with niacinamide, allergic sensitization following administration of folic

acid.

Dosage of iron inadequate for pregnant women.

Insert does not have information on management of iron overdose.

Entry does not list inactive ingredients.

Entry does not state that product is merely supplemental and not a replacement for oral

food intake or for treatment of protein-calorie deficiency states.

Insert does not note that past history of lung disease is a risk for pulmonary toxicity.

Insert has no information about the relation of pulmonary toxicity to total cumulative dose.

Insert fails to recommend monitoring of complete blood count for hematologic adverse

reactions for at least six weeks after receiving a dose of this antineoplastic agent.

Insert has no warning about use of this product with glass containers.

1

2

2

1

1

2

R

2

1

R

1

2

1

1

1

1

R

2

2

2

1

1

Continued on next page
Addendum 3-&Products With an Overall Score of 2-Continued

Overall Query

score Type of drug Source Category Nature of problem score

2 Nonsteroidal anti-inflammatory pi wp

drug

ar

2 Nonsteroidal anti-inflammatory pi dcp

drug ar

2 Nonsteroidal anti-inflammatory pds dcp

drug

ing

wp

2 Nonsteroidal anti-inflammatory

drug

2 Nonsteroidal anti-inflammatory

drug

2 Nonsteroidal anti-inflammatory

drug

2 Opioid analgesic used in

anesthesia

pg

pi

pi

pi

ar

od

od

wp

ing

ind

wp

insert does not have a warning about the pharmacologic idiosyncratic type of anaphylactic

reaction to anti-inflammatory drugs.

Insert does not mention that the usefulness of fever and inflammation as diagnostic signs

of infection in patients on nonsteroidal anti-inflammatory drugs is reduced.

insert does not mention that this nonsteroidal anti-inflammatory drug has been associated

with skin reactions, including erytherna multiform; insert also does not note that

agranulocytosis (which may be fatal) may occur (insert only mentions granulocytosis

which suggests a less serious effect).

Insert does not have full information on clinical pharmacology.

insert does not warn specifically about the following adverse reactions: risk of erytherna

multiforrne and StevensJohnson syndrome, ulcers, renai effects, fluid retention, and use

in cardiac patients.

Document does not include medically important pharmacokinetic information, including

half-life and route of elimination.

Document does not list inactive ingredients.

Document does not warn that there are known effects of this class of drug on the human

fetus, including closure of the fetus, arteriosus, piateiet dysfunction with resultant

bleeding, renai dysfunction or tiiure with oiigohydramnios, gastrointestinal bleeding or

perforation, and rnyocardiai degenerative changes.

Document states that concomitant administration of this drug and sulindac results in a

substantial, “but not statistically significant,” lowering of plasma levels of sulindac, des@e

the fact that plasma levels in the 13 male volunteers included in the study dted had plasma

levels of sulindac lowered by one-third.

Document has no recommendation against use in children.

Document does not include proteinuria among adverse reactions.

Document has no information on the management of overdose.

Entry does not have information about signs and treatment of overdose.

Insert has no information about proteinuria or the nephrotic syndrome.

Insert does not state that this drug is a known teratogen in animals.

insert does not list inactive ingredients.

Manufacturer did not provide adequate evidence of efficacy for relief of pain and fever

associated with acute upper respiratory tract inflammation.

insert does not include information about use in nursing mothers.

Insert does not warn about the euphoria and miosis that may occur with narcotic

analgesics.

1

1

2

1

2

1

R

1

1

1

1

2

2

1

2

R

2

1

1
2 Penicillin-derivative antibiotic

2 Penicillin derivative antibiotic

pi

pi

2 Postmenopausal estrogen pi, pg

2 Progesterone-derivative oral

contraceptive

2 Sulfonylurea oral hypoglycemic

pi

pg

ar

ind

wp

ar

ing

wp

ar

da

ing

ind

wp

ing

ind

ci

wp

Insert does not contain information on secondary rebound respiratory depression or about

a number of other adverse reactions that may occur when this narcotic analgesic is used

in combination with droperidol.

Insert lists indications by types of susceptible pathogen and site of infection separately

rather than listing indications by site of infection, qualifying each by type of susceptible

pathogen.

Insert includes the following indications: ear, nose, throat, and oral cavity infections;

endocarditis.

Insert fails to warn about risk of anaphylactic reactions.

Insert has no information about several drug-lab test interactions (e.g., fake positive

glucose reactions with Clinitest, Benedict’s solution, or Fehling’s solution).

Insert does not include information about the following adverse reactions: gastrointestinal

system (e.g., pseudomembranous colitis), liver function (enzyme elevations), hematopoietic system (anemia, eosinophilia, agranulocytosis).

Insert does not list inactive ingredients.

Insert has no information on carcinogenesis, mutagenesis, use in nursing mothers, and

pediatric use.

Insert does not list gallbladder disease among adverse effects.

No justification for recommendation on insert to increase dosage to 2.5 mg/day in 3-4 days

if no improvement occurs at a dosage of 1.25 mg/day.

Insert does not list inactive ingredients.

Product is indicated for treatment of pelvic pain and mastodynia; company provided no

adequate evidence of efficacy for these indications.

Insert does not caution about the use of oral contraceptives in patients with impaired liver

function.

Insert does not warn about the increased risk of pyridoxine and folate deficiency in oral

contraceptive users.

Entry does not list inactive ingredients.

Entry indicates oral hypoglycemic for diabetes insipidus, but does not note that

desmopressin is the preferred treatment.

Entry does not contraindicate use by patients with known hypersensitivity to the drug.

Entry does not have information about use in pregnancy and nursing mothers.

Entry does not describe the following: loss of control of blood glucose when drugs which

produce hyperglycemia are used; interaction of oral miconazole and oral hypoglycemic.

Entry does not advise conservative doses in patients with impaired hepatic or renal

function.

Entry does not provide data on the safety and efficacy of use of phenformin with

sulfonylurea oral hypoglycemic in patients who are unresponsive to sulfonylurea oral

hypoglycemic alone.

2

1

2

2

1

1

R

1

1

2

R

2

1

1

R

1

1

1

2

2

1

Continued on next page

u)

w
Addendum 3-&Products With an Overall Score of 2-Continued

overall Query

score Type of drug Source Category Nature of problem score

2 Synthetic androgen pi ing

wp

ar

2 Systemic corticosteroid

2 Systemic corticosteroid

2 Thyroid hormone supplement

2 Topical antifungal agent

pi

pg

pi

ing

wp

ar

ing

wp

ing

wp

ind

wp

da

Insert does not list inactive ingredients.

Insert lacks warning regarding decreased HDL and increased LDL in patients receiving

this synthetic androgen.

Insert does not list the following adverse effects: pancreatitis, carpal tunnel syndrome,

prolonged post-therapy amenorrhea thrombocytopenia, Stevens-Johnson syndrome,

cataracts, bleeding gums, fever, nipple discharge, and Guillain-Barre syndrome.

Insert does not list inactive ingredients.

Insert does not warn about prolongation of coma in cerebral malaria risk of activation of

latent amebiasis, and steroid inducement of glaucoma, cataracts, or secondary ocular

infections.

Warnings about enhanced effects of corticosteroids in patients with hypothyroidism and

cirrhosis, and warnings about fat embolism are not included.

Insert has no specific warnings about use of this systemic corticosteroid in cases where

there is a probability of abscess, pyogenic infection, and in patients with intestinal

anastomoses; insert does not have warning about use in patients with myasthenia gravis.

Cutaneous reactions, convulsions, pseudotumor cerebri, vertigo, headache, ophthalmic

disorders, nausea and malaise were not mentioned in the insert.

Insert does not list inactive ingredients.

Insert does not have warning about increased calcium excretion associated with systemic

corticosteroids.

No warning about enhanced effect of steroids in hypothyroidism and cirrhosis.

No warning about need to monitor growth and development of infants and children on

systemic corticosteroids.

No warning about need for gradual reduction of dosage following prolonged therapy.

No outline of routine tests to monitor therapy.

Entry does not list inactive ingredients.

Entry does not include the following: recommendations about monitoring thyroid status

when receiving this product; information about drug interactions (only interactions with

anticoagulants and hypoglycemics are mentioned in entry); information about drugIaboratory test interactions; information about use in nursing mothers, infants, and

children.

Company did not provide adequate justification for indicating this topical antifungal for

treatment of staphylococcal and streptococcal skin infections.

Insert has no warnings and precautions.

Insert has no information about use in pregnancy and in nursing mothers.

insert lacks information on duration of therapy.

R

1

2

R

2

1

2

1

R

1

1

2

2

1

R

2

2

1

1

1
2 Tricyclic antidepressant

2 Uninary anticholinergic and

antispasmodic

2 Urinary tract analgesic

2 Urinary tract analgesic

2 Urinary tract antiseptic

pipa wp

od

pi dcp

pi

pi, pg

pg

wp

ar

ing

ci

wp

od

ing

wp

ar

od

ind

wp

2 Urinary tract antiseptic pi ing

ind

da

Insert has no information about drug interactions.

Insert does not describe signs and symptoms of toxicity.

Insert does not have pharmacokinetic information, including mode of excretion, time of

onset of action, or peak effect.

Insert has no information about use in pregnancy and nursing mothers.

Insert does not list among adverse reactions the following: vertigo, mental confusion,

nervousness, Ieukopenia, tachycardia, palpitations, urticaria, eosinophilia, hyperpyrexia,

disturbances of eye accommodation, and dysuria.

Insert does not list inactive ingredients.

Insert does not include contraindication for use by patients with hypersensitivity to this

product.

Insert does not note that the use of this urinary analgesic should not delay the definitive

diagnosis and treatment of causative conditions.

Insert does not note that this urinary analgesic may interfere with urinalysis based on

spectrometry or color reactions.

Insert does not have section on carcinogenesis, mutagenesis, or impairment of fertility.

(U.S. labeling notes that long-term use of this product has induced neoplasia in rats.)

Insert does not have information on management of overdose, including treatment of

methemoglobinemia.

Insert does not list inactive ingredients.

Insert does not note that this urinary tract analgesic may stain all body fluids, not just urine;

insert does not note that the use of this agent for symptomatic relief should not delay

definitive diagnosis and treatment of causative organisms.

Insert does not caution that this urinary tract analgesic may interfere with urinalysis based

on spectrometry or color reactions.

Insert has no information about use in pregnancy and by nursing mothers.

Insert has no information on caranogenesis, mutagenesis, or impairment of fertility.

Insert does not list the following adverse reactions: headache, rash, gastrointestinal

disturbances, renal toxicity, hepatic toxicity.

Insert does not provide information on management of overdose.

Entry does not note that the same degree of effectiveness against susceptible organisms

is achieved by a related agent with a lower incidence of CNS side effects.

Insert does not state that this urinary tract antiseptic may enhance the effects of oral

anticoagulants, warfarin, or bishydroxycoumarin.

Insert does not list inactive ingredients.

Product is indicated for pyelonephritis and intestinal bacterial diarrhea.

Children’s dosages are adjusted by age rather than weight of the patient.

1

2

1

1

2

R

1

1

1

1

2

R

1

1

1

1

1

g

2 g

1 G

o

o

R s

2

u)

c

1

z

SOURCE KEY: pi= package insert; pg - prescribing guide entry; pipa - package insert pending approval; pl - package label; pds = product document. s—

CATEGORY KEY: dcp = description/clinical pharmacology; ing = ingredients; ind = indications; ci = contraindications; wp = warnings and precautions; ar = adverse reactions; da = dosage and +

administration; od - overdose information.
Addendum 3-4-Products With a Primary Overall Score of 3

Overall Query

score Type of drug Source Category Nature of problem score

3 Analgesic and proteolytic

enzyme combination

pi

3 Analgesic, decongestant, and pi

antihistamine combination

3 Androgenic steroid pi

3 Adrenergic drug pi ing

ind

ci

wp

ar

od

dcp

wp

od

ing

ci

wp

ar

od

ind

a

wp

3 Antacid

3 Antacid combined with bismuth pi

and digestive enzyme

ind

wp

dcp

d

Label does not list inactive ingredients other than alcohol.

Label does not include information on indications and usage.

Label does not include information about contraindications.

Label does not list warnings and precautions.

Label does not list adverse reactions.

Label does not have overdose information.

Company did not provide adecpate evidence of efficacy for this drug combination in human

beings.

insert omits precautions regarding use inpatients with severe hepatic insuffidency, renaJ

damage, or puimonary hemorrhage.

insert does not have information about signs and treatment of overdose.

insert does not list inactive ingredients.

insert does not list contraindications.

insert does not list warnings and precautions.

insert does not have information about use in pregnancy and by nursing mothers.

insert does not list adverse reactions other than drowsiness.

insert has no information about management of overdose.

No adequate support for use of this androgenic steroid in the following: in menopause, in

benign mammary disturbances, in suppression of lactation, and in frtgidity therapy.

important contraindications (such as use in pregnancy) are omitted.

Warnings are omitted regarding use in children and development of hepatic adenomas.

insert does not describe laboratory test interactions (decreased levels of thyroxine-binding

globulin) and drug interactions (may decrease blood glucose in diabetic patients).

Product is indicated for infant feedings to “prevent milk from souring and forming curds in

the stomach,” to aid in digestion, and to prevent constipation; company provided no

adequate evidence of efficacy for these indications.

Label does not warn about use of magnesium containing compounds in renal disease.

Label does not warn about risk of hypermagnesemia in infants subject to chronic

administration.

Company did not provide rationale for this combination.

insert does not note that magnesium containlng compounds are contraindicated in severe

renal impairment or that calcium-containing compounds are contraindicated in hypercaicemia

R

2

2

2

2

2

1

2

2

R

2

2

2

2

2

2

2

2

1

2

2

2

1

2
3 Anthelmintic 3 Anthelmintic 3 Antibiotic

wp

ar

pl wp

ar

da

pl dcp

ci

ar

od

pi ind

da

Insert does not warn about the following: risk of hypermagnesemia in very young children,

bismuth may cause impaction in elderly patients, do not take this antacid if symptoms of

appendicitis are present, do not take within 1-2 hours of other oral medication, do not take

with large amounts of milk or milk products.

Insert has no information about drug interactions, including: cellulose sodium phosphate,

ketoconazole, mecamylamine, methenamine, oral tetracydines, and sodium polystyrene

sulfonate resin.

Insert has no information on drug-test interactions, such as with gastric acid secretion test,

and assessments of serum calcium, phosphate, potassium, and gastrin.

Insert does not note that bismuth may cause black discoloration of feces.

Insert does not list the following adverse effects: constipation or diarrhea metabolic

alkalosis (in renal insuffidency), hypercalcemia, renal calculi, hypermagnesemia, nausea,

vomiting, and stomach cramps.

Label omits specific warning about potential neurotoxicity of the drug, especially in

children.

Label omits precautions for use (e.g., discontinue use if CNS, gastrointestinal, or

hypersensitivity reactions occur; appropriate caution should be exercised for use in

patients with severe malnutrition or anemia).

Label omits reported adverse reactions (e.g., gastrointestinal system and central nervous

system adverse reactions).

Label does not state that the maximum cure rate is usually obtained with a multiple-dose

regimen.

Label does not have information on clinical pharmacology.

Label has no contraindication in patients with epilepsy.

Label has no information on side effects, Including transient neurological effects and

urticarial reactions.

Label has no information on toxicity.

Insert does not note that this antibiotic is not indicated for treatment of the carrier state of

Salmonella typhi.

Company did not provide adequate support for intramuscular injection as an effective

method of administration.

No adequate support for pleural Iavage as an effective method of administration.

Company did not provide support for dosage intervals of 8 hours for adults and 12 hours

for children (U.S. labeling recommends dosages at 6-hour intervals).

22112222212222221

Cnc

Continued on next page

z4
Addendum 3-4-Products With a Primary Overall Score of Continued

Overall Query

score Type of drug Source Category Nature of problem score

3 Anticholinergic antispasmodic pg dcp

ing

ind

wp

ar

od

3 Antidiarrheal combination pi, pg w p

containing an aminoglycoside

antibiotic

ind

wp

ar

3 Antiepileptic drug

od

pi wp

ar

Entry does not include information on pharmacology.

Entry does not list inactive ingredients.

Entry includes indications for symptomatic treatment of irritable bowel syndrome and renal

colic, and as adjunctive therapy in ulcerative colitis, diverticulitis, cholecystitis, and

pancreatitis.

Entry does not note that this anticholinergic drug may potentate the sedative effect of

phenothiazines.

Entry does not note that mental confusion, bloating, suppression of lactation, and

anaphylaxis may occur.

Entry does not note that, with overdose, a curare-like action may occur.

Manufacturer claims that the components of this product have synergistic action, but did

not provide evidence that this was the case.

Insert is promotional in tone (e.g., through use of adjectives “powerful,” “extraordinary,”

and “extremely effective”).

Insert states that one component of the product can eliminate toxins, bacteria and add

from the gastrointestinal tract; manufacturer did not provide evidence that this was the

case.

Insert states that oral aminoglycoside antibiotic is effective in bacterial diarrhea;

manufacturer did not provide evidence of efficacy.

Insert broadly indicates product for symptomatic treatment of diarrhea implying that it is

indicated for nonbacterial diarrheas.

Insert states that the aminoglycoside antibiotic orally “has never provoked reactions that

are generally presented with its parenteral administration.”

Insert does not caution about the following: administration of other nephrotoxic drugs

should be avoided; respiratory parafysis from neuromuscular blockade may occur;

monitoring for development of ototoxicity (insert recommends discontinuation of therapy

if tinnitus develops); CNS depression syndrome has occurred in infants; encephalopathy

has developed from high doses of one component of the product in patients with renal

failure.

The following adverse reactions were not listed: nausea, vomiting, paraesthesias, rash,

fever, urticaria, angioneurotic edema, eosinophilia, deafness, exfoliative dermatitis,

Stevens-Johnson syndrome, dermatitis, anaphylaxis, urticaria, azotemia, Ieukopenia,

thrombocytopenia, pancytopenia, hemolytic anemia, muscular weakness, amblyopia,

vestibular dysfunction, visual disturbances including blindness.

Insert provides no information about the management of overdose.

Insert omits specific warning about use in children under 2 years of age.

Insert does not note that acute pancreatitis associated with use of this antiepileptic may

be fatal.

1

R

2

1

1

2

1

1

1

2

2

2

2

2

2

2

2
3 Antiepileptic drug

3 Antiepileptic drug

3 Antiestrogenic drug

3 Antihistamine

3 Antihistamine

pl dcp

ind

ci

wp

ar

da

pi wp

ar

pg dcp

ind

wp

ar

pi dcp

ing

ind

a

wp

pg ing

ind

wp

ar

Information on clinical pharmacology is not included in the label.

Label does not have indications and usage information.

Label does not provide information about contraindications.

Label does not provide information on warnings and precautions.

Label provides no information on drug interactions.

Label does not provide information on adverse reactions.

Label gives no specific doses for initiation and maintenance.

Insert does not warn that sudden withdrawal of this antiepileptic drug could precipitate

absence (petit real) status.

Insert does not include information on Stevens-Johnson syndrome, a serious adverse

effect of treatment with this antiepileptic.

Entry does not include a section on clinical pharmacology.

Entry broadly indicates drug for anovulatory women, without emphasizing need to

diagnose the cause of anovulation first.

Entry does not include warning about use of this drug in pregnancy.

Entry does not recommend endometrial biopsy in all patients with ovulatory disorders to

rule out endometrial carcinoma as a cause.

Entry does not mention among adverse reactions abnormal uterine bleeding, breast

tenderness, increased urination, weight gain, and rare incidence of massive ovarian

enlargement.

Insert does not include distribution and elimination half-life of drug and its metabolizes (the

half-life is particularly long).

Insert does not list inactive ingredients.

Insert broadly indicates this antihistamine for allergic conjunctivitis and “other allergic

conditions.”

Insert does not contraindicate this drug in patients with hypersensitivity to the drug or any

of its inactive ingredients.

Insert does not have precaution about use in patients with hepatic impairment.

Insert has no information about use in nursing mothers.

Entry does not list inactive ingredients.

Entry includes indications for use in pregnancy, electroconvulsive therapy, anesthesia,

surgery, disease due to radiation, post-fenestration syndrome, and migraine headaches.

Entry does not caution against use in patients with conditions that maybe aggravated by

anticholinergic therapy.

Entry does not warn about dizziness, dry mouth, dry nose, dry throat, blurred vision,

difficult or painful urination, headache, anorexia, nervousness, restlessness, insomnia,

skin rash, thickening of bronchial secretions, tachycardia, epigastric distress, lassitude,

excitation, and nausea.

1

2

2

2

2

2

2

2

2

1

2

2

2

1

2

R

2

1

1

1

R

2

1

2

Continued on next page 2
+

u)

G

Addendum 3-4-Products With a Primary Overall Score of 3 z

Q

Overall Query s

score Type of drug Source Category Nature of problem score g

—

3 Antihistamine pi dcp

ing

ind

wp

ar

od

3 Antihistamine and vitamin B-6 pg dcp

combination ind

wp

3 Antinausea and antivertigo drug pg ing

ind

wp

da

pi ing

ind

wp

3 Antitubercuiosis drug

Insert does not list mechanism of action.

Insert does not list inactive ingredients.

Insert adds indications for nausea and vomiting associated with electroshock therapy,

anesthesia and surgery, Iabyrinthine disturbances, radiation sickness, and postfenestration syndrome; company did not provide adequate evidence of eff icacy for these

indications.

Insert does not have precautions regarding use in conditions that maybe aggravated by

this product’s anticholinergic actions, such as gallbladder obstruction, asthma, narrow

angle glaucoma, emphysema, and prostatic hypertrophy.

Drug interactions, such as with alcohol and other sedatives, are not listed.

Insert does not note that this product may cause anticholinergic effects.

Insert does not have information about symptoms and management of overdose.

No evidence was provided to justify this combination.

Manufacturer submitted no adequate well-controlled studies demonstrating the efficacy

for use in pyloric spasm.

Entry does not include warnings about use of this antihistamine with alcohol or for children

under 12 years of age.

Entry does not include warning that use of antihistamines in children can cause excitability.

Entry omits mention of tartrazine, a particularly sensitizing agent.

Entry includes indication for motion sickness (i.e., any disorder caused by unaccustomed

motions), despite potent side effects; entry indicates product for nausea caused by renal

disease, but does not qualify use by noting that renal function impairment may increase

the risk of side effects due to decreased excretion.

Entry fails to warn physicians to use this product in closely monitored settings.

Company did not provide evidence of safety and efficacy of this drug in children weighing

less than 22.8 kg.

Insert does not list inactive ingredients.

No adequate support for indication for enterococi and Proteus sp.; no statement that rapid

development of resistance to Neisseria gonorrhoeae can occur.

Insert does not warn about fatalities associated with antibiotic-induced hepatic dysfunction

and about increased incidence of hepatomas in mice exposed to this antibiotic.

Insert does not mention that this antibiotic may induce elevations of BUN and serum uric

acid.

1

R

2

2

1

2

1

1

2

2

1

2

2

2

2

R

2

2

1
ar—. Insert does not list a number of CNS effects, including drowsiness, fatigue, ataxia, 1

3 Barbiturate anesthetic

3 Beta blocker

3 Beta blocker

pg, pi dcp

a

wp

ar

da

od

pl dcp

wp

ar

da

od

pg ing

ind

wp

ar

da

od

dizziness, mental confusion, inability to concentrate, pains in extremities,and generalized

numbness.

Insert does not describe in detail the types of hypersensitivity reactions, including urticaria,

pemphigoid reactions, eosinophilia, sore mouth, sore tongue, exudative conjunctivitis, and

fever.

Entry does not include information on clinical pharmacology.

Entry does not contraindicate this barbiturate anesthetic in patients without veins suitable

for intravenous administration, patients hypersensitive to barbiturates, patients in status

asthmatics, and patients with porphyria.

Entry has no recommendation for special care in administering this barbiturate anesthetic

to patients with advanced cardiac disease, increased intracranial pressure, asthma,

myasthenia gravis, and endocrine insufficiency.

Entry does not have information about use in pregnancy and in nursing mothers.

Entry does not include among adverse reactions respiratory depression, myocardial

depression, prolonged somnolence and recovering bronchospasm, and hypersensitivity

reactions.

Entry does not provide detailed information about the use of this barbiturate anesthetic; the

entry only advises physicians to consult the literature.

Entry does not provide information on preparation of solutions and the incompatibility of

this barbiturate anesthetic with other compounds that may acidify the solution.

Entry has no information about management of overdose.

Description, actions, and indications are not included in the label.

Label does not have information about warnings and precautions.

Label does not have information about adverse reactions.

Label does not have information on dosage and administration.

Label does not have information on overdose management.

Entry does not list inactive ingredients.

No adequate support for broad indication for thyrotoxicosis (rather than as adjunctive

therapy for thyrotoxicosis).

Entry has no section on drug interactions.

Entry does not include the following warnings about the use of beta blockers: the signs and

symptoms of acute hypoglycemia and thyrotoxicosis may be masked, the risks of general

anesthesia and surgical procedures may be increased.

Entry does not have information about use in nursing mothers or pediatric use.

Entry does not warn about some adverse effects, including impotence and depression.

Specific dosing recommendations for patients in renal failure are not provided.

Entry has no information about management of overdose.

2

1

2

2

1

2

2

1

2

2

2

2

2

2

R

1

2

2

1

1

1

2

Continued on next page 3
u

Addendum 3-4-Products With a Primary Overall Score of qontinued z

Cn

Overall Query r

score Type of drug Source Category Nature of problem score 8

CD

3 Butyrophenonederivative pi ing

antipsychotic wp

3 Calcium channel blocking agent pg, pi

3 Cephalosporin antibiotic

3 Combination aminoglycoside

antibiotic, opiate, antkpasmodic,

and bulk-forming agents

pi

pg

od

dcp

ci

wp

da

od

ind

wp

dcp

ind

od

Insert does not list inactive ingredients, including tartrazine.

Insert has no precautions about the following: risk of extrapyramidal symptoms with

concomitant discontinuation of antiparkinsonian medications; and risk of increased

intraocular pressure.

For management of overdose, insert recommends supportive care rather than gastric

Iavage, induction of emesis, charcoal slurry, and other specific measures.

Insert does not have information on pharmacokinetics.

Insert incorrectly relates contraindication regarding hypersensitivity to the products

teratogenicity (i.e., insert states that the product “should not be administered to patients

with known sensitivity to the treatment since teratogenic effects in animals have been

reported”).

Insert has no warning about the potential of this calcium channel blocker to induce

hypotension.

Insert does not note that this calcium channel blocker interacts with digoxin by prolonging

AV conduction.

Company did not provide adequate support for the long-term dosage regimen suggested

in the insert.

Insert does not have information on management of overdose.

Product indicated for use in treatment of typhoid fever; company did not provide adequate

evidence of efficacy for this indication.

Insert does not state that penicillin is the drug of choice in the treatment and prevention of

streptococcal infections.

Insert does not make specific reference to risk of pseudomembranous colitis.

Company did not provide rationale for this drug combination and the ratios of its

ingredients.

Company did not support the safety of this combination in children and infants.

Company provided no adequate rationale for indicating use as a general treatment for

“diarrhea”

Entry does not state that oral dehydration therapy is the primary treatment for acute

diarrheal disease.

Entry does not warn against the risk of nephrotoxicity and ototoxicity associated with the

use of an aminoglycoside antibiotic.

Entry recommends an outdated treatment of overdose (in the U.S., activated charcoal

rather than the “universal antidote” is recommended treatment of overdose).

2

1

2

1

1

2

1

1

2

2

1

2

1

2

2

2

2

2
3 Combination analgesic

3 Combination antihistamine,

adrenergic decongestant, and

anticholinergic

pi dcp

pi

wp

ar

da

od

ing

wp

ar

od

Company did not provlde justificatlon for this combination.

Insert does not include a warning about the association between aspirin and Reye’s

syndrome in children.

Insert does not have the following precautions for opiate analgesics: use in pregnant

women; use in patients with ulcerative colitis; increase in biliary tract pressure may result

in biliary spasm or relic; combination may cause urinary retention and oliguria;

combination drug may cause impotence or decline in libido; combination has a prolonged

duration and cumulative effect in patients with hepatic or renal dysfunction; use with

extreme caution in patients with seizures, acute alcoholism, delirium tremens, shock,

untreated myxedema, cor pulmonale, bronchial asthma and chronic pulmonary disease;

tolerance, psychological dependence, and physical dependence may occur in patients

receiving opiate agonists.

Insert omits certain adverse effects associated with opiate analgesics including respiratory

depression and circulatory depression; respiratory arrest, shock, and cardiac arrest;

dizziness; visual disturbances; mental clouding or depression; sedation; coma; euphoria;

dysphoria; weakness; faintness; agitation; restlessness; nervousness; seizures; delirium;

insomnia; dizziness; nausea; vomiting; hypotension; pruritis; urticaria.

Insert omits dosage recommendations for children.

Insert omits information about overdose signs and management.

Insert does not list inactive ingredients.

Insert does not note the anticholinergic effects that are associated with antihistamines.

Insert lacks information about numerous drug interactions.

Insert has no information on use in nursing mothers, caranogenesis, mutagenesis, or

impairment of fertility.

Insert does not state that in children antihistamines can produce paradoxical reactions,

such as irritability and excitation.

Insert does not warn that antihistamines may cause confusion, excitement agitation,

severe memory impairment, and that geriatric patients in particular are susceptible to the

anticholinergic side effects of antihistamines, especially when they are receiving other

drugs that also have anticholinergic effects.

Insert omits mention of numerous adverse reactions associated with antihistamines and/or

sympathomimetic amines.

Insert does not warn that, in children, overdose of antihistamines can cause hallucinations

or death.

Insert does not mention that deaths have been associated with overdose.

1

2

2

2

2

2

R

1

2

1

1

2

2

2

2

o

g

Continued on next page 2

4
Addendum 3-4-Products With a Primary Overall Score of 3

overall Query

score Type of drug Source Category Nature of problem score

3 Combination antihistamine, pi dcp

corticosteroid, and phenothiazine antipsychotic wp

3 Combination expectorant and

analgesic

3 Combination opioid analgesic,

aspirin, and acetaminophen

ar

od

pl wp

od

pi dcp

ing

ind

ci

wp

The manufacturer has not provided justification for this fixed combination product over

each of the components individually.

Insert does not include the following warnings regarding the corticosteroid in this product:

since mineralocorticoid secretion may be impaired, salt and mineralocorticoid may need

to be administered; corticosteroids may cause psychic derangements, ranging from

euphoria, insomnia, mood swings, personality changes, and severe depression to frank

psychotic manifestations; corticosteroids can cause elevation of blood pressure, salt and

water retention, and increased calcium excretion.

Insert does not have specific warnings about phenothiazine use: development of tardive

dyskinesia associated with phenothiazine antipsychotics,

Insert does not have warning about neuroleptic malignant syndrome; no precaution about

cross-sensitivities to other phenothiazines; no warning about the possibility of liver

damage; no warning about pigmentary retinopathy, Ienticular deposits, and corneal

deposits.

Insert does not have the following warnings for antihistamines: overdoses of antihistamines may cause hallucinations, convulsions, or death, especially in infants and children;

products containing antihistamines have additive effects with alcohol and other CNS

depressants.

Adverse reactions associated with each of the components of this product are not listed

with specificity.

Insert does not have information about overdose and treatment.

Label provides inadequate information about the enclosed free sample.

Label does not contain information on the management of overdose.

Insert does not have section describing clinical pharmacology.

Insert does not list inactive ingredients.

Company did not provide evidence of additive analgesic effects of this compound and

decreased toxicity compared with the individual components.

Insert does not have contraindication for persons with hypersensitivity to the components

of this combination analgesic,

Insert does not warn about the following: potential for drug dependence for this opiate

analgesic-containing compound; possibility of Reye’s syndrome and the need to avoid

giving this product to children with flu-like symptoms; warning about giving this

combination to children with asthma; warning about the potential of this drug to cause

drowsiness, and a warning about driving or operating machinery after taking this drug;

warning about the potential for gastric ulceration and gastrointestinal blood loss in this

aspirin-containing combination; precautions about use in patients with head injury, acute

abdominal conditions, or in elderly or debilitated patients; precaution advising to avoid

using this combination in patients with bleeding disorders or in those patients receiving

anticoagulants.

2

1

2

2

1

2

2

2

2

1

R

1

1

2
3 Combination phenothiazine

antipsychotic and tricyclic

antidepressant

3 Combination phenothiazine

antipsychotic and tricyclic

antidepressant

3 Combination phenothiazine,

anticholinergic, and

antispasmodic

pi

pi

pi

od

wp

ar

od

ind

wp

ar

od

dcp

ind

wp

Insert does not have information about use in pregnancy, use in nursing mothers, and

pediatric use.

Insert does not have information about drug interactions with CNS-active drugs.

Insert does not have information about management of overdose.

Insert does not have warnings about risk of tardive dyskinesia, cardiovascular concerns,

and interaction with guanethidine-like drugs.

Insert does not warn that patients with high suicide potential should not be given large

supplies of this drug.

Insert does not list specific adverse reactions associated with this combination phenothiazine antipsychotic and tricyclic antidepressant.

Insert does not mention some signs of toxicity (e.g., plasma levels associated with

overdose, widening of the QRS complex on ECG, oculomotor paresis).

Product is indicated for “anxiety” generally, rather than only for those patients for whom

anxiety and depression cannot be clearly differentiated.

Insert does not warn about risk of neuroleptic malignant syndrome; insert does not warn

specifically about risk of cardiac arrhythmias, myocardial infarction, and stroke.

Insert does not warn that this combination can lower the convulsive threshold in

susceptible individuals.

Insert does not warn that prolactin levels maybe elevated, and that galactorrhea,

amenorrhea, gynecomastia, and impotence may occur; also, an increase in mammary

neoplasms has occurred in rodents.

Insert does not warn about photosensitivity; insert does not warn about risk of paralytic

ileus when product is taken with other anticholinergics.

Insert does not mention the following adverse reactions: persistent tardive dyskinesia,

cerebral edema, abnormal CSF proteins, neuroleptic malignant syndrome, increased

psychotic symptoms, lethargy, paradoxical excitement, restlessness, hyperactivity,

nocturnal confusion, bizarre dreams, and insomnia.

Insert does not describe symptoms and management of overdose in detail.

No adequate clinical data were provided supporting rationale for this combination.

No adequate clinical data were provided to support indication for “digestive disorders

produced or intensified by psychic tension.”

Insert has relatively weak warning on tardive dyskinesia.

1

1

2

2

2

2

1

2

2

1

1

1

2

2

2

2

2

Continued on next page

—

ag
Addendum 3-&Products With a Primary Overall Score of 3-Continued

overall Query

score Type of drug Source Category Nature of problem score

3 Corticosteroid for intramuscu- pi ing

Iar administration ci

wp

3 Methylxanthine bronchodilator pg

3 Monoamine oxidase inhibitor

3 Neuroleptic tranquilizer

pi

pi

ar

dcp

wp

od

ci

wp

da

dcp

ind

Insert does not list inactive ingredients or preservatives.

Insert does not have contraindication for use in systemic fungal infections, idiopathic

thrombocytopenic purpura, and septic arthritis.

Insert does not warn about masking signs and symptoms of infection, elevation of blood

pressure, avoidance of vaccinations, and potential for local atrophy at injection site.

There are no precautions about enhanced effects of this corticosteroid in hypothyroidism

and cirrhosis, caution for use in ocular herpes simplex, risk of psychic derangements,

impairment of growth and development in children, muscle wasting, and menstrual

irregularities.

Insert does not have comprehensive list of adverse reactions by organ system.

Entry does not include bioavailability data, including information about differences in

half-life for different types of patients (e.g., patients with renal deficiency, alcoholics,

smokers, newborns).

Entry does not have the following precautions: use with caution in patients with severe

hypoxemia, hypertension, hyperthyroidism, acute myocardial injury, cor pulmonale, or

liver disease; use with caution in the elderly and in neonates; use cautiously in patients with

history of peptic ulcer.

Insert does not mention drug interactions with Iithium carbonate, propranoiol, furosemide,

hexamethonium, reserpine, chlordiazepoxide, troleandomycin, erythromycin.

No support for statement in entry that when the drug is taken with foods, its absorption will

be slowed, but complete.

Labeling omits information about symptoms and management of overdose.

Insert does not contraindicate use of this monoamine oxidase inhibitor with fluoxetine,

buspirone, or dextromethorphan.

Insert does not note that this monoamine oxidase inhibitor should be administered with

caution to patients receiving disulfiram (Antabuse) because severe toxicity, including

convulsions and death, have been noted in animals who had received this combination of

drugs.

Insert does not note incidence of hematologic disorders with use of this drug.

Insert has no information on risk of developing dependency (particularly in patients with a

history of drug abuse) or information about withdrawal symptoms.

Insert notes that if no response occurs with 30 mg per day “continued administration will

probably not be beneficial” (compare U.S. labeling, which notes that dosage maybe

increased to 60 mg per day).

Language in the properties section of the foreign labeling appears to be promotional in

tone (e.g., “notably favorable therapeutic index” and “an excellent neuroleptic”).

Company provided inadequate data to support use in shock patients.

R

2

2

2

2

1

2

2

1

2

2

1

1

2

1

1

2
3 Nonsteroidal anti-flammatory pi

drug

3 Nonsteroidal anti-inflammatory w

drug

3 Nonsteroidal anti-inflammatory pi

drug

3 Ocular sympathomimetic

decongestant combination

pi

wp

ar

da

od

ind

wp

ci

wp

ar

od

ind

wp

ar

od

dcp

wp

ar

Insert omitted several warnings (e.g., reduce concomitantly-administered opioids, monitor

patient closely, and have available treatments for hypotension induced by this drug).

Insert omits precautions about use in patients with impaired liver function, use in

pregnancy, and use in labor and delivery.

Insert does not list hallucinations among adverse effects.

Insert omits information about dosage and administration.

Insert omits information about signs of overdose and treatment.

Product is indicated broadly for conditions “requiring] analgesic or anti-inflammatory

activity,” as opposed to just osteoarthritis and rheumatoid arthritis.

insert does not warn about the following: severe hepatic reactions, serum-sickness-like

syndrome, anaphylaxis, and bronchospasm.

Insert does not have a section on drug interactions.

Insert does not warn about the markedly increased ulcer risk with doses above 20 mg per

day.

Contraindications are omitted for use in pregnant women, based on animal studies of

fetotoxicity, minor skeletal malformations, and delayed ossification.

Entry omits mention of drug interactions with aspirin and other nonsteroidal antiinflammatory drugs.

Several important adverse reactions are not included in the entry (e.g., edema, urticaria,

pruritis, tinnitus).

Insert does not have information on symptoms and management of overdose.

Product is indicated for minor ailments (such as headaches) despite potent side effects;

insert does not note that safer alternatives are available.

Insert does not caution about use in patients with acute porphyria.

Insert has no information about use in pregnancy or in nursing mothers.

Insert does not note that agranulocytosis and death have occurred with use of product

(notes only that granulocytopenia rarely occurs).

Insert does not mention the following adverse effects: skin reactions, allergic reactions,

fever, anaphylactic shock, brochospasm, gastrointestinal symptoms, and drug-induced

toxic epidermal necrolysis.

Insert has no information about management of overdose.

Company did not provide evidence of efficacy of combination over individual components

alone.

Insert does not list warnings and precautions.

Insert does not list adverse reactions.

2

1

1

2

2

2

2

1

2

2

1

1

2

2

2

1

1

2

2

1

2

2

Continued on next page
Addendum 3-4-Products With a Primary Overall Score of Continued

overall Query

score Type of drug Source Category Nature of problem score

3 Oral contraceptive pl dcp

ing

ind

a

wp

3 Phenothiazine antipsychotic pi

3 Piperazine-derivative antihis- pi

tamine/vasodilator

3 Piperazine-derivative antihis- pi

taminehasodilator

ar

ind

a

wp

ar

ind

wp

da

od

dcp

ind

wp

ar

od

Label does not include section on clinical pharmacology.

Label does not list inactive ingredients.

Label has no information on indications and usage.

Label does not list contraindications.

Label has no warnings about cardiovascular disorders, myocardial infarction, other

thromboembolic and thrombotic diseases, and other risks associated with oral contraceptives.

Label does not include precautions.

Label does not list adverse reactions.

Insert does not note that this phenothiazine antipsychotic is not drug of choice for

generalized nonpsychotic anxiety because of the risk of tardive dyskinesia.

Insert does not note that use in “anxiety states” is limited to generalized anxiety disorder

and does not note lack of evidence of efficacy in other anxiety states (e.g., due to physical

disease, agitated depression mimicking anxiety, character pathologies).

Insert contradicts U.S. labeling in recommending use in behavioral disorders associated

with mental retardation.

Insert does not note that this phenothiazine antipsychotic may have additive effects with

anticholinergics (such as atropine) and interaction with organophosphate insecticides.

Insert does not warn about risk of exfoliative dermatitis, lupus-like syndrome, and cardiac

arrest.

Insert does not mention among adverse reactions risk of sudden death secondary to

asphyxia due to inhibition of cough reflex.

Manufacturer provided inadequate evidence, or poorly designed studies to support

indications for cerebral trauma sequelae, postapoplectic sequelae, and symptoms of

cerebral arteriosclerosis,

Insert does not note that extrapyramidal symptoms have been associated with this drug.

Insert asserts that product “hardly affects blood pressure.”

Insert does not provide recommendations about pediatric use.

The pediatric dose on the current labeling is too high; adult dosages may also be too high.

Insert provides no information about overdose.

Insert omits information about clinical pharmacology.

Company provided inadequate evidence of efficacy of drug in treatment of cerebral

arteriosclerosis, cerebral or cranial trauma, and postapopiectic disorders.

Insert omits general antihistamine precautions.

Insert omits general antihistamine adverse effects.

Insert omits information about signs and treatment of overdose.

1

R

2

2

2

2

2

2

2

2

1

2

1

2

2

2

1

2

2

1

2

2

2

2
3 Synthetic androgen

3 Systemic antifungal agent

3 Systemic corticosteroid

3 Systemic corticosteroid

pi

pg

pi

pi

ind

ci

wp

ind

wp

ing

ind

wp

ing

ind

wp

ar

Product is indicated for the treatment of virginal breast hyperplasia; company did not

provide adequate evidence of efficacy for this indication.

Product is indicated for the treatment of precocious puberty.

Insert omits contraindications regarding use in patients with undiagnosed genital bleeding.

Insert omits warning that patients should be monitored during treatment for signs of hepatic

dysfunction.

Entry does not state that this product is not indicated for trivial infections.

Entry omits warnings regarding prophylactic use, tumorigeniaty, use in pregnancy,

teratogenicity, and suppression of spermatogenesis.

Insert does not list inactive ingredients.

A number of overly broad and unsupported indications are listed: indication for “arthritis

in generaI,” “dermatitis in general,” allergic rhinitis (without qualification that systemic

corticosteroids should only be used in severe cases), osteoarthritis, corneal marginal

ulcers, “purpura vascular alergica,“ “pseudohemophilia” cirrhosis of the liver, hepatic

coma, hepatitis A virus, acute pancreatitis, orchitis, toxoplasmosis (without qualification

regarding the limited situations where its use as adjunctive therapy maybe indicated),

“certain types of tuberculosis” (without qualification about the limited situations where it

may be indicated).

Insert does not warn about the following: increased potassium and calcium excretion,

development of cataracts, increased risk of ocular infections, risk of reactivation of

tuberculosis in those with a positive tuberculosis test (the insert lists tuberculosis as a

relative contraindication to glucocorticoid therapy).

Insert does not caution about the following: increased effect of steroids in hypothyroidism

and cirrhosis; risk of hemorrhage with concurrent administration of steroids and aspirin in

hypoprothrombinemia; risk of using systemic steroids in diseases where intestinal

perforation may occur, including recent intestinal anastomosis and diverticulitis; caution

about use in renal insufficiency; and caution about use in patients with myasthenia gratis.

Insert does not list inactive ingredients or preservatives.

Product is indicated for torticollis and is indicated for hay fever without qualification that the

use of systemic corticosteroids is only justified in severe cases of hay fever that are

intractable to adequate trials of conventional treatment.

Insert does not provide the following precautions: warning against vacdnating patients

who are receiving this corticosteroid; precautions regarding the enhanced effects of

systemic steroids in hypothyroidism and cirrhosis; caution about use in patients with ocular

herpes simplex, psychic derangements, and ulcerative colitis.

Insert has no information about use in pregnancy.

Insert omits significant adverse reactions, including fluid retention and electrolyte

disturbances, muscle weakness, peptic ulcers, and impaired wound healing.

1

1

2

2

2

2

R

2

2

2

R

2

2

1

2

Continued on next page
Addendum 3-4-Products With a Primary Overall Score of 3-Continued

overall Query

score Type of drug Source Category Nature of problem score

3 Systemic corticosteroid pi dcp

ind

wp

ar

3 Systemic corticosteroid pg

3 Thiuram-derivative drug used pi, pg

in alcoholism treatment

ing

wp

ar

dcp

ing

wp

ar

Insert does not have information about actions or pharmacokinetics.

Insert includes indications for hemodynamic shock and endotoxic shock.

Insert does not warn about increased calcium excretion with corticosteroid administration.

Insert does not have a warning about the possible need for salt or mineralocorticoid

replacement if mineralocorticoid secretion is impaired; insert does not note that the rate

of absorption with intramuscular administration is slower than with intravenous administration.

Insert does not list the following adverse reactions: congestive heart failure in susceptible

patients, hypokaiemic alkalosis, musculoskeletal side effects (e.g., muscle weakness,

steroid myopathy, decreased muscle mass, osteoporosis, vertebral compression fractures), pancreatitis, ulcerative esophagitis, thin fragile skin, petechiae and ecchymoses,

facial erythema, increased sweating, suppression of reactions to skin tests, convulsions,

pseudotumor cerebri, headache, menstrual irregularities, suppression of growth in

children, secondary adrenocortical and pituitary unresponsiveness, particularly in times of

stress, ophthalmic disorders (cataracts, exacerbation of glaucoma etc.), blindness with

intralesional therapy around the face and head, negative nitrogen balance, hyperpigmentation, hypopigmentation, subcutaneous atrophy, sterile abscess, Charcot-like arthropathy.

Entry does not list inactive ingredients.

Entry does not warn about patients’ decreased resistance to infections while on steroids.

Entry does not describe with specificity the adverse reactions associated with corticosteroids.

Entry has no warning about blood pressure elevation.

Insert does not have section on clinical pharmacology.

Insert does not list chemical or structural formula or inactive ingredients.

Insert does not warn against possible severe reactions to this product.

Insert does not warn about carcinogenicity.

Insert does not contain a suggestion that patient carry an ID card indicating that he or she

is taking this drug.

Insert does not have warning about possible reaction with alcohol that may occur in hepatic

insufficiency and in patients with cerebral damage.

Insert states that “precautions should be taken” when using this product in concomitant

conditions (such as diabetes and hypothyroidism) but does not state specifically that these

conditions may elicit an accidental reaction.

insert does not alert physicians to the possibility y that patients who are dependent on

alcohol may also be dependent on narcotics and sedatives.

insert does not list all of the characteristics of the reaction of this drug with alcohol.

insert states that this drug “does not produce any side effect unless an alcoholic drink is

ingested.”

1

2

1

2

2

R

2

2

1

1

R

2

1

1

2

2

1

1

2

u

zm
3 Topical corticosteroid oral paste

3 Topical nitrofuran antibiotic

3 Tricyclic antidepressant

pi

pi

pg

dcp

ci

wp

ar

dcp

ing

wp

dcp

ing

wp

ar

da

od

Inadequate evidence to justify statement in insert that [w]hen, used topically in 0.1 %

concentration [this product] produces results clinically superior to 1% concentrations of

other corticosteroids.”

Insert does not contraindicate product in patients with hypersensitivity to its ingredients,

and in patients with viral, fungal, or bacterial infections of the mouth or throat.

Insert does not warn about use in pregnancy.

Insert does not warn about masking signs and symptoms of infection.

Insert does not recommend further evaluation if substantial repair of oral tissues has not

occurred in 7 days.

Insert does not warn about adverse reactions that may occur from systemic absorption of

steroid preparations.

Insert does not describe the antimicrobial spectrum of this antibiotic.

Insert does not list inactive ingredients.

Insert does not caution about overgrowth of nonsusceptible organisms.

Insert does not warn that various skin reactions may occur.

Insert has no information about use in pregnancy.

Entry has no clinical pharmacology section.

Entry does not list inactive ingredients.

Entry has no warning about risk of developing extrapyramidal symptoms, tardive

dyskinesia or neuroleptic malignant syndrome.

There is no warning about the following: that this tricyclic antidepressant may cause an

exacerbation of paranoid symptoms in paranoiacs, the drug may cause manic depressive

patients to shift into mania the drug may cause schizophrenic patients to develop

increased symptoms of psychosis.

Entry does not include list of drug interactions other than with monoamine oxidase

inhibitors (e.g., alcohol, barbiturates, other CNS depressants, anticholinergics, and

interactions with electroconvulsive therapy).

Entry does not include admonition to prescribe this antidepressant in the smallest suitable

amount in view of the risks of suicidal overdose.

Entry lacks warnings about the following adverse reactions: skin rash, drug fever,

drowsiness.

There is no mention that dosage should not exceed 300 mg per day until this dosage is

tried for two weeks.

Entry does not have information about overdose.

1

2

1

2

2

1

2

R

2

1

1

1

R

2

2

2

2

1

2

2

Continued on next page

o
Addendum 3-4-Products With a Primary Overall Score of 3-Continued

overall Query

score Type of drug Source Category Nature of problem score

3 Xanthine-derivative bronchodi- pg dcp Entry does not include information on bioavailability (including differences in half-life for 1

Iator newborns, renal deficient patients, alcoholics, and smokers).

wp Entry does not warn about manifestations of toxidty from conventional doses and 2

excessive doses, including convulsions, tachycardia ventricular arrhythmias; or that

children may have a marked sensitivity to the CNS stimulant action of this drug.

Entry does not include caution about use in patients with liver impairment or severe 1

hypoxia.

Entry does not list drug interactions, such as with erythromycin, troleandomycin, and 1

Iincomycin.

ar Entry omits adverse reactions associated with this xanthinederivative bronchodilator, 2

including tachycardia extrasystoles, flushing, hypotension, circulatory failure, lifethreatening ventricular arrhythmias, tachypnea albuminuria increased excretion of renal

tubular cells and red blood cells, diuresis, hyperglycemia, syndrome of inappropriate

antidiuretic hormone.

od Entry does not include information on treatment of overdose. 2

SOURCE KEY: pi - package insert; pg. prescribing guide entry; pipa. package insert pending approval; pl -. package label; pds - product document.

CATEGORY KEY: dcp= description/clinical pharmacology; ing - ingredients; ind = indications; ci - contraindications; wp - warnings and precautions; ar - adverse reactions; da - dosage and

administration; od - ovedose information.
Results of the OTA Survey 89

Addendum 3-5-Products With Labeling That

Was Adequate Except for Failure To List

Inactive Ingredients

Type of drug Source

Aminoglycoside antibiotic for ophthalmic and otic

administration

Antacid

Anthelmintic drug

Antihistamine

B complex vitamin

Combination aminoglycoside and polymyxin

antibiotic for ophthalmic use

Combination synthetic opioid and aspirin

Corticosteroid for ophthalmic administration

Dietary fiber supplement

Long-acting nitrate vasodilator

Multivitamin and multimineral preparation

Multivitamin and multimineral preparation

Quinoline-derivative antiprotozoal agent

Selective alpha-blocking agent

Synthetic androgen

Topical analgesic combination

pi

pl

pg

pi

pi

pi

pi

pi

pg

pi

pi

pi

pi

pi

pi

pi

SOURCE KEY: pi - package insert; pg - prescribing guide entry; pl -

package label.

Addendum 3-6-Products With Labeling That

Was Not Evaluated Fully (Score = NA)

Type of drug Source

Aminoglycoside antibiotic

Aminoglycoside antibiotic for ophthalmic and otic

administration

Anabolic steroid

Anesthetic for ophthalmic administration

Anticholinergic antispasmodic

Arterial vasodilator antihypertensive

Artificial sweetener

Combination corticosteroid and antibiotic for

ophthalmic administration

Combination topical antifungal

Corticosteroid and anesthetic combination for

topical administration

Direct-acting arterial vasodilator

Methylxanthine bronchodilator

Multivitamin and multimineral preparation

Multivitamin and multimineral preparation

Multivitamin with iron and calcium

Nitrate vasodilator

Nitrate vasodilator

Opioid analgesic

Oral contraceptive

Penicillin-derivative antibiotic

Phosphoric acid-derivative antibiotic with

anesthetic

Polyene antifungal agent

Polyene antifungal and antiprotozoal agent

Quinolone antibiotic

Quinoline antiprotozoal drug

Systemic corticosteroid

Tetracycline analogue antibiotic

Thiazide diuretic

Topical anthelmintic

Vinca alkaloid antineoplastic agent

Vitamin and vasodilator combination

pi

pi

pi

pi

pi

pi

pi

pi

pl

pg

pi

pl

pg

pi

pi

pi

pi

pi

pg

pi

pi

pi

pi

pg

pi

pi

pi

pi

pi

pi

pi

SOURCE KEY: pi= package insert; pg - prescribing guide entry; pl -

package label.
Drug Prescribing

Information

in the

United States and

Other Countries 4

T

he approval and labeling of pharmaceuticals sold in the

United States is governed by provisions of the Federal

Food, Drug and Cosmetic Act of 1938, as amended

(FDCA; 21 U.S.C. § 301-392). The Food and Drug

Administration (FDA), within the Public Health Service of the

Department of Health and Human Services, administers this

Act. Under the FDCA, new drugsl cannot be marketed in the

United States without explicit FDA approval, which is dependent on meeting the evidentiary criteria of detailed regulations

that assure, to the extent possible, the safety and efficacy of

pharmaceuticals. At the time of drug approval, proposed labeling must meet statutory requirements that have been translated

into specific regulations addressing content and format. Review

of all labeling materia12 for pharmaceuticals is a critical part of

FDA’s New Drug Application (NDA) process. The approved labeling provides information to physicians, pharmacists and, in

certain cases, consumers. It also sets the legal bounds for promotional claims for the drug and for warnings and other infor1 A drug is considered a new drug under the FDCA if: 1) it contains an active ingredient that has never been marketed in the United States; 2) it contains a derivative of an

active ingredient i.e., the active ingredient is a chemical derived from an active ingredient already marketed; 3) it is a combination of two or more known and approved ingredients not previously marketed together in a single product; or 4) it is a drug already on

the market, but it is to be marketed for use under different conditions, in a different

dosage form for a new therapeutic use, in a new formulation or is manufactured in a different manner (157,244) (21 U.S.C. § 321(p)). A modification in the formulation includes a change in the active ingredient(s), inactive ingredients (excipients), preservatives, flavors, and/or dyes (222).

2 “Labeling” includes both the “label,” which is defined as a display of any written,

printed, or graphic matter on the “immediate container” of the drug, and any written,

printed or graphic matter that accompanies the drug, including package inserts, containers and wrappers 21 U.S.C. § 321(k)(m).

1I

91
92 I Drug Labeling in Developing Countries

mation that must be disclosed in advertising and

promotion of the drug (157).

Physicians, however, are not limited in prescribing to only those uses approved by FDA;

they are permitted to use drugs “according to

their best knowledge and judgment” (44 FR

37434). “Off-label” uses of prescription drugs

are common and include uses for which there is

substantial and convincing evidence of safety

and efficacy (but which the sponsor has never

submitted to FDA for consideration) as well as

many uses for which convincing data of efficacy

are absent. Many off-label uses of pharmaceuticals are medically acceptable and, for the purposes of this study, the medically acceptable indications for products are not limited to those

indications that are approved by the FDA. FDAapproved labeling was not used as a “gold standard.”

This chapter describes the FDA labeling requirements for prescription and over-the-counter

(OTC) drugs sold in the United States and for

those exported to other countries, and discusses

parts of the drug approval process that are relevant to labeling. The off-label use of prescription

drugs in the United States is also discussed. The

chapter ends with a brief discussion of some aspects of pharmaceutical labeling in other industrialized countries that may help to explain why

those labels often differ from U.S. labeling, and a

description of drug information sources in developing countries.

U.S. DRUG LABELING LAWS AND

REGULATIONS

 Prescription Drug Labeling

Prescription drug labeling provides information that medical practitioners need in order to

use a drug safely and effectively in the care of

patients (44 FR 37437). Labeling consists of a

package label (including the immediate container and associated material, e.g., a box) and all

other labeling material included with the package, such as a package insert. FDA first required

that a package insert be included with most drugs

in 1961, with the intent of ensuring that every

drug was accompanied by adequate directions

for use, including indications; effects; dosages;

routes, methods, frequency and duration of administration; and any relevant warnings, side effects, and precautions (114, 25 FR 12592 (1960);

26 FR 8389 (1961)). Although FDA regulations

do not specifically require a package insert, it is

usually not possible to fit adequate directions for

use and warnings on a drug package (21 U.S.C. §

352; 21 C.F.R. § 201.100), so inserts have become standard for prescription drugs (21 U.S.C.

§ 352; 21 C.F.R. §201.22,201.50-.59, 201.100

and 21 1.137).

The package label for a prescription drug

must include:

1.

2.

3.

4.

5.

6.

7.

8.

the name and place of business of the

manufacturer, packer, or distributor;

the name or names of the drug, both proprietary and official or commonly recognized names;

the names and quantities of active ingredients and in certain cases, inactive ingredients;3

the route of administration;

a statement about the quantity of the container, such as weight, measure, or numerical count;

an identifying lot or control number;

a warning that “Federal law prohibits dispensing without a prescription;”

a warning that the product may be habit

forming, if applicable;

3 The following inactive ingredients, including quantity and proportio% must be included in the labeling: alcohol, bromides, ether, ch.lorofo~ acetanilid, acetophenetidin, amidopyrine, antipyrine, atropine, hyoscine, arsenic, digitalis, digitalis glycosides, mercury, ouabain,

strophant.l@ strychnine, thyroid, or any derivative, thereof (21 U.S.C. $ 352(e)(l)).
9.

10.

11.

— .

Drug Prescribing Information in the United States and Other Countries 93

additional warnings, when appropriate,

for products containing certain ingredients, e.g., phenylalanine or sulfites;

a recommended dose, and the expiration

date; and

a statement to the pharmacist indicating

the proper container for dispensing.

If there is insufficient space on the package,

certain information, such as dosage and route of

administration, may appear only on the package

insert (21 C.F.R. $ 201.100).

FDA regulations (21 C.F,R. $$ 201.56,

201.57) require that the labeling (which usually

consists of a package insert) contain adequate directions for use, including information in the following areas:

1.

2.

3.

4.

5,

6.

7.

8.

9.

10.

11.

12,

The

description of drug, including qualitative

and/or quantitative ingredient information;

clinical pharmacology;

indications and usage;

contraindications;

warnings;

precautions;

adverse reactions;

warnings about drug abuse and dependence;

overdosage information;

proper dosage and administration;

how supplied; and

date of most recent revision.

following sections may be included, if appropriate:

13. animal pharmacology and/or animal toxicology;

14. clinical studies; and

15. references.

FDA regulations (153, 21 C.F.R. § 201.57(f))

require significant detail in each information category. The “precautions” section, for instance,

must contain each of the following subsections:

1.

2.

3.

4.

5.

6.

7.

8.

9.

In

general precautionary information for the

physician;

precautionary information the physician

should provide the patient;

laboratory and clinical tests that can be

used to monitor the patient;

information on possible interactions with

other drugs, foods, or laboratory tests;

a summary of findings from animal studies

of carcinogenesis, mutagenesis, and impairment of fertility;

if applicable, information on any potential

for the drug to cause physical defects and

other harm to a fetus when taken during

pregnancy;

for drugs used during labor and delivery,

potential effects on the mother, or on the

later growth, development, and other functional maturation of the child;

precautions for nursing mothers; and

precautions for pediatric use.

contrast to most other countries, prescription drug labeling in the United States is directed

primarily to the physician. The patient usually

receives prescription drugs from a pharmacist in

a container that specifies, at a minimum, the

name and address of the dispenser, the prescription serial number and date it was filled, the

name of the prescriber, and, if stated by the physician in the prescription, the name of the patient,

directions for use, and cautionary statements (21

U.S.C. § 353(b)(2)). More detailed patient labeling, usually in the form of a patient package insert, is required when the risk of serious side

effects makes it essential that patients have complete instructions (157). Patient package inserts

are required for oral and injectable contraceptives, intrauterine devices, estrogens, and progestational products (21 C.F.R. § 501, 502, 515,

516). In other countries, including most developing countries, patients usually purchase prepackaged pills or liquids that come with a package insert (207).
94! Drug Labeling in Developing Countries

STANDARDS OF EVIDENCE

The FDA permits listing only those indications that can be supported by “substantial evidence of effectiveness based upon adequate and

well-controlled” clinical trials submitted to FDA

by the manufacturer for formal review (21 U.S.C.

§ 355(c)(3)(d); 21 C.F.R. § 201.57(e)). Warnings

must be placed on the label if there is a “reasonable association” between a drug and a serious

hazard; a causal relationship need not be proven

(21 U.S.C. § 355(d); 44 FR 37434). In addition,

the FDA may require warnings against using the

drug for specific, common, off-label indications

if there is a lack of substantial evidence of effectiveness and if using the product for those offlabel indications my result in serious adverse effects (21 C.F.R. § 201.57). In addition to the

items that must appear in labeling, there is also a

stricture that the label not contain any false or

misleading statements (21 U.S.C. § 353(a)). The

FDA may allow the manufacturer to omit any

clearly inapplicable section or subsection of the

labeling. (21 C.F.R. $ 201.56).

CHANGES IN LABELING

The FDA must approve all changes in labeling; however, companies may implement

changes that provide physicians with additional

safety information before receiving FDA approval. Changes of this type include:

●

●

●

adding information to, or strengthening, sections on warnings, precautions, adverse reactions, drug abuse or dependence, or overdosage;

adding instructions about dosage and administration that will increase the safe use of

the product; and

deleting false, misleading, or unsupported

claims for effectiveness.

Labeling changes that have little impact on the

safe use of the product may also be made without

FDA approval (e.g., minor editorial changes, an

extension of the expiration date based on data

from an FDA-approved study, a change in the

size of the container for drugs sold in pill or capsule form, or changes in information on how the

drug is supplied provided they do not alter the

dosage information) (21 C.F.R. $ 314.70). All

other changes require prior FDA approval (21

C.F.R. $ 314.70).

 OTC Drug Labeling

OTC products are sold directly to consumers,

and requirements for their labeling differ from

those for prescription drugs. OTC labeling must

contain adequate directions for use by the general public, adequate warnings against unsafe use,

and must be (51 FR 16259):

clear and truthful in all respects, not false or

misleading in any particular, and understandable to the ordinary citizen, including individuals of low comprehension, under customary

conditions of purchase and use.

Before purchase, the consumer will see only

the information on the outside package label, and

FDA specifies the format for information that

must appear there. The principal display panel

(the part of a label most likely to be presented,

displayed, shown, or examined under customary

conditions of display for retail sale) must identify

clearly the name of the product, state the quantity

of contents (e.g., 100 capsules, 125 milligrams

each), and include a statement identifying the

pharmacological category or principal intended

action[s] (e.g., analgesic, antacid, decongestant).

These identifying statements must be in bold

type of a size that is comparable to the most

prominent printed material on the package (a

minimum size of print is prescribed by regulation) (21 C.F.R. $5201.60, 201.61, 201.62). The

immediate container must also include a declaration of the active ingredients; the name of the

manufacturer, packer, or distributor; lot number;

expiration date; and any special warning required

by the FDA (e.g., presence of yellow dye no. 5 as

inactive ingredient or the Reye’s syndrome warning for aspirin-containing products) (21 C.F.R.
Drug Prescribing Information in

$$201.1, 201.17, 201.18, 201,20, 201.314(h)).

All this information must appear on the outside

labeling or be visible through the outside labeling.

Information on the ingredients, directions for

use, adequate warnings, and dosage information

must be included in the labeling, as it is for prescription drugs. In most cases, labeling covers the

entire package, and a package leaflet may also be

included (56, 21 C.F.R. § 201.1-201.20).

In 1972, the FDA began a review of OTC

drugs then on the market. This was an extension

of the Drug Efficacy Study Implementation

(DESI) that included all drugs with New Drug

Applications (NDAs) approved by the FDA before 1962. Both reviews were prompted by the

1962 amendments to the FDCA which, for the

first time, required that a manufacturer prove the

efficacy of a new drug (in addition to its safety)

before the FDA would approve it for marketing

(170). Because of the large number of OTC drugs

on the market (estimates varied from 100,000 to

500,000) (100), it was impractical to review efficacy data for each one. Instead, the FDA established panels of experts to examine products by

therapeutic class. As of July 1991, final monographs had been published for 33 classes of OTC

drugs including antacids, antibiotics (first aid),

stomach acidifiers, stimulants, and certain cough/

cold medicines (246). These monographs, and

others still under review, set forth the conditions

under which an OTC drug is considered safe and

effective, and they contain specific ingredient requirements, testing procedures, and labeling

standards (166, 21 C.F.R, Part 33 1).

With the exception of the indications section,

all other labeling information (e.g., directions for

use, statement of identity, warnings, etc.) must be

taken

the United States and Other Countries 95

verbatim from the OTC monograph (21

C.F.R. Part 330; 51 FR 16258). Labeling information for an OTC drug for which there is no

monograph is reviewed by the FDA on a productby-product basis, the same as for prescription

drugs (21 C,F.R. $$330.11, 330.12, 330.13).

 Advertising of Prescription and

OTC Drugs

FDA-approved labeling is the basis for all prescription and OTC drug advertising, and FDA

regulates promotional material for prescription

drugs. 4 OTC drug advertising is regulated primarily by the Federal Trade Commission (15

U.S.C, § 45, 52, 55). FDA regulations require

only that advertisements recommend or suggest

the product for the approved uses under the conditions contained in the labeling (21 C.F.R. §

330.l(d)).

FDA regulations for prescription drugs require

that every advertisement contain an accurate

summary of the side effects, contraindications,

and efficacy, consistent with the prescribing information contained in the package insert (21

U.S,C. § 352(n); 21 C.F.R. § 202.1 (e)).5 In addition, a prescription drug advertisement is subject

to a “fairness and balance” test. The advertisement must present a balanced account of the clinical information, i.e., the indications cannot be

overstated or the side effects and warnings minimized (21 C.F.R. § 202.1(e)). Misleading or false

information in one part of the advertisement cannot be corrected by a brief statement containing

accurate information in another part (21 C.F.R. §

201.l(e)(3)).

Regulation of advertising involves not only

judging the content of a particular advertisement,

but also deciding what constitutes an advertise4 Advertising includes all multimedia delivery of product information to prescribing physicians (170).

5 Reminder advertisements-advertisements that call attention to the name of the drug but do not include indications or dosage information-are exempt from including all clinical information. Instead, these advertisements need only contain the name of the drug, the active ingredients (and quantitative information on active ingredients, optional), quantity of package tiormatio~ and name and address of manufacturer, packer, or distributor (21 C.F.R. 202. l(e)(2)(i)), The FDA has the discretion to require more complete information if the use of the drug

is ‘associated with serious injuries or signit7cant incidence of fatalities (21 C.F.R. 202.1 (e)(2)(i)).
96 I Drug Labeling in Developing Countries

ment. Companies promote their products through

many different media, including press conferences, scientific symposia, supplements to medical journals describing company-funded studies,

and industry supported journals for physicians

(123). If the activity is purely educational, it does

not fall within FDA’s jurisdiction. However, if it

is primarily promotional it may be subject to

FDA review (123). The line between these two

activities is not always clear.

 Labeling of Pharmaceuticals for Export

FDA labeling requirements apply to drugs

marketed within the United States and are designed to protect U.S. citizens. The U.S. Government has no authority to impose U.S. labeling

requirements on foreign countries. The FDCA,

however, does address some aspects of labeling

for drugs exported from the United States.

EXPORT OF APPROVED DRUGS

Once a drug has been approved by FDA for

sale in the United States, it may be exported to

other countries either in unfinished (bulk) or finished (packaged in final dosage) form. If exported in finished form, it must (with a few exceptions) be accompanied by the FDA-approved

labeling, regardless of which country is receiving

it. Most pharmaceutical products exported from

the United States are not in finished dosage form,

but in bulk form for repackaging and labeling

abroad (178,243). One company in the OTA survey stated that less than 1 percent of its foreign

sales consist of exports of finished dosage form

pharmaceuticals that include FDA-approved labeling (96),

There is no statutory provision that permits a

company to export finished approved pharmaceuticals with labeling that differs significantly

from the FDA-approved version (45).

EXPORT OF UNAPPROVED DRUGS

One of the many and wide-ranging effects of

the 1938 FDCA was to curtail the export of drugs

that had not been approved in the United States

(69). This condition held absolutely until passage

of the Drug Export Act in 1986, which amended

the FDCA to allow limited export of unapproved

drugs under specified conditions.

The Drug Export Act was driven by the economics of the pharmaceutical industry. Congress

determined that the total ban on exports of unapproved drugs imposed hardships on the U.S.

pharmaceutical industry and the domestic economy without providing significant health benefits

(241). The reason was that some products developed by U.S.-based companies were approved

for sale in other developed countries before they

were approved for sale in the United States. Since

most pharmaceutical companies were multinational, they could shift their production facilities

abroad to avoid the export ban. Presented with

evidence from the congressional General Accounting Office and other experts that up to 70

percent of the pharmaceuticals approved in the

United States were first approved in another

country, the Senate Committee on Labor and

Human Resources concluded that the net result

of the export ban was to drive capital investment

and jobs abroad and widen the trade deficit (24 1).

Congress estimated that if exports of unapproved drugs were allowed, the U.S. economy

might benefit from an increase of between 2,482

and 40,000 jobs, and an increase in annual exports worth as much as $1.76 billion (241).

Provisions of the Drug Export Amendments Act

To be eligible for export, a drug must be

shown to be acceptably safe in preclinical tests

(including pharmacologic and toxicologic tests

on animals) and be under an approved

Investigational New Drug (IND) exemption for

clinical trials in human beings in the United

States (i.e., the manufacturer must be actively

seeking approval in the United States). An unapproved drug may be exported only to an industrialized country listed in the Act and only after the

country has approved its sale (21 U.S. C. §

382(b)(l)(B)). Twenty-one countries judged to
Drug Prescribing Information in the United States and Other Countries 97

have adequate regulatory systems are listed in the

Act, and the Secretary of HHS is given the authority to add others.

The U.S. exporter of an unapproved drug must

certify that all regulatory requirements of the importing country will be met (21 U.S. C. §

382(b)(l)(F)). In addition, the drug must be manufactured in accordance with current FDA standards for good manufacturing practice, must be

unadulterated, and the manufacture of the drug

for export must not have an adverse impact on the

public health or safety of U.S. citizens (21 U.S.C.

§ 382(b)(l)(D),(E)). The exporter must also obtain a written agreement from each importer stating that (69):

●

●

●

the importer will not re-export the drug to a

country not included on the list of countries

to which unapproved drugs may be exported

from the United States,

the importer will provide the exporter with

any information on re-export of the drug,

and

the importer will maintain records of wholesalers to whom the drug is sold (21 U.S.C. §

382a(b) (3)(B) (vii)).

These latter requirements are designed to prevent

drugs from being re-exported to countries not on

the approved list6

.

The U.S. exporter must cease exporting a drug

if:

● the receiving country withdraws approval of

the drug, or withdraws the drug from sale;

● the drug is withdrawn from the U.S. approval process; or

 FDA rejects the drug for marketing in the

United States (i. e., does not approve the

completed New Drug Application) (21

U.S.C. § 382(c)(l)(A)-(C)).

Finally, the exporter must file an Annual Report

with the Secretary of Health and Human Services

demonstrating that the exporter is still in active

pursuit of FDA approval (21 U.S.C, § 382(c)

(l)(D)). As of April 1991, the FDA had approved

74 applications and 38 amendments (an amendment is submitted for approval to export to additional countries) for exporting drugs under the

Drug Export Amendments (60).

There is no U.S. label for unapproved drugs,

and the only labeling requirement for drugs exported under these provisions is an outside shipping label stating that the drug may be sold or offered for sale only in the countries to which

export of the drug is authorized.

Selection of Countries Listed in the Drug Export Act

Congress selected countries for listing in the

Drug Export Act only if they had “sophisticated

drug approval system(s) comparable” to the

FDA. In the original Senate bill, 15 “first tier”

countries were designated. These countries were

selected on the basis of having (241):

●

●

●

●

adequate resources to do comprehensive scientific and medical evaluations of the safety

and efficacy of the drugs evaluated,

sufficient resources to effectively regulate

the content of labeling,

sufficient resources to monitor adverse drug

reactions, and

a drug authority that had “general characteristics” of an effective regulatory authority

(e.g., appropriately trained personnel and

enforcement procedures).

Pharmaceuticals that were not approved in the

United States could be exported to these countries in accordance with the provisions discussed

above.

The original bill also designated “second tier”

countries, which the Secretary of Health and

6 A letter sent by 52 members of the European Parliament to Senator Edward Kemedy confirmed that re-export was a wncem since no

country in the European Community “has laws to prevent the re-routing of such imports to other countries” (69).
98 I Drug Labeling in Developing Countries

Human Services would select. These were to be

countries with adequate health authorities and the

means to assure that labeling of the unapproved

drugs would be consistent with labeling from

first tier countries. In essence, labeling used in

the first tier countries would be required in second tier countries as well. Finally, the bill recognized as a “third tier” those developing countries

with extensive health needs, but without the capacity to develop or test pharmaceuticals for

unique needs, particularly for “tropical diseases.”

These countries would be allowed to receive exports of unapproved drugs for these diseases only

(see discussion on Export of Tropical Disease

Drugs, below).

The final version of the bill was passed in a

hurried compromise reached after certain provisions of the Senate bill met with opposition from

members of the House Subcommittee on Health

and the Environment of the Committee on

Energy and Commerce (45,72). The compromise

bill passed with a single list of 21 countries that

could receive exports of unapproved drugs other

than tropical disease drugs, and the notion of first

and second tier countries was dropped (45). The

Secretary of Health and Human Services was

given authority to add to the list of 21 countries

using the same criteria as in the original bill; to

date, no counties have been added (21 U.S.C. §

382(b)(4)(B)). The current list includes all of the

European Community countries (except Greece)7

plus Australia, Austria, Canada, Finland, Iceland,

Japan, New Zealand, Norway, Sweden, and

Switzerland.

EXPORT OF TROPICAL DISEASE DRUGS

The Drug Export Amendments also contain

special provisions governing the export of unapproved drugs for tropical diseases, These provisions differ from those for all other unapproved

drugs in that they allow export to developing

countries with less sophisticated regulatory systems, and they allow export of drugs that are not

in the U.S. approval pipeline. This latter provision acknowledges that few manufacturers will

make an investment in pursuing FDA approval of

tropical disease drugs which have a negligible

U.S. market (72). For a tropical disease drug to

be eligible for export, the Secretary of Health and

Human Services must find “credible scientific

evidence;’ including human studies, that the drug

is safe and effective in the prevention or treatment of a tropical disease in the importing country (21 U..S.C. § 382(f)(l)(A)).

The procedural requirements for exporting

tropical disease drugs are similar to those for

other unapproved drugs: the drug must be manufactured in accordance with current good manufacturing practices and must not be adulterated;

the manufacturing of the drug in the United

States must not pose a threat to U.S. public

health; the outside shipping package must carry a

statement that it is for export only and indicate

the specific counties in which it may be sold; the

drug must accord with the specifications of the

importer; sale of the drug must be in accordance

with the laws of the importing country; and finally, the exporter may not sell the drug in the

United States.

 Approval of New Drugs in the

United States

Before a new drug may be marketed in the

United States, it must be approved by the FDA,

following a process laid down in the FDCA and

codified in regulations. FDA’s approval process

must balance the need to assure the safety and efficacy of products entering the U.S. market with

the desire to make new therapeutic products

available as quickly as possible. A drug is defined as “new” if:

7 The European Community Countries included are: Belgi~ Denmar ~ France, Germany, Ireland, Italy, Luxembourg, the Netherlands,

Portugal, Sp@ and the United Kingdom,
Drug Prescribing Information in the United States and Other Countries 99

●

●

●

●

it contains an active or inactive ingredient

that has never been used in a pharmaceutical

marketed in the United States;

it contains a derivative of an active ingredient, i.e., the active ingredient is a chemical

derived from an active ingredient already

marketed;

it is a combination of two or more known

and approved active ingredients that were

not previously marketed together in a single

product; or

it is already on the market but is to be marketed for use under different conditions, in a

different dosage form, for a new therapeutic

use, in a new formulation,8 or is manufactured in a different manner (157,244) (21

C.F.R. § 310.3(a)).

If a company seeks to market a product that duplicates one already on the market (but no longer

under patent), it is also subject to FDA review,

but the process may be an abbreviated one (222).

In each case, the company seeking FDA approval

for marketing must submit ample evidence that

the drug is both safe and effective for the recommended uses.

The safety and efficacy of a new drug is

demonstrated with evidence gathered by the

company from laboratory, animal, and clinical research. Highly specific FDA regulations guide

the types of studies required and allowed (particularly once clinical trials begin). The research,

development, and review process for a new drug

comprises four stages: preclinical research and

preparation of an Investigational New Drug

Application (IND), clinical trials, approval of

New Drug Application (NDA), and postmarketing surveillance. The complex process of development and approval can take many years to

complete. In 1988, the FDA estimated that the

preclinical research and development phase takes

an average of 18 months, clinical research averages 5 years, and the NDA review process, 24

months. These periods are subject to considerable variability, however, and in extreme cases,

the approval process may take up to 15 years

(244).

PRECLINICAL RESEARCH AND THE

INVESTIGATIONAL NEW DRUG APPLICATION

Preclinical research covers the period between

identification of a chemical or biological agent

that may have therapeutic value and the submission of an application to the FDA requesting permission to begin studies in human beings. During

this

and

●

●

time, experiments are conducted in vitro9

in laboratory animals to determine whether:

the substance is likely to provide a therapeutic benefit in humans and

the administration of the substance, under

tightly controlled circumstances, is not likely to cause undue harm or otherwise unreasonably endanger human subjects (235) (21

C.F.R. § 3 12.23(8)).

During this phase, the company carries out toxicologic and pharmacokinetic studies to determine how the drug is metabolized and excreted in

animals, and what the lethal dose is in several animal species (235).

When data are sufficient to justify clinical tests

in humans, the company submits an IND application to the FDA. Technically, the IND is a request

for an exemption from the legal prohibition on

the interstate transport of unapproved pharmaceutical products (21 U.S.C. § 355(a)). However,

it is far more than a technical step. FDA scrutinizes the IND application and will not permit

clinical trials unless the pharmacologic and toxicologic information gathered from in vitro and

animal studies adequately supports the sponsor’s

8 In addition to the active ingredient, ahnost all drugs contain one or more of the following: inactive ingredients (excipients), preservatives, flavors, and dyes. Any modification in formulation can affect a drug’s activity (222).

9 In vitro studies include all laboratory tests carried out on biochemical elements, cell cultures, and isolated animal organs.
100 I Drug Labeling in Developing Countries

conclusion that it is “reasonably safe” to conduct

studies in humans (21 C.F.R. § 312.23(a)(8)). In

addition, the design of the proposed initial clinical trials must be such that valid evidence, satisfying the statutory standards for safety and efficacy, will be produced by them, and that risk to

human subjects will be minimized (52 FR 8798).

The FDA also requires that the clinical trial be

approved by the Institutional Review Board

(IRB) of the institution at which it will take

place. The primary function of the IRB is to “assure the protection of rights and welfare of the

human subjects” (21 C.F.R. § 56.102(g)). To further insure the safety of the human subjects, the

FDA requires prompt reporting of any seriousl0

and unexpected adverse reactions associated with

the use of the drug (21 C.F.R. § 312.32).

The IND contains the first sample of labeling

material in the form of a brochure that will be

provided to each clinical investigator.11 The investigator’s brochure must contain a complete

description of the drug substance and chemical

formulation, if known; a summary of the pharmacologic and toxicologic effects of the drug in animals and, if known, in humans; a description of

possible risks and side effects to be anticipated

on the basis of previous experience with the drug

or with similar compounds, and requirements for

special precautions and monitoring during the

clinical trials (239) (21 C.F.R. § 312.23 (a)(5)) .12

The investigator’s brochure is updated as the

clinical trials proceed (21 C.F.R. § 312.55).

If the FDA does not issue a “clinical hold”

order within 30 days of receiving an IND application, the sponsor may begin clinical trials (21

C.F.R. § 312.40). FDA’s involvement in the drug

approval process begins once the IND is allowed

to proceed. The FDA must be kept apprised of

ongoing clinical trials through annual reports,

amendments, and safety reports (21 C.F.R. §

312.30-33). The IND becomes a working document for the sponsor and the FDA as the drug

moves through the clinical testing phase. Although FDA does not manage the clinical trials, it

has the legal authority to monitor progress and to

halt further studies if necessary (21 C.F.R. §

312.42).

CLINICAL TRIALS

Clinical trials are conducted in three stages,

though the divisions are somewhat arbitrary—

FDA describes the process as “organic and evolutionary” (52 FR 8798, 8806 (1987 )).13 Phase I of

clinical testing focuses on safety, and accordingly, the FDA protocol review is limited to safety

issues (21 C.F.R. § 312.22(a); 52 FR 8798, 8806

(1987)). These trials provide data on how the

drug is metabolized in the body and its effect on

the various organs and tissues, including side effects associated with increasing doses (21 C.F.R.

§ 312.21). Phase I studies may also provide some

early evidence on effectiveness. Phase I trials

generally involve a relatively small number of

healthy volunteers (20 to 80 people) who take the

drug for a short period of time (21 C.F.R. §

312.21). These studies measure changes in the

individuals taking the drugs, and do not usually

compare them with a “control” group. According

to the FDA, about 80 percent of the drugs that

enter Phase I do not lead to NDAs (53 FR 8798,

8807). Often, toxic effects at doses too small to

10A ~e-iou~ ~va~e ~g effect in humans is defined as cancer, a congenital ZiIIOWdY, or a fati, ~e-~=tening, or P rmanently disabling

event. A serious adverse drug effect in animal studies is defined as evidence of mutagenicity, teratogenicity, or carcinogenicity (21 C.F.R.

312.32; 52 FR 8798 (1987)).

11 ~~vestigator is the ~son who ac~ally conducts the clinical investigation by directing the adminhation or dispensing of the drug

to the subjects. There maybe more than one investigator for a single study.

12 H the &ug WM used previously for another indicatio~ or if the drug was approved in anothn Country, me sponsor WY have information on prior use in humans.

13 ~s description of tie p~ses of c~c~ M for new drugs does not apply in the SpeCfiCS tO Ce* therapeutic ClaSSM of ~g~ n~

tably anti-cancer and anti-AIDS agents, though the general principles are similar.
Drug Prescribing Information in the United States and Other Countries 101

provide a therapeutic benefit are revealed at this

stage (244) (52 FR 8797, 8807).

The purpose of Phase II and Phase III clinical

tials is to “distinguish the effect of a drug from

other influences, such as spontaneous change in

the course of the disease, placebo effect, or biased observation” (21 C.F.R. § 314.126). The design of the clinical trial is critical to insure that

the results are reliable. The FDA requires that a

“well-controlled” clinical trial have the following

elements (21 C.F.R. § 314.126(b)(3)):

● a clear statement of the objectives of the

study and the proposed or actual methods of

analysis;

● a design that permits a valid comparison

with a control group (patients that receive either a placebo, no treatment, or active treatment with a drug of known efficacy) or, in

special cases, comparison of historical experience in patients; 14

• the subjects selected have the condition

being studied, or have been exposed to a

condition against which prophylaxis is being

tested;

• the method of assignment of subjects to

treatment or control groups minimizes bias

and is intended to insure comparable groups

of subjects with respect to such variables as

sex, age, severity of disease, duration of disease, and use of medications in addition to

the drug being tested; and

• measures are taken to minimize bias by the

subjects, observers, and analysts of the data.

To support an indication for a drug, a company

must provide FDA with at least one well-controlled clinical trial demonstrating efficacy. In

most cases, two are required (100).

Phase II clinical trials may begin as soon as

Phase I studies have provided sufficient evidence

that there are no unacceptable safety risks, and

the investigators have sufficient information

about pharmacokinetic and pharmacologic effects to design scientifically valid studies (21

C.F.R. § 312.21) Phase II studies are designed to

provide the first clear demonstration of the efficacy of the drug for a particular indication, and to

identify short-term, common side effects and

other risks. They may test different dosage levels

and schedules, typically on 200 or so people who

have the condition for which the drug is being

tested, under highly controlled conditions (244)

(21 C.F.R. § 312.21).

Phase III studies are designed to measure and

evaluate the overall risks and benefits of the drug

(21 C.F.R. § 312.21). Often, several thousand patients will participate over several years, under

conditions more similar to clinical practice (244).

Because of the number of participants, Phase III

studies may reveal less common, though not truly

rare, side effects. Information about side effects

will be included in product labeling if the drug is

approved (244) (21 C.F.R. § 312.21(c)).

As clinical trials are progressing, the company

may be completing additional animal studies.

Depending on the nature of the drug, the sponsor

may have to test for special toxic reactions

caused by chronic use, or determine whether the

drug is carcinogenic, mutagenic, or impairs fertility (157,235). This information will be required for the product’s label. When all clinical

and animal studies are completed, the sponsor

may submit an NDA for approval to market the

drug.

NDA REVIEW

FDA regulations specify the format for presenting information and data in the NDA, and require certain analyses (21 C.F.R. § 314.50). Assessment of proposed labeling, which must be

supported by research findings, is part of the

NDA review. If the company wants to omit any

14 Historical con~ols Me gener~ly s~n as the weakest type of control and are used only ti special C-W% such w ~ s~dies of dis~es

with high and predictable mortality or studies of drugs in which the effect of the drug is obvious (e.g., general anesthetics) (21 C.F.R.

312.126(I))(v)).
102 I Drug Labeling in Developing Countries

section or subsection normally required in prescription drug labeling, it must explain why this

information is not necessary (21 C.F.R. $312.50

(c)(2)(i)). For example, if the drug is absorbed

systemically and there is no evidence that the

drug can cause any harm to a fetus, the required

precautions for use during pregnancy might be

omitted (157).

According to statute, FDA has 180 days to review an NDA, not including time waiting for additional information from the company (244) (21

C.F.R. § 314.100). The 180-day period is often

extended, in large part because the company may

be required to submit amendments (244,248) (21

C.F.R. § 314.160). During the review period, the

sponsor must submit quarterly reports with any

new safety information about the drug that might

affect labeling statements about contraindications, precautions, warnings, and adverse reactions (21 C.F.R. $314.50 (vi)(b)), and to propose

amendments to labeling based on these findings.

In the end, an NDA may consist of 2 to 15 volumes of summary data and 10 to 100 volumes of

raw data (consisting of more than 100,000 pages

of text, data tabulations, statistical analyses, and

patient case report forms) (235,244). In 1989,

FDA estimated that the average approval time for

a completed New Drug Application was 30.9

months and the median was 25.9 months

(83,245). Some drugs are given higher priority

and are reviewed in shorter time.15

Once the FDA has completed its review, it will

either not approve the product or it will approve it

with or without certain changes in labeling or restrictions on conditions of marketing (21 C.F.R.

$$314.110, 314.120). If the sponsor accepts the

changes and restrictions that the FDA requests,

the drug may be marketed. The NDA will be rejected if the sponsor has failed to submit sufficient evidence to demonstrate the safety and efficacy of the drug under the proposed conditions

for use (21 U.S.C. § 355(d); 21 C.F.R. § 314.125;

50 FR 7452, 7486). An NDA will also be rejected

if the proposed labeling does not comply with the

specific requirements in Part 201 of the FDA regulations (21 C.F. R. Part 201; 21 C.F. R. §

314.125) A sponsor whose NDA is not approved

may amend the application, withdraw it, or request

a hearing (21 C.F.R. § 314.120).

 Post-Marketing Surveillance

The approval of an NDA does not mark the

end of a sponsor’s obligation to submit data to

FDA. The sponsor must continue to monitor the

performance of drugs in the market and must

submit various reports to FDA summarizing its

findings. FDA imposes post-marketing surveillance reporting because the marketing of the drug

to a much larger population than included in clinical trails may result in the discovery of rare, latent, or long-term adverse effects (50 FR 7452,

7471).

The company must file a report within 15 days

of discovering either a new adverse drug experience that is serious and unexpected or that an expected serious reaction is occurring with increased frequency (21 C.F.R. § 314.80; 50 FR

7452,747 1). The sponsor must also file quarterly

reports for the first 3 years after a new drug is approved, summarizing all other adverse reactions

and providing an overview of all safety-related

information gathered over that period. After the

initial 3 years, these reports may be submitted annually (21 C.F.R. § 314.80). The sponsor must

file another annual report summarizing all significant new information that might affect the labeling, safety, or effectiveness of the product (21

C.F.R. § 314.81). The sponsor must also file

copies of mailing pieces, labeling, or advertising

devised for the promotion of the drug at the time

15 Unti JmW 1992, tie FDA tied new drugs on the basis of chemical type and the perceived POtentid benefit. k general, a new mOlecular entity was given a higher ranking than a new formulation of a drug already on the market. The FDA recently revised the classifications

into two categories: “priority” and “standard.” Promising drugs for AIDS have been given especially high priority (100,239).
Drug Prescribing Information in the United States and Other Countries 103

of initial public dissemination (21 C.F. R. §

314.81(3)).

These reporting requirements insure that companies continually monitor the safety and efficacy of their products. The discovery of a new side

effect or adverse reaction may prompt a change

in labeling, or in rare cases, withdrawal of the

drug from the market (50 FR 7452, 747 1).

Failure to respond to new safety and efficacy data

may place the label in violation of FDCA’s requirement that it not contain any false or misleading statements, or the company may find itself

subject to a product liability suit if the omission

leads to personal injury.

 The DESI Review

The 1962 amendments to the FDCA propelled

U.S. drug regulation into the “modern” era by requiring that sponsors prove the efficacy of their

products before they could be sold. This was the

first major overhaul of the law since amendments

in 1938, which for the first time required a showing of safety. The provision requiring evidence of

efficacy applied not only to new drugs, but also to

drugs approved between 1938 and 1962. Like all

other major industrialized countries, thousands

of products were on the U.S. market, most having

been approved at a time when standards for clinical trials had yet to be developed. Nonetheless,

the FDA was required to review the evidence of

efficacy for all these products and determine

whether they met the new criteria for approval

(see above, Drug Approval section).

As an early step, FDA published a Federal

Register notice asking industry for effectiveness

data on all drugs approved between 1938 and

1962, They received responses on 3,443 drug

products with a total of 16,000 indications, each

of which had to be evaluated. FDA contracted

with the National Academy of Sciences (NAS) to

carry out the initial review. NAS formed 30 expert panels to evaluate the information, and completed the task in 1969. They found that almost

60 percent of the products had at least one “effective” indication; 6 percent had at least one “probably effective” indication; 19 percent, “possibly

effective;” and 15 percent, “ineffective” or “ineffective as a freed combination.” (For only 12.2

percent of the drugs were all indications “effective.”) They also reported that, overall, the drugs

were not effective for about 60 percent of the

therapeutic indications listed in the labeling

(215).

This was not the end of the process, since

eventually every product had to be classified either as having at least one indication for which it

was effective, and therefore marketable under the

amended FDCA, or as being ineffective for all indications. The middle categories could not remain. FDA took direct control over the remainder

of the process, which was named the Drug

Efficacy Study Implementation, or DESI.

Companies were invited to submit further data on

indications rated as less than effective and, if necessary, to carry out additional studies, developed

in consultation with FDA. All drugs undergoing

additional testing were allowed to remain on the

market until a final determination was made, but

each was required to carry a “DESI box” in the

labeling, stating the category in which it had been

placed by the NAS review (215).

As of May 24, 1984, the FDA had taken final

action on 3,355 individual drug products (98 percent). By that time, the percentage of products

with acceptable evidence of efficacy for at least

one indication rose from the original 60 percent

to 64.6 percent. Very few products (3 percent)

that had been judged “ineffective” by NAS were

later determined to be “effective,” but about 39

percent of the “probably effective” category and

about 18 percent of the “possibly effective” category were eventually judged effective.

Many fixed combination products were casualties of the DESI process. Products rated as “ineffective as a fixed combination” had at least one

effective drug component, but either lacked evidence of a therapeutic contribution of each of the

other drug components or the fixed dosage relationship was considered unacceptable for reasons
104 I Drug Labeling in Developing Countries

of safety (215). The DESI review led FDA to

publish regulations specifying when a combination drug is acceptable (21 C.F.R. § 300.50; 36

FR 3126; 36 FR 20038). Two or more drugs may

be combined in a single dosage form when each

component makes a contribution to the claimed

effects and the dosage of each component

(amount, frequency, duration) is such that the

combination is safe and effective for a significant

patient population requiring the concurrent therapy provided by two or more active ingredients

(21 C.F.R. § 300.50). A second active ingredient

may also be included if it enhances the safety or

efficacy of the principle active ingredient, or if it

minimizes the potential for abuse of the principle

ingredient (21 C.F.R. § 300.50).

The DESI process changed not only which

drugs remained on the market, but also the labeling of those drugs, which had to meet the new

standards of the 1962 amendments. The NAS

panels had been critical of the labeling they

found initially, characterizing it as “poorly organized, repetitive, out-of-date, evasive and promotionally oriented” (215). Had the DESI process

not taken place, the companies themselves would

undoubtedly have made some of these changes,

but some might have occurred much later or not

at all.

Other countries have, to varying degrees,

taken steps to remove ineffective older products

from the market and to improve the labeling of

those that remain, but their efforts have rarely

been as thorough as the DESI process.

 “Off-Label” Use of Prescription Drugs

In practice, U.S. physicians are guided in their

drug prescribing only partially by FDA-approved

labeling. Physicians may prescribe drugs not

only for approved indications but also for unapproved (“off-label”) indications. Some unapproved indications are appropriate and based on

sound scientific evidence, but others may be

based on little or no evidence, and may be useless

or even harmful when used for those indications.

Unless formal application is made to the FDA,

with evidence from well-controlled clinical trials,

as is required for NDA approval, these other indications may never be evaluated fully and will not

appear on the label. Pharmaceutical companies

are prohibited from promoting their products for

unapproved indications, but unapproved indications appear commonly in medical literature, and

some achieve a somewhat formal status by their

listing in respected drug compendia (see below).

The “medical importance” standard used by

OTA in evaluating foreign labeling for this project is described in chapter 2. This discussion of

off-label drug use further explains OTA’s rationale for supplementing FDA-approved indications

with indications from recognized compendia and

using expert opinion as the final arbiter of decisions on the appropriateness of the labeling of

survey drugs.

The practice of off-label prescribing has been

a longstanding topic of discussion. For many

years, individual physicians were concerned primarily with potential malpractice claims for prescribing outside of FDA-approved indications.

More recently, concern has shifted to questions

of reimbursement by insurers for products prescribed for unapproved uses (167). FDA’s position is not that unlabeled uses are illegal; in fact,

FDA has no official position on unlabeled indications unless and until the drug’s sponsor submits

an official petition for a labeling change. FDA

made its position known in a 1982 article that

stated that unlabeled uses of drugs might represent the very best medicine or might be extremely hazardous, but it stressed that the medical literature and drug compendia are often more up to

date than the approved label. At the same time,

FDA did not sanction information appearing

elsewhere as equivalent in quality to the FDA-approved label (167).

Despite continued interest, almost nothing had

been done until fairly recently to quantify the extent of drug use for unapproved indications. Two

recent studies, published in 1991, have confirmed

high rates of off-label prescribing: one study
Drug Prescribing Information in the United States and Other Countries 105

(203) examined a selection of 15 popular outpatient drugs and the other (126) focused on cancer

chemotherapeutic agents. A lower rate of offlabel prescribing was found in a study of pediatric inpatients (217).

Serradell and Patwell used claims for physician visits and outpatient prescription drugs from

a large prepaid health plan to determine the extent of drug use for indications other than the

FDA approved ones, and to identify some patterns of use (203).

The analysis was based on claims made during

the frost half of 1988 for 15 drugs which were

linked with physician visits where these drugs

were prescribed. Sample drugs were chosen

among: 1) oral or topical dosage forms, and 2)

those “most frequently mentioned by surveyed

physicians working in outpatient clinics” from a

descriptive study of unlabeled indications (202).

Drugs for AIDS and cancer were excluded.

The final analysis was based on 8,339 diagnosis-prescription pairs, placed in the following categories:

1.

2.

3.

4.

5.

FDA-approved indication;

“non-label” use, meaning it is not an FDAapproved indication but is mentioned in

major drug compendia;

unknown;

prescribed for “general symptoms;” and

“non-indicated,” meaning it is listed in the

USP Drug Information compendium (247)

as an indication for which the drug should

no? be prescribed.

Combining the “non-label” and “non-indicated”

categories, from 22 percent to 50 percent of the

prescriptions for each drug were written for offlabel uses, with an average of about 30 percent.

One limitation of this study is that some errors

probably occurred in matching diagnoses with

prescriptions, but the error is unlikely to be so

great as to materially change the results of the

study.

The General Accounting Office (GAO), an

agency of the U.S. Congress, surveyed a sample

of oncologists to find out about their off-label use

of anticancer drugs (126). The Senate Committee

on Labor and Human Resources asked GAO to

investigate this issue because health insurers had

begun denying reimbursement for off-label cancer drug use, causing oncologists to alter, or to

consider altering, the way they practiced medicine. This issue had become a source of friction

between third-party payers and the medical community.

The sample of oncologists was chosen to be

nationally representative and to represent “11

States with the highest prevalence of cancer.”

They were asked to “provide information on age,

sex, disease, and drugs prescribed for the next

three patients they met with after receiving the

questionnaire” (the study had two other parts that

will not be discussed here). Fifty-six percent of

the 1,470 oncologists contacted responded to the

survey, so the analysis was based on 681 oncologists reporting on their treatment of 2,018 patients.

Out of more than 5,000 drug administrations,

one-third were for off-label uses. About 9 percent

of the off-label uses were for indications not cited

in the major prescribing compendia. More than

50 percent of all patients received at least one

drug for an off-label indication. The extent of offlabel use varied with the type and stage of cancer.

In general, off-label use was higher for patients

who had cancers for which there was no generally accepted treatment, and for those with more

advanced disease (126).

Pediatric drug prescribing presents a particular

problem because most drugs have not been tested

in children and therefore cannot be labeled for

their use. Only one study has examined the rate

of off-label pediatric drug use. The study examined the drugs prescribed for inpatients at a children’s hospital over a 3-week period. (217). The

appropriateness of each off-label use was judged

by a group of experts who had evaluated the literature on each unlabeled indication. The investi-
106 I Drug Labeling in Developing Countries

gators found that 7 percent of the 951 prescriptions written were for unlabeled indications, and

of those 7 percent, about 40 percent were considered appropriate. About 15 percent of the unlabeled uses were considered inappropriate, and on

the remaining 45 percent, the experts did not

reach consensus.

These studies demonstrate that off-label use of

drugs is widespread; however, only the last study

attempted to determine how much off-label use is

“medically appropriate.” In an editorial in the

Journal of the American Medical Association accompanying the GAO article (158), a prominent

Mayo Clinic oncologist discussed the ways physicians may rationalize off-label drug use in cancer treatment:

●

●

●

●

●

because there are delays in FDA approvals

for new indications;

because there is no incentive for a company

to seek approval for new indications if a

drug is no longer under patent;

because for rare tumors it is impossible to

carry out definitive clinical trials;

because current standards for approval, requiring evidence of improved duration or

quality of life, are too stringent; or,

the weakest argument of all, because patients and their families demand treatment,

even when none is likely to help.

FDA’s 1982 policy statement on unlabeled

uses of drugs mentioned the existence of compendia and literature that might appropriately be

consulted for prescribing information, though the

statement did not include any particular publications by name. Among the most prominent in the

United States are the United States Pharmacopeial Convention’s Drug Information for the

Health Care Professional (USP DI) (247), the

American Medical Association’s Drug Evacuations (7), and the American Hospital

Formulary Service’s Drug Information (8). All

three of these publications contain some information about nearly all of the products sold in the

United States (and Canada, for the USP Dl).

They all represent consensus opinions of medical

specialists, and all contain information about unlabeled indications. According to an analysis of

the USP DI database in 1990, more than 25 percent of the accepted indications listed were not

approved by the U.S. FDA or by the Canadian

regulatory authority. The specialty area with the

highest percentage of unlabeled indications was

oncology; more than 50 percent of the indications accepted by the USP DI were not approved

in the United States or Canada (121).

OTA chose generally not to question companies about off-label uses listed in the foreign labeling if they were mentioned in prominent U.S.

drug information compendia. In the majority of

these cases, OTA did not evaluate the evidence of

efficacy independently, but chose to avoid becoming embroiled in disputes over the evidence,

or lack thereof, for uses accepted by the U.S.

medical community.

DIFFERENCES IN DRUG LABELING

AMONG INDUSTRIALIZED NATIONS

Multinational corporations must abide by the

laws of the countries in which they operate. A

pharmaceutical marketed in Germany by a U.S.

multinational must be labeled in accordance with

German law, and the label may well differ from

U.S. labeling. Registration requirements (including labeling provisions) differ somewhat among

industrialized nations, but it is assumed that all

such countries have the resources and expertise to

enforce these requirements. Differences among nations in philosophy of drug approval and labeling, differences in the practice of medicine, and

differences in the history of drug regulation all

may affect what ultimately appears on a drug

label. In the course of this study, OTA was criticized by a number of companies participating in

the survey for relying to a great extent on the U.S.

labeling in its evaluations; these companies argued that labeling from other industrialized

countries was often at least as, if not more, relevant. What follows is a brief discussion of some
Drug Prescribing Information in the United States and Other Countries] 107

of the major sources of difference in labeling

among industrialized nations. It is beyond the

scope of this study, however, for OTA to evaluate

in detail drug labeling regulations of the various

industrialized countries. These regulations are in

a state of flux owing in part to ongoing “harmonization” of regulations among members of the

European Community. For the purposes of this

report, however, the laws and regulations affecting labeling of the late 1980s are most relevant.

 Differences in Labeling Objectives and

Standards of Evidence

The FDA-approved package insert is intended

to inform the practicing physician about a product, and to serve as a reference for key information. In other countries, only the judgment of the

drug regulatory authority is presented on the

label, without reference to the scientific evidence

on which the judgment was based (23). In

Germany, for instance, as of 1986 the law required only patient package inserts and not physician inserts (190). Germany and other countries

may rely on physicians acquiring knowledge

about drugs from other sources (23).

Not all countries require the same type of evidence for drug approval of efficacy for labeled

indications as the United States. The regulatory

agencies of France and Germany, for example, do

not necessarily require demonstration of efficacy

by placebo-controlled randomized clinical trials;

in some cases observational trials may be sufficient (132,190). In Germany, proof of safety and

efficacy were not required until 1978. Prior to

that time, the German drug law required only that

manufacturers register pharmaceuticals, and permitted the drug regulatory authority to prohibit

the sale of a product only if it was found to produce intolerable side-effects (190). Prior to 1978,

there were 145,000 drugs on the market; the

German Government allowed these products to

remain on the market until the end of 1989, at

which time it was required that they be submitted

for approval on the same basis as new pharmaceuticals (190). Similarly, in France the standards

for review of new drugs were substantially revised in 1976, and drugs marketed prior to 1976

were to be reviewed between 1984 and 1990

(214).

 The Approval Process

The manner in which drugs are approved may

influence the content of the labeling. In France

and Germany, committees of outside experts are

brought together to evaluate the safety and efficacy of the drugs (190,252). In the United Kingdom, consultants and academic experts work

with the staff of the Medicines Control Agency

(the regulatory authority) to evaluate new drugs.

In the United States, the technical evaluation is

carried out by FDA staff, although FDA has the

option to use advisory committees of outside experts (51). Some have suggested that in countries

in which individual professional drug regulators

(as opposed to committees) are responsible for

approving a drug (as in the United States), there

is a greater tendency to err on the side of safety

(51). Although no single person is responsible for

new drug approvals by FDA, individual reviewers are responsible for preparing summary reports on the NDA, which may become the basis

of the approval. This contrasts with many

European countries, where responsibility for an

official decision is delegated to an expert committee (51 ). Also, unlike the United Kingdom,

France, or Germany, the FDA has strict rules prohibiting individuals with conflicts of interest

from participating in drug reviews (44).

COMPANY DEVELOPMENT OF

INTERNATIONAL PRODUCT LABELING

All companies have some explicit policies and

procedures for developing labeling information

for new drugs and for updating existing labeling.

OTA asked the companies participating in the

survey to provide information on their labeling

policies. This brief discussion highlights the sim-
108 I Drug Labeling in Developing Countries

ilar and dissimilar features of various company

policies. Some companies requested that this information remain confidential, so no company

names are given.

All companies state that their general objective in labeing is to provide full disclosure of information about their products. In a practical

sense, the centerpiece of most labeling policies is

a product document developed by the medical

and regulatory staff at corporate headquarters.

This may be called the “Medical Guideline

Sheet;’ “Corporate Product Document,” “Global

Prescribing Information,” “International Product

Document,” or another name.

Well-stocked pharmacy in Thailand.

Product documents are used to develop labeling for each country in which the product is sold,

but the degree to which the full document is reproduced varies. One company stated that the

product document is translated and submitted as

a proposed package insert to the local authority.

Another company submits labeling of the exporting country (an industrialized country in nearly

all cases) to the local authority for drugs sold in

developing countries, rather than reverting to the

original product document. Another company

stated that subsidiaries may request from headquarters deviations from or modifications to the

text of the product document to comply with

local requirements. Another stated that the product document is used in “negotiations” with local

regulatory authorities. All the companies require

modifications of the product document to be reviewed and approved at corporate headquarters.

Most companies described procedures for updating product documents and country-specific

labeling. Some companies require review of

company-specific labeling at the time of re-registration, where that is required (e.g., every 5 years

in Panama). One company described a labeling

review procedure carried out by visiting auditors.

All companies require notification of subsidiaries

when a product document is updated.

These procedures differ for some companies

for “local” products, i.e., those manufactured and

sold locally or regionally, but not worldwide. For

local products, proposed labeling may be prepared locally and then approved by corporate

headquarters.

One company’s labeling policy specifies in detail the required content of the product document.

Of particular interest for this study is the required

listing of inactive ingredients for all oral preparations. (No other policy submitted to OTA included this requirement.)

One of the most important factors that influences the labeling requirement of developing

countries is their ties to certain industrialized

countries, particularly as former colonies. Developing countries often have adopted the legal systems of former colonial powers, including their

drug registration and labeling laws. These countries may require that all new drug applications

include the labeling used in the former colonial

power. Kenya, for example, may look to English

labeling and Cameroon might look toward

France for labeling standards. Many companies

stated that the labeling used in developing countries should be assessed in light of the labeling

used in the former colonizing country. (See ch. 3

for discussion of how this was considered in

OTA’s evaluations.)
Drug Prescribing Information in the United States and Other Countries I 109

SOURCES OF PHARMACEUTICAL

INFORMATION IN DEVELOPING

COUNTRIES

Prescribing information in developing countries is usually available from the manufacturer

through package inserts, product monographs or

through other forms. Abbreviated prescribing information is made available through commercially produced local prescribing guides. In addition,

physicians may have pharmaceutical reference

texts. In many developing countries prescribing

guides are the most widely distributed and frequently consulted source of pharmaceutical information.

 Package Inserts and Labels

Virtually every country, regardless of its state

of development, has a system for registering drugs.l6

In general, drug registration systems in developing countries are less sophisticated than those of

the United States and other industrialized countries in what they require of companies and in the

way they review applications. Regulatory bodies

in developing countries rarely have the resources

or, in many cases, the expertise to carry out rigorous evaluations of new pharmaceuticals, including a thorough evaluation of the claims made

about products.

Most developing country drug registration

systems have some labeling requirements (159).

Many developing countries require that the outside package carry a significant amount of information (159,273). According to a World Health

Organization (WHO) survey, there is general

agreement on what categories of information

should appear in package inserts and/or on packaging and container labels. All together, the following information should be covered (107,273):

1. Brand name

2. Generic name

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Names of active ingredients

Content of the active ingredients per dose

Major indications for use

Precise instructions for dosage

Form of administration

Major side effects

Major precautions and contraindications

Major interactions

What to do in case of side effects or overdosage

Expiration date

Storage conditions (at least when special)

Name and address of manufacturer (or license-holder or distributor)

The registration and labeling requirements for

the four countries included in this study are summarized in appendix B.

zg

—------ .

Rural health facility in Kenya.

Although these labeling requirements appear

to be fairly comprehensive, they provide little detail about the content of the information to be included in each category. The drug regulatory authority is responsible for determining whether the

information submitted is complete and accurate.

lb Dmg ~egl~hation ~efms t. tie prWess by which tigs are approved for market@. k order to re@ster a ~g a comP~Y -Y‘Ub

mits information on the safety and, in some cases, efficacy of the drug, as well as the labeling text that the company proposes to include with

the drug.
110 I Drug Labeling in Developing Countries

This requires trained personnel who have the

time and resources to thoroughly evaluate the

proposed labeling submitted by a company

(107,159). Developing countries may need to

rely on the judgments of the regulatory systems

of industrialized countries. WHO has taken several steps to assist developing countries in improving their pharmaceutical labeling and in providing more complete prescribing information to

health care workers. (See ch. 7.)

 Prescribing Guides

Commercial prescribing guides—mostly of

the related “Index of Medical Specialties” (IMS)

series and the “Para Los Medicos” (PLM) series

in Latin America-are available in most developCorner pharmacy in Latin America.

ing countries and in some developed countries,

and are distributed free to physicians. The stated

aim of the guides is to provide physicians with a

quick means of determining which drugs are

available in their country. In practice, they often

serve as the main source of prescribing information (212). They are published privately, paid for

by advertising, and are updated at regular intervals (from monthly to 3 or 4 times a year).

Prescribing guides (IMS-type and others) are organized differently in different parts of the world,

but they typically have relatively short entries for

products. Many of the early studies of drug “labeling” in developing countries actually were

based on analyses of prescribing guide entries.

(see app. A.) These studies have been critical of

the entries, on the one hand, for failing to include

all appropriate warnings and precautions, and, on

the other hand, for including indications that lack

evidence of effectiveness.

Prescribing guide entries are based on the data

sheets submitted by companies to drug regulatory authorities when they seek approval. The content of prescribing guide entries, however, is not

regulated by the government. Traditionally, the

guides’ publishers have controlled the length and

content of the product entries. Since the mid1980s, however, pharmaceutical companies have

increasingly exercised their influence over the

publishers in determiningg the content of the entries. In July 1988, publishers of the Index of

Medical Specialties compendia for Africa, the

Caribbean, and the Middle East agreed to allow

companies to review the entries for their products. Negotiations with other publishers are in

progress (212).

PHARMACEUTICAL ADVERTISING AND

PROMOTION

Pharmaceutical companies promote their

products through print advertising and directly to

physicians and other health care providers

through sales representatives (known commonly

as “detail men”). These activities are, in general,

less strictly regulated in developing countries

than in the United States and other industrialized

countries.

Detail men present product information to

physicians and pharmacists, and are considered

by the pharmaceutical industry as an important

means of diffusing information quickly (160). A

1981 study suggested that the ratio of representatives to physicians was higher in developing than

developed countries (1: 10 in the United States

and most Northern European countries, 1:8 in
Drug Prescribing Information in the United States and Other Countries I 111

Ecuador; 1:5 in Colombia; 1:4 in Tanzania; and

1:3 in Guatemala, Mexico, and Brazil) (210). The

United Nations Center on Translational Corporations reported that, in 1978, multinational corporations spent $250 million on promotional activities in Argentina (25 percent of the value of

the companies’ total sales in Argentina), and in

1979 foreign companies spent $320 million in

Brazil (22 percent of total sales in Brazil). Both

of these countries have large private pharmaceutical markets. Approximately two-thirds of the

advertising budgets in Argentina and Brazil were

spent on detail men and free samples (223).

Detail men are widely acknowledged to be an important source of drug information in developing

countries.

The role of the detail man is controversial.

Most commentators agree that drug promotion

that provides physicians with current, accurate

scientific information about new products is very

useful. However, by its nature, promotional activities are also used to gain and maintain market

share (279). The detail man functions not only as

an educator, but is also a salesperson, A study in

the United Kingdom of sales representatives

from 24 drug companies found that approximately 86 percent were given sales targets to achieve

(78). Ideally, these functions are compatible, but

in practice they may conflict. Pharmaceutical

representatives operating in developing countries

have been accused of exaggerating the claims for

their products and glossing over potential risks

(39,77,210).

Promotion by detail men has been studied by a

number of researchers, and many potential problems have been identified. This OTA study did

not include an independent evaluation of promotion by detail men.

Advertising in medical journals and prescribing guides is an important source of information

for physicians in developing countries, as it is in

the rest of the world. WHO, the International

Federation of Pharmaceutical Manufacturers

Associations, and various public interest groups

have focused their attention to a much greater degree on advertising than on labeling because of

the greater visibility and influence of advertising.

The extent to which authorities regulate pharmaceutical advertising varies considerably among

nations. A number of developing countries, including those in this study, have comprehensive

regulations governing pharmaceutical advertising

but many countries are unable to monitor compliance because of lack of resources (107,137).

Other countries have less comprehensive regulations for advertising, or none at all. In a number of

countries (e.g., Costa Rica, El Salvador, Guatemala,

Honduras, India, Nicaragua, Panama, Singapore,

Syria, Thailand, Trinidad, and Zimbabwe), advertisements need not carry warnings and contraindications (20).

Consumer groups and academics have criticized advertisements that multinational corporations have used in developing countries (39,41,

67,154,210). A recent study examined pharmac -

eutical advertisements in independent medical

journals from 18 industrialized and developing

countries (Finland, Norway, Sweden, Spain,

France, Italy, Ireland, United Kingdom, Switzerland, Turkey, India, Nepal, Pakistan, Sri Lanka,

Tanzania, Zimbabwe, Brazil, and Denmark) (93).

Researchers from each country examined adver -

tisements according to a single protocol. A total

of 6,710 advertisements, most for brandname

drugs of MNCs, were included.

Many of the advertisements were found to be

deficient. Using the WHO ethical criteria for

drug promotion (see ch. 7) as a standard, warnings and precautions were missing in half the advertisements and side effects and contraindications, in about 40 percent. The information

content of the advertisements differed “surprisingly little between industrialized and developing

countries” (93).

Pharmaceuticals advertisements were given

low marks in a recent study of advertisements in

leading U.S. medical journals (262). In a detailed

review of 109 advertisements, 92 percent were

judged by medical and pharmacy professionals to

be out of compliance with FDA standards in at
112 I Drug Labeling in Developing Countries

least one of 28 areas, with an average of four Advertising and promotional materials are imareas out of compliance. The reviewers would portant ways to convey information to physihave rejected or required major revisions to 62 cians, especially information about new prodpercent of the advertisements. Many problems ucts, or new information about old ones. There

related to an imbalance between information appears to be significant scope for improving the

about efficacy versus side effects and contraindi- information content of these materials.

cations.
Multinational

Pharmaceutical

Corporations and

U.S. Extraterritorial E

Jurisdiction I 5

T

he largest pharmaceutical companies in the world have

sales of over one billion dollars annually and operate

across the globe. While every company has headquarters

in a particular country, they all have manufacturing and

other facilities in other countries. Foreign operations may be

managed or controlled by the headquarters, but they are subject

most directly to the laws of the countries in which they are located. For U.S.-based multinational corporations (MNCs), U.S. law

applies fully to a company’s domestic operations, but only certain aspects of foreign operations that affect U.S. commerce directly are governed by U.S. law. The extent to which drug labeling in developing countries can be influenced by U.S. law is,

therefore, limited, The discussion of U.S. extraterritorial jurisdiction in this chapter is key to understanding the potential for

the United States to extend its control over labeling beyond U.S.

borders. This chapter also describes MNCs generally, including

their basic structure and operations, and more specifically, characteristic features of typical U.S. pharmaceutical MNCs.

THE MULTINATIONAL CORPORATION

The distinguishing characteristic of an MNC is that it has direct investments in several countries. The MNC does not merely

market its product in other countries, but owns or controls production or service facilities in foreign countries. This is often referred to as direct foreign investment, which under U.S. law

means ownership of at least 10 percent of voting securities of a

corporation or an equivalent interest in an unincorporated firm

(236). (Others define it as investment accompanied by significant ownership of at least 10 to 25 percent of stock in the foreign

company or significant management control (256)). The MNC’s

“A strange

justice that

is bounded

by a river”

Pasca l

113
114 I Drug Labeling in Developing Countries

foreign investments are directed and managed

according to a business strategy that links the entire enterprise (80). Some scholars further distinguish MNCs as those enterprises that transact a

substantial amount of business abroad so that

their financial status is dependent on operations

in several countries and their management decisions take into account multinational alternatives

(80).

Suburban pharmacy in Latin America displaying

products from around the world.

It may be somewhat misleading to refer to an

MNC as a single entity when it actually consists

of a number of separate corporations linked economically, operating in different countries (80).

Some experts use the term MNC to describe the

headquarters of the enterprise, and describe the

entire operation as a “multinational enterprise.”

In this report, the term MNC is used to refer to

the entire enterprise.

 The Rise of the U.S. Multinational

Corporation

U.S. MNCs have existed since the early 1900s,

but have attained their great prominence since

the 1950s (253). In the early expansionary years,

there was considerable concern that direct investment by multinationals could pose a threat to national sovereignty and hinder rather than promote

This

economic development of host countries.

was of particular concern to developing

countries. These concerns led to the negotiation

of codes of conduct that set standards of behavior

for MNCs (255). The codes, voluntary agreements between countries, were negotiated between industrial countries and within the United

Nations to address the concerns of investment in

developing countries (125,255).

The concern over foreign direct investment

has largely dissipated, and it is, on the whole,

seen as a positive force, especially for developing

countries. One reason may be that developing

countries have become more comfortable and sophisticated in controlling foreign investment and

in insuring that it meets their countries’ economic needs (255).

Expansion of U.S. MNCs has continued in the

1980s as Eastern Europe, the former Soviet

Union, and China began to allow direct foreign

investment, mainly through joint ventures with

domestic partners. The dominance of U.S.

MNCs has eroded, however, as non-U.S. multinationals, primarily from Western Europe and

Japan, have taken a larger role in the world economy (92). In 1960, U.S. direct investment abroad

accounted for one-half of all foreign investment

in the world; by 1987, it accounted for one-third

(238). The number of MNCs based in developing

countries has also increased, but they are still few

and small relative to the multinational giants of

the industrial countries (225).

The rapid growth of MNCs has transformed

the world economy in just 30 years. According to

one U.S. business magazine, “competition for

goods, services, and ideas pays no respect to national borders or the old geopolitical divides that

supposedly separate North from South, East

from West” (124). However, while the MNC has

changed the nature of global markets, the international legal system has continued to treat the

separate corporate entities of an MNC as separate corporations, subject to the laws of their host

countries. One commentator has noted that,
Multinational Pharmaceutical Corporations and U.S. Extraterritorial Jurisdiction I 115

“while the home country regulates the head and

shoulders of the MNC, various other countries

regulate its limbs and extremities” (172). Although the MNC is a single corporate enterprise

and major strategic business decisions are made

at corporate headquarters for all operations, individual subsidiaries are usually managed by nationals of the country in which they are located,

and national legal systems address the individual

parts.

 The Structure of U.S. Multinational

Pharmaceutical Corporations

A U.S. MNC is a company with headquarters

in the United States and with subsidiaries in

other countries. The foreign subsidiaries often

are incorporated under the laws of the “host”

countries in which they are located. The country

in which corporate headquarters is located is referred to as the “home” country. A large U.S.

pharmaceutical MNC may have up to 50 or more

foreign subsidiaries, of which perhaps a third are

major operations. For example, the 1989 BristolMyers Squibb Company’s annual report filed

with the U.S. Securities and Exchange Commission (29) (the “1989 10-K”) states that the company owns 22 major manufacturing facilities in

Australia, Brazil, Canada, Denmark, England,

France, Italy, Japan, the Netherlands, the Philippines, and Venezuela, and has well over 100

foreign subsidiaries. Pfizer Inc.’s 1989 10-K

(176) states that its major manufacturing facilities are located in Great Britain, Ireland, France,

West Germany, Japan, Brazil, India, Mexico,

Argentina, Spain, and South Korea, with an additional 40 plants around the world, and a total of

more than 150 foreign subsidiaries.

Subsidiaries of these companies that do not

produce pharmaceuticals may be small marketing facilities, they may be “holding companies”

whose sole function is to own stock in or supervise the management of other companies, or they

may be engaged in other commercial activities.

In addition to making pharmaceuticals for human use, Merck & Co., for example, is a diversified corporation that develops and markets animal health and agricultural products and specialty chemicals, e.g., for water treatment, oil field

drilling, food processing, cleaning, and disinfecting (155).

In the pharmaceutical industry, foreign operations are usually carried out by subsidiaries

owned entirely or in the majority by the parent

corporation. Complete ownership is preferred

because it allows the company to protect its technology and trademarks, maintain control over the

quality of production, and ultimately, protect its

reputation (65). But joint venture arrangements,

in which a certain percentage of the subsidiary’s

stock is held by host country nationals, are common. A joint venture may be the only way a company is a!lowed by a foreign government to operate the subsidiary. This is particularly true in

some developing countries whose governments

Pharmaceutical paekaging in Latin America.

are attempting to promote national businesses

(181). It is the smaller MNCs, however, that are

more likely to be forced by host governments to

enter into joint ventures, because they do not

have the bargaining power to insist on complete

ownership (65).

Developing countries account for less than 10

percent of worldwide pharmaceutical production

(68), and in 1980 (the latest year for which data
116 I Drug Labeling in Developing Countries

are available) a handful of developing countries-Argentina, Brazil, Egypt, India, Mexico,

and the Republic of Korea—accounted for twothirds of it (68). Developing countries rely heavily on imports of finished products or bulk products which are then repackaged for sale by

subsidiaries of MNCs (223). Certain developing

countries, however, are beginning to require that

MNCs establish more sophisticated manufacturing facilities in their countries.

Indonesia recently passed legislation requiring

all foreign-controlled pharmaceutical companies

to establish Indonesian production of at least one

raw material used in pharmaceuticals sold there

Drug packaging in Kenya.

(135). Similarly, in India, foreign companies

must establish a certain percentage of bulk drug

manufacturing capacity, rather than just formulation and packaging plants (140). Producing active ingredients involves more investment and

transfer of technology than does formulation.

Because the risk of disclosing trade secrets is also

higher, companies generally prefer to avoid

transferring technology (182).

By selling the rights to its patents, a manufacturing process, a trademark, marketing services,

or other technical skills, MNCs also may license

their proprietary products to a foreign company

for production and sale. In return, the MNC receives royalties on the products. This arrangement allows the company to sell its product

abroad without taking the risks of direct investment (18 1). Syntex Corporation, for example,

told OTA that at least one of its products included

in the OTA survey was produced and marketed in

Panama under a licensing arrangement with another company, and another one was produced

and marketed in Thailand by a subsidiary of another MNC (213). The degree of control exercised by the licenser over the way in which a

product is marketed or labeled is determined by

the licensing contract.

INTERNATIONAL LAW AND

EXTRATERRITORIALITY

Most international law is “customary” law,

embodying general principles recognized by

most civilized nations (105). The goal of international law is to promote stability among nations.

Long-range interests of individual nations and

the need for reciprocity in international relations

determine the legal domain which each nation

will claim as its own (136). International law is

made by countries entering into treaties in which

they agree to take, or refrain from taking, certain

actions. International agencies, such as the

United Nations, can influence the development

of international law by promulgating guidelines

or codes of conduct, but such proclamations are

effective only if adopted by individual states. The

United Nations International Court of Justice

(ICJ) was setup to resolve disputes among countries, but the system works only when countries

submit to the Court’s jurisdiction and adhere to

its decisions. To date, the ICJ’s docket has been

very light (6).

A nation’s decision to exercise extraterritorial

jurisdiction is usually guided by the basic principles of international law: the territorial principle,

the nationality principle, and the protective principle. The territorial principle remains the fundamental doctrine of international law. It provides

that each nation has the exclusive right to regu-
Multinational Pharmaceutical Corporations and U.S. Extraterritorial Jurisdiction 117

late the conduct of all residents, individuals, and

corporations within its borders (82). A corollary

to the territorial principle is that foreign governments do not have the right to interfere in the internal affairs of another State. Therefore, under

an absolutist interpretation of the territorial principle, the United States would never have the

right to exercise jurisdiction over a foreign subsidiary of a U.S. company because such action

would impinge on the sovereign interests of the

country in which the subsidiary operates (73).

The territorial principle, however, is not absolute. The protective principle recognizes a

country’s right to extend its jurisdiction to conduct occurring outside its borders if the action

threatens the national security or functioning of

government activities. Examples of such conduct

are counterfeiting currency or forging entry visas

outside a country’s boundaries (189). A broader

exception is the nationality principle, which recognizes a country’s interest in maintaining some

degree of control over its citizens residing or

traveling in other countries. Other examples are

the U.S. policy of requiring its citizens to pay

certain income taxes when residing abroad (237),

and the selective service law, which requires all

male U.S. citizens, regardless of foreign residence, to register for U.S. military service (50

U.S.C. App. § 453).

The nationality principle may also be applied

to corporations, which, in legal terms, are “persons.” However, there is international disagreement on how the nationality of a corporation is

determined. Most nations assert that a corporation is a citizen of the country in which it is incorporated, or the country housing the center of

the corporation’s activities. A subsidiary, although part of a larger corporation with headquarters in another country, is usually considered

a national of the country in which it operates. The

United States, however, has exercised jurisdiction over foreign corporate subsidiaries based on

ownership or control by a U.S. corporation, primarily to enforce trade embargoes and boycotts,

a practice that is a source of international controversy (2,218).

The United States is also a proponent of extraterritorial jurisdiction based on the effects

principle, which holds that a nation may exercise

jurisdiction over certain conduct occurring outside its territory if it has a “substantial,” “direct,”

or “adverse” effect within the country. It is usually limited to acts “generally recognized as constituent elements of a crime or tort under the laws

of the States that have reasonably developed legal

systems” (73). The effects principle can be viewed

as a modification of the territorial principle in

that jurisdiction is based on addressing an adverse effect within the territory. The effects principle, however, is not universally accepted as a

legitimate basis for extraterritorial jurisdiction

under international law (218).

The United States has used the effects principle primarily to enforce economic laws, antitrust

laws in particular. The effects principle was first

pronounced in a 1945 case in which a U.S. court

was asked to decide whether U.S. antitrust laws

could be applied to an anticompetitive agreement

between several European companies and a

Canadian corporation. The Canadian corporation

had corporate links to the United States. The

court decided that “a state may impose liabilities,

even upon persons not within its allegiance, for

conduct outside its borders that has consequences

within its borders which the state reprehends”

(228). The controversial U.S. position on antitrust law is discussed later in this chapter.

Principles of international law can only provide general guidance, especially when debating

extraterritorial jurisdiction. Application of one

principle may lead to results that are contradictory to another principle. Which principle should

be given greater weight in a particular situation

can be determined only by examining the competing interests of the countries and other parties

involved. In many situations, one country may

believe a particular extraterritorial act is in accordance with international law, and another will see

it as contrary. As one U.S. court stated, “[f]rom
118 I Drug Labeling in Developing Countries

the body of international law, Congress may pick

and choose whatever recognized principle of international jurisdiction is necessary to accomplish the purpose sought by the regulation” (229).

To understand the U.S. position on extraterritorial jurisdiction, it is helpful to examine U.S.

statutes, court cases, and other actions concerning extraterritorial jurisdiction in the field of foreign relations law.

 U.S. Foreign Relations Law

The American Law Institute’s recent Restatement (Third) of the Law: The Foreign Relations

Law of the United States (6) (the “Restatement”),

developed by prominent U.S. judges, legal academicians, and lawyers, is the most thorough analysis of U.S. foreign relations law. The Restatement

brings together all relevant precedents in an attempt to develop a coherent doctrine that addresses the question of extraterritorial jurisdiction “as it would be pronounced by a disinterested

tribunal, whether United States or some other national or an international tribunal.”

In international law, where no single body provides a definitive legal opinion (as the Supreme

Court does for U.S. constitutional law), the

Restatement is very influential. A criticism of the

Restatement is that it reflects the U.S. view of international law and, especially with respect to extraterritorial jurisdiction over U.S. foreign subsidiaries, the U.S. interpretation of international

law is at odds with most other countries (186,

220). The Restatement should be cited with caution because it not onlysummarizes the law as reflected in judicial cases and legislative and executive actions, it expands on the precedents and

prescribes what direction the law should take, so

it does not necessarily reflect current law.

The Restatement recognizes that the territorial, nationality, and effects principles provide a

basis for exercising jurisdiction over an activity,

person, or corporation. With respect to MNCs,

the general rule is that country A may not exercise jurisdiction over a subsidiary incorporated

under the laws of country B merely because it is

owned or controlled by citizens of country A.

There are, however, limited exceptions to this

rule, including regulations directed at the parent

corporation (located and incorporated in country

A), requiring that uniform accounting standards

be used for all MNC operations; regulations requiring that certain information about foreign operations be disclosed to investors; and regulations

requiring that tax returns of the entire MNC be

consolidated. These laws may be important to the

regulating country and should not interfere in the

internal affairs of the host country.

The Restatement also recognizes that, in certain circumstances, regulation of foreign subsidiaries is necessary to further important national

interests. The United States has regulated foreign

subsidiaries to enforce trade sanctions in time of

war or when it has felt the actions of another

country threatened U.S. interests. The Restatement cautions that these actions should not be

taken unless it is important for carrying out an essential national program, and the regulation will

not conflict with the laws or policies of the host

country. The Restatement specifically rejects asserting extraterritorial jurisdiction over “predominately local issues, such as industrial and labor

relations, health and safety practices.”

The framework provided by the Restatement

invariably leads to conflicts with the foreign

country sovereign right to regulate activities

within its territory. The United States has been

more willing than most countries to regulate extraterritorially (186) and not surprisingly, the

Restatement attempts to present concrete guidelines for resolving the types of conflict that have

arisen when the United States has enforced its extraterritorial laws and regulations.

The Restatement’s approach to resolving disputes over extraterritorial jurisdiction is based on

the longstanding international doctrine of comity.

Comity captures in a single word a complex and

ill-defined concept used by courts in setting limits on their extraterritorial powers. It has been defined by the U.S. Supreme Court as (94):
Multinational Pharmaceutical Corporations and U.S. Extraterritorial Jurisdiction 119

...neither a matter of absolute obligation on the

one hand, nor one of mere courtesy and good

will upon the other. . .it is the recognition which

one nation gives to the legislative, executive, or

judicial acts of another nation, having due regard both to international duty and convenience,

and to the rights of its own citizens or of other

persons under the protection of its laws.

U.S. courts have relied on the comity doctrine

to decline jurisdiction to show respect for foreign

sovereignty, protect parties’ expectations in international commerce, and to avoid interference in

foreign relations (175).

Elements of the principle of comity have been

integrated into the Restatement’s “rule of reasonableness,” which can be used to decide whether

an extraterritorial action is in accordance with international law. According to the rule, a nation

should exercise extraterritorial jurisdiction only

if: 1) it has a legal basis for exercising jurisdiction under the nationality or effects principle, and

2) it determines that it is reasonable to exercise

jurisdiction in the particular situation. For example, if the United States wanted to regulate foreign subsidiaries operating in Latin America, it

should consider the links between the business

carried out by the foreign subsidiaries and the

United States. The United States is less justified

in regulating a foreign subsidiary engaged in

purely local business transactions, or one that is

owned partially by foreign nationals than it is in

regulating one with significant business transactions with the United States and owned entirely

by the parent company.1

The character of the activity to be regulated

may also be relevant. For example, if the foreign

subsidiary’s main activity is building roads or

hospitals under contract to the foreign government, U.S. legislation affecting this contract will

interfere with the foreign government’s sovereignty. Consideration should also be given to the

expected impact of the regulation on current

business practices and on whether reasonable

commercial expectations will be disrupted.

Finally, the Restatement instructs the United

States to evaluate the impact that the proposed

legislation would have on the current international political, legal, and economic system and on

the likelihood of direct conflicts with the other

country’s laws (6). These considerations involve

balancing the competing interests of the countries involved directly in the situation, and the

impact the decision will have on international

economic and social discourse (136). Depending

on the weight given to various factors, analyses

using the rule of reasonableness could support

two contradictory positions, providing for little

predictability (73).

The Restatement claims that the rule of reasonableness is emerging as a principle of international law (6), but there is debate over this point

in international legal circles (175). Even the U.S.

Government has not endorsed the approach unconditionally, and might choose to exercise

extraterritorial jurisdiction when the factors enumerated above appear to weigh against the decision (25). The rule of reasonableness is relevant

to the debate because it reflects, to some degree,

U.S. interpretation of extraterritorial jurisdiction

and sets forth some of the factors that lead to

disagreement in related disputes. It should be

noted, however, that many other countries believe

that U.S. extraterritorial jurisdiction does not extend as far as provided for in the Restatement

186).

A final issue not considered by the Restatement, but important in international economic

and business policy, is national treatment. The

U.S. Government often protests the actions of

foreign governments when they give preferential

treatment to their own national companies, placing U.S. foreign subsidiaries at a disadvantage.

1 Other countries would object to the United States exercising jurisdiction on the basis of U.S. ownenship of a corporation that is located

and incorporated abroad (2),

330-065 0 - 93 - 5 QL 3
120 Drug Labeling in Developing Countries

By passing U.S. legislation intended to control

the operations of foreign subsidiaries of U.S.

MNCs, and also expecting the host government

to extend preferential treatment to those subsidiaries as if they were national companies, the U.S.

Government may itself be perceived as a source

of unfairness (25).

 Extraterritorial Jurisdiction in the

US. Courts

U.S. courts are concerned primarily with illegal conduct within the United States, but sometimes the courts apply U.S. law to acts occurring

outside the country. 2 One area in which U.S.

courts have been particularly active with respect

to foreign corporations, including subsidiaries of

U.S. companies, is in antitrust law. There are

other areas of law in which U.S. courts struggle

with the proper limits of extraterritorial jurisdiction over foreign subsidiaries; however, antitrust

law has been particularly fertile and the doctrines

developed by the courts are generalizable to other

areas of judicial action.

The primary antitrust statute is the Sherman

Act (15 U.S.C. § 1-7), which makes it illegal for

an individual or corporation to enter into any

agreement, conspiracy, or combination that restrains trade among the States or among foreign

nations, or to take any action to monopolize trade

(i.e., to control prices or preclude competition).

The Federal Trade Commission Act (15 U.S.C. §

45 et. seq.) and the Clayton Act address other aspects of anticompetitive behavior. These three

statutes have been called by the Supreme Court

the “Magna Carta of Free Enterprise” (230).

The application of U.S. antitrust laws extraterritorially has not been without controversy, and

has been opposed by a number of foreign governments (73,218). Opposition stems from the fact

that antitrust law was originally unique to the

American legal system. The United States was,

therefore, prosecuting companies for actions that

were legal in the countries in which they took

place. Although a number of European countries

have recently passed antitrust laws, few impose

penalties as severe as those in the United States

(104). Most controversial have been private antitrust suits brought by U.S. citizens. Because

they are private, the U.S. Government cannot

readily use diplomatic channels to ease the conflicts they engender (185).

In 1982, Congress amended the Sherman Act

with the effect of constraining the extraterritorial

reach of antitrust law. The changes were made in

response to concern that U.S. businesses were

being hindered from entering into international

transactions because of uncertainty about the applicability of U.S. antitrust laws (234). Congress

noted that there was a lack of consistency both

among judicial interpretations and between the

judiciary and the executive branch over the

“quantum and nature of the effects required to

create jurisdiction” (234). For example, while

one court required conduct that “directly affect[s]

the flow of foreign commerce into or out of this

country” (221), another court reasoned that “it is

probably not necessary for the effect on foreign

commerce to be both substantial and direct as

long as it is not de minimus” (50).

To remedy this situation, the amendments provided that a transaction between two foreign

firms, even if U.S.-owned, would not be subject

to U.S. antitrust laws unless there was a direct,

substantial, or reasonably foreseeable effect on

domestic commerce (15 U.S.C. § 6a, 15) (58).

Absent a significant adverse effect, a foreign

transaction that violates U.S. antitrust laws and

involves U.S. companies or their subsidiaries is

subject only to the laws of the country in which

the business is conducted (234). In addition,

Congress stated in the legislative history that the

amendments were not designed to alter the right

2 The court must decide that a case: 1) concerns conduct that is under the jurisdiction of U.S. law and 2) that it has jurisdiction over the

defendants. This section addresses only issues of the former type (“subject jurisdiction”) and not of the latter type (“persoml jurisdiction”).
Multinational Pharmaceutical Corporations and U.S. Extraterritorial Jurisdiction 121

of U.S. courts to “recognize the special international character of transactions” and to employ

notions of comity to decline to exercise jurisdiction over a case, even when the antitrust act

specifically gave the court the authority to prosecute the case (234).

The instruction on employing notions of comity gave U.S. courts the right to take into account

diplomatic and political considerations in deciding whether to exercise jurisdiction, even when

there is an effect on U.S. commerce. The factors

that courts consider are (27,141 ,219):

1.

2.

3.

4.

5.

6.

the degree of conflict with foreign law or

policy,

the nationality and allegiance of the parties

and the principal places of the business of

any corporations,

the extent to which enforcement in either

country can be expected to achieve compliance,

the relative effect of the conduct on the

United States as compared to other nations,

whether there was intent to harm the

United States, and

the relative importance of the violations

under U.S. law versus the law of the foreign country in which the conduct occurred.

 Trade Embargoes and Economic

Sanctions

Trade embargoes and other economic sanctions have been used by the United States in

times of war to conserve U.S. resources, to cut

off critical supplies to enemies, and to preserve

neutrality (161). More recently, trade sanctions

have been used to express opposition to domestic

and foreign policies of other countries, e.g., violating human rights laws, supporting terrorism,

or using military force within another country’s

borders (218).

A trade embargo or economic sanction is usually implemented after the President issues an

Executive order, pursuant to congressional authority, announcing the sanctions and the reasons

for them. The Executive order will often instruct

an executive agency, e.g., the U.S. Department of

Commerce or Treasury, to promulgate regulations to implement the sanctions. A trade embargo may prohibit all U.S. export trade with a certain country, or may be limited to certain goods,

such as military equipment. Alternatively, the

United States may halt all financial transactions

with a country and may freeze its financial assets

held within the United States. To make the embargo more effective, the United States sometimes orders U.S.-owned or -controlled foreign

subsidiaries to cease trading with a targeted

country (76). Several statutes authorize the

President to take such action during peacetime.3

The Export Administration Act (EAA) (50

U.S.C. App. § 2401 et. seq.) permits extraterritorial export controls. The EAA authorizes the

President to restrict the export of goods and technology that would “make a significant contribution to the military potential of another country”

or prove detrimental to the national security of

the United States, or to impose such restrictions

as necessary to further “significant foreign policy

goals” of the United States. (50 U.S.C. § 2402,

2404, 2405).

The EAA’s extraterritorial provisions were

first applied to limit the compliance of U.S.-controlled foreign subsidiaries with an Arab trade

boycott of Israel, The antiboycott provision,

however, applied only to transactions relating directly to “U.S. commerce,” which occur when the

foreign subsidiary acquires goods and services

from a person in the United States to fill a specific order for a person outside the United States

3 The Trading with the Enemy Act of 1917 (50 U.S.C. $ 5(b)) authorizes the imposition of embargoes during times of congressionally declared war.
122 I Drug Labeling in Developing Countries

(15 C.F.R. § 769.1 (1991)). Foreign subsidiaries

were also exempted if the national laws of their

host country required compliance with the boycott, recognizing the host country’s sovereign

right to regulate commerce within its borders

(218).

The second statute commonly used to impose

economic sanctions is the International Emergency Economic Powers Act (IEEPA)(50 U.S.C.

§ 1701-1706).

Enacted in 1977, the IEEPA authorizes the

President to act when faced with:

. . . any unusual and extraordinary threat, which

has its source in whole or substantial part outside the United States, to national security, foreign policy or the economy of the United States,

if the President declares a national emergency

with respect to such threat (50 U.S.C. § 1701).

The President is authorized to investigate, regulate, or prohibit certain financial transactions,

such as transactions in foreign exchange, banking

transactions, and property transfers. (50 U.S.C. §

1702). The IEEPA was used by President Carter

in 1981 to freeze Iranian assets held by U.S. corporations or their foreign subsidiaries. In addition, President Carter prohibited all U.S. banks

and their wholly owned foreign banking subsidiaries from engaging in financial transactions with

Iran (218). In 1990, President Bush invoked the

IEEPA, as well as the EAA, to impose comprehensive economic sanctions against Iraq.4

Under each of these statutes, the President

may assume jurisdiction over a foreign subsidiary based on its ownership or control by a

U.S. corporation or U.S. citizen (133).5 However,

this extraordinary power is available only during

a national emergency or when foreign policy

considerations make such action imperative

(218).

Before issuing regulations under these statutes, the President must make a case that important U.S. interests are being threatened and no

amount of compromise or negotiation can address the problem. Sanctions cannot be implemented under the EAA or the IEEPA until the

President has consulted with Congress and, in the

case of the EAA, with the affected industries.

The EAA requires the President to conclude that

(162):

1.

2.

3.

4.

5.

export controls are likely to achieve the intended foreign policy purpose;

the United States can effectively enforce

the sanctions;

the sanctions are consistent with U.S. foreign policy objectives;

the benefit to U.S. foreign policy objectives

exceeds any adverse effects the sanctions

will have on U.S. exports and international

competitiveness, including the impact on

the reputation of U.S. companies as reliable suppliers of goods; and

reasonable effort has been made to achieve

the desired aim through negotiation or

other means (50 App. U.S.C. § 2405).

There are comparable procedural requirements

under the IEEPA (50 U.S.C. § 1703). Despite the

limits on using these sanctions, a number of foreign countries contend that the United States

does not have the legal right to exercise jurisdiction over foreign incorporated subsidiaries under

any circumstances (59).

In response to these objections, the United

States has, at times, controlled the actions of

U.S. -owned foreign subsidiaries by regulating

the behavior of the U.S. citizens or domestic corporations responsible for the operations and corporate policies of the subsidiaries. This approach

is less controversial because the right to exercise

some control over private citizens, whether they

4 See also 55 FR 31803, 55 FR 31805, 55 FR 33089, and 55 FR 33091.

5 The use of control as a test for exercising jurisdiction over separate corporate entities is also found in domestic law. See e.g., 47 U.S.C.

~ 2 19(a), 49 U.S.C. $310, and 26 U,S.C. $ 825c. See also reference number 19.
Multinational Pharmaceutical Corporations and U.S. Extraterritorial Jurisdiction I 123

reside at home or abroad, is recognized under international law, as is the right to regulate domestic corporations.

The effectiveness of indirect controls depends

on the situation. For example, the 1970 regulations that implemented trade sanctions against

Rhodesia in support of a United Nations effort to

promote self-determination for the black majority population (The United Nations Participation

Act, 22 U.S.C. §287 (1979)) were worded very

broadly to capture almost all possible transactions. The regulations prohibited U.S. citizens

and residents who were officers, directors, and

principal managerial personnel of foreign subsidiaries from authorizing or permitting the foreign

subsidiary to engage in a prohibited transaction

with Rhodesia. A U.S. citizen could be in violation of the regulations even if he did not actively

engage in the transaction (218).

The Rhodesian regulations contrast with similar regulations implemented during the 1980 boycott of the Moscow Olympics, under which U.S.

citizens and domestic corporations were prohibited from “actually” authorizing, arranging, directing, or participating in a prohibited transaction

(15 C.F.R. § 385.2 (d)(3) (1982)) (218). These

terms imply that direct involvement was a necessary element for attributing liability to a U.S. citizen or corporation. This left open the possibility

of U.S.-owned foreign subsidiaries engaging in

business transactions related to the Moscow

Olympics.

The indirect approach to regulating foreign

operations of U.S. MNCs does not interfere directly with another country’s sovereign right to

control the actions of corporations operating

within its borders. Wholly owned subsidiaries

that are managed almost exclusively by foreign

nationals may escape regulation. However, even

indirect regulations may cause international tension because U.S.-owned foreign subsidiaries

may feel pressure to support U.S. policy or may

b See genemlly reference numbers 233 and 240.

be directed to do so by the corporate parent, even

if technically exempted from the regulations.

 The Foreign Corrupt Practices Act

In the examples discussed above, foreign subsidiaries were caught in disputes between the

United States and foreign governments. In some

cases, the actions of U.S.-owned foreign subsidiaries themselves may prompt regulation. The

prime example is the Foreign Corrupt Practices

Act (FCPA) of 1978, which addresses the bribery

of foreign officials by U.S. MNCs. The FCPA is

one of the few pieces of legislation that requires

foreign operations of a U.S. MNC to comply

with the same standards for corporate behavior

that govern domestic companies. However, the

FCPA does not regulate the foreign subsidiary directly, but instead imposes liability on a U.S. domestic corporation or it officers, directors, stockholders, agents, or employees if they knowingly

bribe a foreign official or authorize a payment

that they know will be used as a bribe (15 U.S.C.

§ 78dd-1, 78dd-2).

In 1977, the U.S. Securities and Exchange

Commission (SEC) revealed that approximately

400 U.S. companies, including 117 large and

prominent corporations, had used secret “slush

funds” to bribe or make questionable payments

totaling over $300 million to foreign officials

(26,231). Twenty-two pharmaceutical and health .

care companies admitted to making total payments of more than $31.4 million (210).6 Most of

these transactions occurred in other countries,

and according to some corporations, were necessary to compete there.

Congress, however, concluded that such

bribery could lead to public scandals with serious

foreign policy implications. According to a

House of Representatives report, the 1976 revelation that Lockheed Corp. had made significant

payments to certain government officials in
124 I Drug Labeling in Developing Countries

Japan “shook the Government of Japan to its political foundations and gave opponents of close

ties between the United States and Japan an effective weapon to drive a wedge between the two

nations” (233). Alleged payments by U.S. corporations to certain officials in the Italian Government were judged to have “jeopardized U.S.

foreign policy. . with respect to the entire NATO

alliance” (233).

Foreign policy implications were not, however, the only concern. Congress believed that corporate bribery offended the moral expectations

and values of the American public and distorted

the competitive market because firms that were

too inefficient to compete on price, quality, and

service were able to compete with bribes. In addition, exposure of these illegal payments could

lead to costly lawsuits, cancellation of contracts,

and even appropriation of assets, thereby adversely affecting U.S. investors and destroying

investor confidence in U.S. corporations (122,

233).

The FCPA was passed despite testimony by

the U.S. Department of State that it would be

“presumptuous” and “counterproductive” to impose U.S. standards in countries with differing

histories and cultures, and despite opposition

from business leaders who claimed they would

no longer be able to compete in certain countries

(26). The legislation attacked the problem of corruption on two fronts: 1) accounting practices for

public corporations were changed to prevent

companies from hiding such payments and 2)

bribery of foreign officials by any U.S. citizen,

resident, or U.S. domestic corporation was made

a criminal act.

Under the latter provision, U.S. citizens and

U.S. corporations, their directors, officers, employees, agents, or stockholders are prohibited

from offering or promising money or anything of

value to any other person, knowing that all or part

of the gift would be offered, given, or promised

to any foreign official to influence an official act

or decision (15 U.S.C, § 78dd-2(2),(4)). A payment is illegal if it “induce[s] the recipient to

misuse his official position” (66). The FCPA permits payments designed to facilitate routine governmental actions (so-called “grease payments”)

as may be necessary to obtain permits, licenses,

visas, work orders, phone service, power, and

water supply. (15 U.S.C. § 78dd-l(b),(f)(3 )(A),

78dd-2(b),(h)(4)). In addition, a U.S. citizen or

corporation is not guilty if he or she makes a payment without knowing that it will be used improperly. However, this knowledge will be imputed if the circumstances warrant (66):

. . .a knowledge of the facts will be inferred

where the defendant had notice of the high probability of the existence of the fact and failed to

establish an honest, contrary belief.

Violations of the FCPA are punishable by substantial monetary penalties and in certain cases,

imprisonment (15 U.S.C. § 78dd-l(a), 78dd2(b), 78dd-l(g)) (66).

The original bill introduced into the House of

Representatives applied the bribery provisions to

U.S.-owned foreign subsidiaries directly, because

Members believed that failure to include them

would create a “massive loophole” through

which questionable payments could be made

(233). Congress eventually rejected direct regulation of corporate subsidiaries operating abroad

because of the “inherent jurisdictional, enforcement, and diplomatic difficulties raised by inclusion of foreign subsidiaries of U.S. companies in

the direct prohibitions of the bill” (232). However, by allowing courts to impute knowledge to

a company or individual if the circumstances

warrant, the FCPA is designed to apply to most

transactions.

Despite the fact that the FCPA has such broad

extraterritorial reach, it has engendered little international opposition. One reason might be that

it applies only to U.S. nationals and domestic

corporations, over which the United States clearly has jurisdiction. In addition, almost every

country has national laws prohibiting bribery, extortion, kickbacks, and other such payments

(204). At the time the FCPA was passed, the
Multinational

Organization for Economic

Pharmaceutical Corporations and U.S. Extraterritorial Jurisdiction I 125

Cooperation and

Development, which consists of the United

States, Japan, and most Western European countries, issued voluntary guidelines for MNCs including a statement that MNCs should not bribe

or make any other improper payments or illegal

political contributions to public officials (49).

The United Nations was also considering a resolution condemning corrupt practices in international commerce and calling for unilateral and

multilateral action to end such practices (204).

Therefore, despite the fact that many countries

were not prepared to take unilateral action

against their MNCs, there was international consensus that bribery of foreign officials by multinational enterprises should be controlled.

 Extraterritorial Regulations Relating to

the Health and Safety of Foreign Nationals

The Restatement leaves activities that primarily affect the health, safety, and welfare of the national population in the exclusive domain of national laws. Attempts to regulate these domestic

issues would impinge on the sovereignty of the

host country to control activities within its borders (6).

There are few examples of U.S. legislation that

force foreign subsidiaries to comply with domestic health, safety, and labor standards when operating abroad and those that do exist are mostly

designed to protect U.S. citizens. For example,

the United States recently extended the protections afforded by age-discrimination laws to

American citizens working for U, S.-owned or

-controlled foreign subsidiaries (29 U.S. C, §

623(h)) (43,293),

Although it may be risky to draw conclusions

about the limits of U.S. extraterritorial jurisdiction relating to health and safety from the lack of

such regulations, this lack and some related history cannot be ignored. In the late 1970s, for example, strong evidence linked the aggressive

marketing of infant formula by subsidiaries of

U.S. companies in developing countries to an increase in infant mortality. (See ch. 6.) Legislation

was introduced in the House of Representatives

to regulate these marketing practices. The legislation did not pass and instead, Members of

Congress asked the World Health Organization to

convene an international meeting on the issue

(250). The injuries caused by the marketing practices primarily affected foreign nationals, many

in developing countries. Congress deferred to an

international forum rather than trying to change

the situation through U.S. law.

Deference to an international forum is consistent with the principles of international law. To

justify an exercise of unilateral extraterritorial

jurisdiction, the United States must have a strong

foreign policy interest that cannot be served by

any alternative action. Under the effects principle, the action the United States seeks to regulate

must have an adverse effect within the United

States. This is sometimes further limited to foreign actions that violate criminal or civil laws of

countries with developed legal systems (59,73).

In the case of the FCPA, Congress recognized

that bribery of foreign officials could lead to

scandals that could both damage foreign relations

and have domestic financial implications if investors lost faith in U.S. companies. In addition,

bribery is almost universally seen as a crime.

The U.S. interest in promoting the health and

safety of foreign nationals is not analogous to

preventing bribery, and it is difficult to find support under international law for exercising extraterritorial jurisdiction over foreign drug labeling. The United States has limited authority, if

any, to regulate the subsidiaries under the effects

principle. This study assumes that U.S. corporations are in compliance with national laws and

are, on the whole, providing information that is at

least as good as, or better than, information provided by other companies. There is no evidence

that U.S. companies are violating laws or acting

in a manner that could lead to sanctions or other

actions that could erode investor confidence. This

leaves the nationality principle; however, the

United States is virtually alone in its position that
126 I Drug Labeling in Developing Countries

foreign subsidiaries incorporated in foreign

countries can be considered nationals of the

United States for purposes of U.S. laws.

The justification for exercising extraterritorial

jurisdiction over pharmaceutical labeling would

be a moral interest in having U.S. pharmaceutical

companies lead the way in providing comprehensive and informative labeling, as defined by U.S.

standards. This probably does not reach the

“major national interest” required by U.S. precedents and the Restatement. In addition, the

United States’ interest must be weighed against

the factors that do not support U.S. jurisdiction,

primarily the fact that many developing countries

have laws regulating pharmaceutical labeling,

and the U.S. law would primarily protect foreign

citizens. These countervailing factors do not necessarily preclude all forms of extraterritorial jurisdiction, but they cannot be ignored.

SUMMARY

From a business perspective, MNCs operate as

unified corporations, but their actions in each

country are governed almost entirely by host

country laws, and to only a limited extent by the

laws of the home country. This is consistent with

the main principle of international law, which

recognizes the sovereign right of each country to

regulate activities within its borders. This right is

not absolute, however, and the United States has

assumed extraterritorial jurisdiction over activities in foreign countries in a number of cases,

more than the rest of the world has generally approved of.

Many examples of U.S. extraterritorial jurisdiction over foreign subsidiaries concern trade

and economic sanctions implemented during

times of war or international tensions. Under

these laws and regulations, the United States is

controlling foreign subsidiaries of U.S. companies because their actions may undermine important foreign policy goals. In a sense, the subsidiaries become pawns in an international dispute

rather than being the focus of the action.

The debate over extraterritorial jurisdiction revolves around determining to what extent a U.S.

foreign policy interest or a domestic interest is

significant enough to support extraterritorial action. The only obvious precedent for regulating

drug labeling by foreign subsidiaries is the

Foreign Corrupt Practices Act. In the FCPA, the

behavior of foreign subsidiaries was the focus of

the legislation because bribery had adverse impacts on U.S. foreign relations, as well as domestic interests. The FCPA does encroach on the sovereignty of foreign nations because it addresses

bribery of foreign officials. It does not, however,

directly regulate the actions of the foreign subsidiaries, and limits the criminal penalties to U.S.

corporations or U.S. citizens. Moreover, it does

not conflict with other nations’ laws because

most counties forbid bribery. There are significant problems applying this precedent to the

issue of drug labeling, however.

Direct regulation of the drug labeling practices

of U.S.-controlled foreign subsidiaries would be

a bold step beyond current U.S. interpretations of

international law. Although many developing

countries appear committed to improving the labeling of pharmaceuticals, it is not known

whether the governments of such countries

would welcome unilateral action by the United

States. Even indirect regulation of U.S. subsidiaries would be an extraordinary approach to the

problem of inadequate labeling. Although the

United States has amoral interest in ensuring that

its corporations do not cause injury to any consumer, regardless of citizenship, the United

States cannot ignore the sovereign right of the

foreign country to set its own consumer safety

standards. Problems related to extraterritorial jurisdiction could be avoided through a collaborative effort with developing countries, or by including in any legislation a provision for national

regulatory authorities to reject U.S. attempts to

control foreign labeling, in whole or in part.
Codes of Conduct

and Voluntary

Guidelines for

Pharmaceutical

Information 6

T

his chapter examines the potential for improving the

quality of drug labeling in developing countries through

means other than strengthening national drug regulation

directly. Every country has laws governing at least some

aspects of pharmaceutical registration and labeling, and a designated individual or agency to carry out those laws, In the United

States and other industrialized countries, substantial resources

are devoted to making sure the laws and regulations are upheld,

even then with imperfect results. There is convincing evidence

that in many, if not most, developing countries either the laws

are too weak to ensure a safe and effective drug supply, or more

commonly, the governments are unable to allocate sufficient resources to implement the laws fully.

Legitimate differences of opinion may exist about the extent

of this problem, but both the OTA survey and a recent survey by

Silverman, Lydecker, and Lee (212) confirm that pharmaceutical

manufacturers are providing inadequate prescribing information

for at least some of their products sold in developing countries.

SiIverman, Lydecker, and Lee make the important point that,

overall, labeling by domestic companies in developing countries

is worse than that of multinational corporations (MNCs), but

both studies found significant problems with multinational labeling as well.

Alternatives to national regulation include codes of conduct

and voluntary guidelines drawn up by international bodies (e.g.,

agencies of the United Nations). The main targets of codes and

guidelines have been multinational corporations, which still

leaves the problem of domestic companies to be solved. This

study has focused only on U.S.-based multinationals; the mechanisms discussed in this chapter would apply to all multination127
128 I Drug Labeling in Developing Countries

als and in some cases, to domestic companies

(e.g., when a code of conduct is adopted as law in

a country).

There is no current international code of conduct for pharmaceutical labeling. The draft

United Nations Code of Conduct for Transnational Corporations, which generally addresses

labeling of all consumer goods by multinational

corporations, comes closest, but it may never be

ratified. A possible model for a pharmaceutical

code is the World Health Organization (WHO)

Code of Marketing of Breast-Milk Substitutes,

which addresses the promotional practices of

multinational corporations in developing countries. WHO has developed guidelines, which are

of lesser standing than codes of conduct, for

pharmaceutical promotion (“Ethical Criteria for

Medicinal Drug Promotion”) (264).

Codes of conduct usually refer to voluntary

actions of governments, but in the case of pharmaceuticals, the International Federation of

Pharmaceutical Manufacturers Associations

(IFPMA) has adopted its own code of conduct

for marketing and labeling. A discussion of the

provisions of this code and its impacts are included in this chapter.

CODES OF CONDUCT AND GUIDELINES

UNDER INTERNATIONAL LAW

Since the 1970s, countries have become increasingly interested in the role MNCs play in

national and global economics. A result of the increased attention has been the development of

codes of conduct providing standards for national laws to regulate MNCs, and business Widelines that MNCs may adopt as corporate policy.

Codes of conduct have been formulated by both

governmental and nongovernmental organizations, including the United Nations (U. N.) and its

agencies, the International Labor Office (ILO),

the Organization of Economic Co-operation and

Development (OECD), the International Chamber of Commerce, and regional organizations.

The codes range from broad pronouncements of

principle which multinationals should follow,

such as the OECD Guidelines for Multinational

Corporations, to codes aimed at corporate operations, such as the U.N. Conference on Trade and

Development Code of Conduct on Restrictive

Business Practices (98).

Codes of conduct function as formal pronouncements by nations on policy matters (48).

They are not legally binding instruments unless

adopted into the national law of a country or ratified as a treaty. Nonetheless, when a number of

countries endorse a code of conduct, through a

U.N. resolution or other legal instrument, it is

likely to have an impact. Codes are “politicallyagreed behavior which cannot be legally enforced directly, but cannot either be legitimately

infringed” (125). Even the process of developing

a code, through the pooling of information, opinions, and experiences, may facilitate regulation

and increase cooperation.

Rather than becoming parties to a code of conduct, countries may instead endorse a resolution,

stating general agreement with a set of principles, but assuming no obligation to take further

action. Such instruments are usually called

guidelines, and as the name implies, are meant to

provide a framework for further action. Though

not as strong a force as a code of conduct, guidelines may become the basis of national laws or be

used to develop codes of conduct.

One might question the purpose of codes of

conduct, given what seems to be rather weak

means of enforcing them. It is important to remember, however, that all international law is, to

some extent, voluntary because it is based on the

consent of individual nations. There is no supranational organization with the power to enforce

international laws, nor is there a legislative body

in which the majority of nations can bind the minority (25 1). The main difference between inter-
Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information 129

national law1 and voluntary codes of conduct is

the degree to which a country agrees to be bound

and the corresponding action that the international community will take in response to a breach of

a country’s obligations. If an obligation is established under international law, it might be acceptable for another country to take retaliatory action

to enforce that obligation; for example, through a

trade embargo. A country would not be justified

in taking such extreme retaliatory action in response to infractions of a code of conduct by another country, but might respond by not abiding

by the code with respect to that country.

A related question is why codes of conduct are

not adopted as multilateral treaties, which have

the strongest standing under international law.

Codes represent a compromise that allows countries to come to agreement on certain policies,

and to relieve tensions within the international

community without giving up their sovereign

right to regulate within their borders. Many

countries perceive treaties that address domestic

issues (e.g., the treatment of corporations operating within a country’s borders) as unacceptable

threats to sovereignty (125).

Codes serve a number of purposes. The principles embodied in a code maybe used as a model

for national regulation; its widespread endorsement provides assurance that such legislation is

acceptable to the international community and its

enforcement is unlikely to create international

tensions. Courts and other governmental agencies may also look to codes of conduct when interpreting relevant national laws or interpreting

the reasonableness of private contractual provisions, However, some countries, including the

United States, might disagree that codes of conduct should be used by courts or government

agencies. These “minimalist” countries emphasize the voluntary nature of codes of conduct and

resist efforts to expand their significance beyond

a statement of general principles if their provisions are not adopted in national legislation or

other binding instruments (11).

A question with respect to MNCs is whether,

and under what circumstances, they will comply

with a code of conduct that has not been implemented in national laws. Even where codes have

no formal legal standing, they create standards

by which corporations’ actions can be measured.

Corporate behavior that is at variance with the

code may result in adverse publicity or governmental action (125).

Although codes of conduct may be enforced

only by the signatories, most codes establish an

organization to monitor implementation and to

provide interpretations of the code as needed.

This organization is a locus for continued exchange of information and debate among signatories. It can also receive reports of violations

and arbitrate complaints. Although these organizations usually have authority to clarify the

meaning of provisions that apply in a particular

dispute, in most cases they may not make a finding on the merits of the dispute, but they do provide a public forum for debate and may serve as

triggers for further political intervention (125).

In sum, codes of conduct are political instruments that are likely to influence corporate and

governmental behavior, but because they are voluntary, their influence may be limited. Industrialized countries have not been willing to agree to

binding international agreements to govern the

operations of MNCs, so codes of conduct provide an alternative means of affecting MNC behavior (125).

] The Statute of the International Court of Justice identifies three sources of international law in order of importance: 1) international conventions or treaties, 2) customary international law, and 3) general principles of law recognized by civilized nations. Customary international law is derived from the practice of states. A practice rises to the level of customary international law when the practice is adopted by most

statm and the states conform with the practice out of a “recognition that a rule of law or legal obligation is involved” (105),
130 I Drug Labeling in Developing Countries

 The United Nations Code of Conductor

Translational Corporations

Work on the U.N. Code of Conduct for Transnational Corporations (the “Transnational Code”)

began in 1977 and a draft was completed in 1982.

While agreement was reached quickly on roughly 80 percent of its provisions (225), the code has

not been, and may never be, adopted in full. As

drafted, however, the Translational Code is more

comprehensive than any international voluntary

code now in existence. It attempts to create a single framework for the rights and responsibilities

of MNCs and governments with respect to foreign investment by providing guidelines on how

MNCs, both privately and government owned,2

should operate in host countries,3 and how the

host countries should treat MNCs operating within their borders (224). Most of the provisions on

which there is agreement address the role of the

MNC in the host country. These include requirements that MNCs observe national laws, respect

fundamental human rights, adhere to sociocultural objectives, support consumer and environmental protection, comply with the fiscal policies of

host countries, and observe fair labor standards

(225).

The Code also contains general guidelines for

consumer protection, although this is not its central focus. The current draft requires that all

MNCs obey the consumer laws of the countries

in which they market products (this includes all

types of consumer products, not only pharmaceuticals) and provide consumers with “all appropriate information on the contents and, to the extent

known, on possible hazardous effects of products, . .by means of proper labeling, informative

and accurate advertising or other appropriate

methods” (227). MNCs would also be called on

to cooperate with international organizations in

developing and promoting national and international health and safety standards (227). Both of

these provisions could require an MNC to go beyond the requirements of national laws. However, no more specific guidance is given on what

is meant by phrases like “appropriate information” or “possible hazardous effects,” or on acceptable means of conveying the information.

MNCs would retain a great deal of discretion in

deciding the appropriate content of labeling if the

Translational Code were ratified as it now

stands.

The Code calls for national laws and bilateral,

regional, and multinational agreements to implement it (227). The Commission on Translational

Corporations, which drafted the Code, is the international body designated to assist with its implementation. The Commission is expected to:

1.

2.

3.

4.

facilitate dialogue among governments,

trade unions, consumer groups, and other

relevant groups;

develop procedures for providing clarification of the Code;

help negotiate Code-related agreements between governments or translational corporations; and

act as an information clearinghouse on issues related to the Code.

Some commentators question the need for the

Code, believing that it reflects outdated political

concerns about the nature of foreign direct investment and the role of MNCs in developing

countries, based on the experiences of the 1960s

and 1970s (22,226). The U.N. Centre on Translational Corporations concedes that developing

countries have become more sophisticated in regulating MNCs and that tensions between industrialized and developing countries have eased

2 mere is n. ~ractic~ di~~ction ~m=n WUSmtioti colorations and MNCS, except that some commentators use ~C to refer to Privately owned companies, while the term translational corporatio~ as used in the UJW. Transnational Code, refers also to government owned

companies.

3 A host courmy is the country in which an MNC has a foreign subsidiary. The home country is the country in which the MNC has its

headquarters.
Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information 131

since they began drafting the Code. However,

supporters still believe that the Code can make a

contribution, even in the changed investment environment (225). As of early 1993, negotiations

are being conducted at a higher level, being

chaired by the President of the U.N. General

Assembly.

 International Code of Marketing of

Breast-Milk Substitutes

The WHO International Code of Marketing of

Breast-Milk Substitutes (Breast-Milk Substitutes

Code) is not directed at pharmaceuticals, but is of

relevance because it was developed in response

to specific marketing practices of MNCs and, at

the time of drafting, was seen as a possible precedent for a pharmaceutical marketing code.

For a number of years, MNCs advertised aggressively, and successfully promoted the use of

breast-milk substitutes (infant formula) in developing countries. The marketing programs included direct promotion to the public through radio,

television, posters, handouts, and through the use

of “milk nurses” —sales representatives dressed

as nurses who marketed infant formula to new

mothers in maternity wards (180). The companies marketed formula directly to health providers as well, giving free samples, calendars,

booklets, and “lavish assistance” in the form of

“social entertainment at conferences, travel and

fellowships, and of funds for research” (120).

Consumer groups and physicians began to

criticize these marketing practices because companies ignored the health implications of their

successful marketing. Many mothers in developing countries did not understand the difficulty

they would have using infant formula once they

left the hospital. The lack of clean water and the

high cost of the formula made it impossible for

many of them to use formula correctly. Once they

became aware of these problems, however, most

mothers could no longer return to breast feeding

because lactation had ceased after they began to

use formula. The contaminated or diluted bottles

of formula mothers were forced to use led to an

increase in malnutrition and diarrhea, and in

some cases, the infant’s death.

A public campaign was instituted against these

marketing practices, including the initiation in

1977 of an international boycott against Nestle

Corp., one of the leading manufacturers of

breast-milk substitutes. The boycott was organized by a U.S. group called the Interfaith Center

on Corporate Responsibility, but was soon taken

over by the International Baby Food Action

Network (IBFAN), an organization devoted solely to carrying out this campaign (180). In 1981,

after considerable international debate (including

congressional hearings in the United States),

WHO member countries adopted a voluntary

International Code of Marketing of Breast-Milk

The WHO Code of Marketing of Breast-Milk

Substitutes encourages breast feeding infants.

Substitutes (268,269). The Code was adopted by

118 countries; the United States was the only

WHO member country to vote against it.

The Code instructs manufacturers to refrain

from certain promotional practices, including direct advertising to the public and distribution of

free samples. Samples may be distributed to

health professionals only if necessary for professional evaluation or research at an institutional
132 I Drug Labeling in Developing Countries

level. In addition, financial or material inducements are not to be used to promote products, and

bonuses based on volume of sales are prohibited

(269).

The Code also contains detailed instructions

for proper labeling. Article IX requires that all

containers of infant formula include a “clear,

conspicuous, and easily readable and understandable message” informing the consumer that

breast feeding is superior. The label should not

contain pictures or text that idealize the use of infant formula, for example, by describing formula

as being “humanized,” or “maternalized,” and

should not include pictures of infants, except if

necessary for graphic illustration of instructions.

The label should also state that the product

should be used only on the advice of a health

worker and should provide instructions for use

and carry warnings about the health risks associated with inappropriate preparation. Labels

should also include a list of the ingredients, instructions on proper storage conditions, a batch

number, and the expiration date.

IMPLEMENTATION OF THE CODE

The Resolution adopting the Breast-Milk

Substitutes Code instructed the Director General

of WHO to “give all possible support to Member

States” for its implementation and in particular,

in the preparation of national legislation and

other measures related to the promotion of breast

feeding (268). To assist in this effort, each country is required to make an annual report to WHO

on the actions it has taken toward implementation, information that is compiled in a biannual

report. According to the 1990 report, over the

previous 9 years, more than 150 countries and

territories had taken some action to implement

the Code, but as of 1988, only 6 developing countries had adopted the Code in its entirety (21).

Other steps taken by developing countries include (281):

●

●

●

●

●

education of health officials on the BreastMilk Substitutes Code;

adoption of country-specific codes of conduct based on the principles of the BreastMilk Substitutes Code, often with a mechanism to monitor and enforce compliance;

adoption of legislation implementing certain

provisions of the Code, or revisions of existing legislation to implement the Code;

government control of all imports and distribution of infant formula; and

public education on the benefits of breast

feeding.

Consumer organizations have played an active

role in promoting the Code. IBFAN, which has

more than 100 affiliates working in over 60 countries, supports research, education, and other efforts to implement the Code (281). The International Organization of Consumers Unions

(IOCU) has published a guide for health care

workers that explains the Code. The guide is available in eight languages and more than 25,000

copies are in circulation. Consumer groups also

have helped educate and train health workers in

countries with limited resources (28 1).

Industry has also responded to the Code. The

International Association of Infant Food Manufacturers, an industry group with 35 member

companies in 15 countries, has instituted a complaint mechanism and is developing an arbitration mechanism to address violations of the Code

that cannot be dealt with by direct negotiations

between the company and the complainant (281).

Nestle Corp. created the Nestle Infant Formula

Audit Commission (NIFAC), an independent

nine-person commission that reviews allegations

that Nestle’s advertisements, promotional activities, or corporate policies violate the Code.4 As

of 1984, NIFAC had reviewed 80 complaints,

with the number of complaints declining over the

years (180).

4 WAC was headed origindy by former U.S. Senator and Secretary of State (during the Carter Administration) Edmund Muskie (180).
Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information 133

Despite widespread support for the Code, several countries report that manufacturers continue

to distribute free samples of infant formula in

hospitals and clinics (188,28 1). However, the

more aggressive marketing practices, such as the

use of milk nurses, have stopped (180). The requirement that countries report their progress

under the Code, as well as the actions of public

interest groups and industry with respect to violations, has kept the issue of breast-milk substitutes

on the international agenda.

 A Code of Marketing of Pharmaceuticals

At the same time the Breast-Milk Substitutes

Code was being drafted, WHO also debated developing a code of conduct for the marketing of

pharmaceuticals (270). The pharmaceutical industry opposed the idea and in 1981, when the

move for a pharmaceutical code was strongest,

the International Federation of Pharmaceutical

Manufacturers Associations (IFPMA) developed

its own industry code for marketing practices

(see below) (145,251). WHO reportedly decided

to refrain from promoting its code until it could

evaluate the impact of the IFPMA Code (223).

The debate remained alive, however. Heated discussions took place at the Sixth Session of the

U.N. Council for Trade and Development in 1983

(174), as public interest groups continued to

press for a WHO code. WHO’s rejection of the

idea was made clear in 1986 when the Director

General stated that there is no place for “supranational regulation by WHO of drug promotion”

(103,263).

In addition to industry opposition to a WHO

pharmaceutical code, the U.S. executive branch

has, in the past, expressed opposition to WHO

formulating codes directed at specific industries.

The United States, under the Reagan Administration, voted against the Code on Breast-Milk

Substitutes for this reason (48, 183). The response

to a pharmaceutical code, however, could be different depending on the political climate.

U.S. governmental support for a code of conduct could be spurred by public support. A major

impetus behind the Breast-Milk Substitutes Code

was public outcry against the marketing practices

of infant formula companies, generated by intense publicity by consumer advocates. There is

currently no strong, vocal public support for a

pharmaceutical code, and it may be difficult to

generate interest for one. Unlike the Breast-Milk

Substitutes Code, which addressed easily understood marketing practices, a pharmaceutical code

must address a range of pharmaceutical products

and complex national standards for safety, efficacy, and labeling. Given the statements of WHO,

the strong industry opposition, and the lack of

clear public support, a WHO code on pharmaceutical marketing is unlikely to materialize in the

foreseeable future.

 The Ethical Criteria for Medicinal Drug

Promotion

In 1968, WHO adopted Ethical and Scientific

Criteria for Pharmaceutical Advertising (267).

This document was revised and expanded in

1988 to cover a broad range of “informational

and persuasive activities by manufacturers and

distributors” (273). The revisions were based on

results of a 1986 survey of governments and private parties that posed questions about the role of

scientific data sheets, symposia, free samples,

medical representatives, package inserts for patients, packaging and labeling, advertising, and

promotion of pharmaceuticals to health professionals and the general public. The survey also

asked about what information was included with

pharmaceutical products exported from the responding countries.5

The revised document, now called the Ethical

Criteria for Medicinal Drug Promotion, (Ethical

5 Respondents included 17 (of 24) governments (11 industrialized, 6 developing) and 14 (of 18) associations, representing the drug industry, pharmacists, consumers, and medicaJ specialties (273).
134 I Drug Labeling in Developing Countries

Criteria) focuses on various aspects of pharmaceutical promotion, including the content of drug

advertising to medical professionals and the public, the use of medical representatives, the provision of free samples to the public, post-marketing

surveillance, dissemination of information, drug

packaging and labeling, patient information, and

package inserts and booklets. The Ethical Criteria do not specify criteria for labeling and packaging. They instruct companies to comply with

national laws, and if there are no national laws or

if the laws are rudimentary, the company is expected to provide information consistent with

that required by another reliable drug authority.

In addition, the Ethical Criteria state that all text

and illustrations on the drug package and label

should provide only reliable, truthful, informative, and current information supported by scientific data. Companies are instructed not to use information that is likely to induce medically

unjustifiable drug use or give rise to undue risks

(264).

The Ethical Criteria give more specific standards for advertisements than for labeling. They

state that advertisements should usually contain:

1.

2.

3.

4.

5.

6.

7.

8.

9.

the names of active ingredients, using either the international non-proprietary

names (INN)6 or generic names;

the brand name;

the content of active ingredients per

dosage form or regimen;

the name of other ingredients known to

cause problems;

approved therapeutic use;

dosage form or regimen;

side-effects and major adverse drug reactions;

precautions, contraindications, warnings;

major interactions;

10.

11.

name and address of manufacturer

tributor; and

references to scientific literature as

or disappropriate.

These categories of information are derived

from WHO’s drug information sheet, which is

suggested as a guideline for labeling (271).

The Ethical Criteria are not as strong a pronouncement of public policy as a code of conduct

would be. The preface to the Ethical Criteria

“urges Member States to take into account the

Ethical Criteria in developing their own appropriate measures” and “appeals to pharmaceutical

manufacturers and distributors” to use these criteria (264). The document also states that the

Ethical Criteria:

. . constitute general principles that could be

adapted by governments. . ,as appropriate to

their political, economic, cultural, social, educational, scientific and technical situation, their

national laws and regulations.

The Ethical Criteria do not constitute legal

obligations, and do not necessarily represent the

consensus of all WHO member countries (264).

The Executive Director of the IFPMA, to

which the U.S. Pharmaceutical Manufacturers

Association belongs, has stated that its members

have not adopted the Ethical Criteria because

their Code of Conduct (discussed in detail below)

is binding on its membership and with respect to

prescription drugs, is fully congruent with the

Ethical Criteria, even though the two documents

differ in the amount of detail each contains (285).

Consumer groups, however, are very concerned

with many of the details. For example, whereas

both the Ethical Criteria and the IFPMA code

permit abbreviated information with reminder

advertising, the Ethical Criteria limit the defini6 Since 1950, WHO has coordinated the development of International Non-Proprietary Names (INNs) for pharrnaceuticds, and as of

1989, WHO had selected over 5,000 INNs for phamnaceutical substances (257). WHO recently published its 60th list of proposed international non-proprietary names (194).
Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information 135

tion of reminder advertisements to printed advertisements that do not make claims for the drugs

(i.e., promote them for a specific indication)

while the IFPMA Code has no such restriction

and leaves the definition of a reminder advertisement to the companies (196).

WHO’s recent evaluation of the Ethical Criteria notes that “effective oversight and control of

promotion is possible only when a comprehensive drug licensing [registration] system is in effect” (285). Control of promotional material requires specific standards for individual drugs,

which means the country must have reviewed the

scientific evidence for the individual drug and determined the proper labeling. Even countries with

strong registration systems may not regulate advertisements effectively (285). Few countries

screen advertisements before they appear. This is

the case in the United States, where a recent

study found that a large percentage of pharmaceuticals ads did not meet FDA regulatory standards (262).

The World Health Assembly, the legislative

body of WHO, recently asked member states to

intensify efforts to implement the Ethical Criteria

by involving government authorities, pharmaceutical manufacturers, firms engaged in promotion

of pharmaceuticals, health personnel responsible

for prescribing, dispensing, supply and distribution of drugs, universities and other teaching institutions, professional organizations, professional and general media (e.g., medical and other

journals), and consumer groups. The Director

General of WHO was directed to convene a meeting of the Council for International Organizations

of Medical Sciences (CIOMS)7 and other interested parties to discuss new approaches to implementing the Ethical Criteria (265).

IFPMA CODE OF PHARMACEUTICAL

MARKETING PRACTICES

The International Federation of Pharmaceutical Manufacturers Associations (IFPMA), formed

in 1968, is an association of associations. It comprises about 50 associations of pharmaceutical

manufacturers (e. g., the U.S. Pharmaceutical

Manufacturers’ Association) from 51 countries

(108). The member companies of the IFPMA

manufacture close to 80 percent of the world’s

prescription pharmaceuticals (excluding those

manufactured in China and the former Warsaw

Pact countries) (91). IFPMA registered as a nongovernmental organization with WHO in 1971,

stating its intent to collaborate in the following

areas: technical and scientific assistance, economic assistance, and medical assistance.

In 1981, after widely publicized criticism of

some pharmaceutical companies practices in developing countries, IFPMA adopted “A Code of

Pharmaceutical Marketing Practices” (IFPMA

Code) as industry’s statement on what constitutes

proper promotional practice for prescription

drugs. 8 The IFPMA Code is a model that can be

used by companies belonging to IFPMA’s member associations in setting corporate policies for

promotion and advertising. The IFPMA Code applies primarily to advertising, not labeling, but it

reflects industry’s philosophy on the type of information that should be provided with its products.

7 In order to facilitate international adverse drug reaction reporting, representatives from regulatory authorities and manufacturers formed

CIOMS with the objective of developing an appropriate, internationally acceptable form for reporting adverse drug reactions. CIOMS is also

involved in a collaborative project between pharmaceutical manufacturers, representative bodies of medical specialties, and national drug

regulatory authorities, that will involve updating the classification and deftition of adverse drug effects, an essential requirement for postmarketing surveillance (285).

B The IFPMA Code is directed at promotion and advertising of pharmaceutical products directed to the health care professions, but advertising of setf-medication products to the general public is excluded from the scope of the Code, as is advertising to pharmacists where this

is intended to support advertising to the public of such products (1 11).
136 I Drug Labeling in Developing Countries

Section I of the Code outlines general principles that should govern all printed advertising. It

states that industry has an obligation to provide

“scientific information with objectivity and good

taste, with scrupulous regard for truth and with

clear statements with respect to indications, contraindications, tolerance and toxicity” (1 11). In

addition, a product should be promoted only for

those indications supported by current scientific

evidence, and no product should be promoted as

being safe and effective for an indication until it

is approved for that use. Pharmaceutical companies are also expected to provide essential information on the safety, contraindications, sideeffects, and toxic hazards of their products,

subject to the legal, regulatory, and medical practices of the country.

Section IV of the Code expands on these requirements with respect to printed promotional

material and recommends that all advertisements

include: the name of the drug (usually the brand

name); a list of active ingredients, using the

International Non-proprietary Name (INN), if

possible; at least one approved indication for use,

with dosage and method of use; and a succinct

statement of side-effects, precautions, and contraindications. Exceptions are made for short advertisements, known as “reminders,” provided

the reminder states that further information is

available on request. Finally, the word “safe” is

not to be used without qualification in any advertisement (11 1).

The remaining sections of the Code cover

other promotional practices, such as the use of

medical representatives, symposia, medical congresses, and other means of verbal communication. The Code confirms the importance of these

promotional practices for the dissemination of information, but stresses that scientific objectives

should be their main focus. The Code requires

that medical representatives be “adequately

trained and possess sufficient medical and technical knowledge to present information on their

company product in an accurate and responsible manner” (1 11). This stops short of WHO’s

Ethical Criteria, which require that medical representatives refrain from providing inducements

to prescribers and dispensers and that the main

part of medical representatives’ remuneration

should not be directly related to their sales volume (264). The IFPMA Code also stipulates that

supplies of samples should be limited to the

amounts necessary for a health professional to

become familiar with the drug. The Ethical

Criteria state that free samples of prescription

drugs should be provided only in modest quantities and generally only on request (264). The

IFPMA Code also responds to criticisms that

pharmaceutical companies sometimes make

medical promotional material look scientific. The

Code states that promotional material, such as a

mailing or medical journal advertisement, must

“not be designed to disguise its real nature”

(111).

 Implementation Mechanisms

The original Code did not contain provisions

for monitoring or enforcement. In 1982, apparently in response to criticism from consumer

groups, the IFPMA established a complaint procedure for reporting alleged violations (90). Not

all complaints go directly to the IFPMA because

all member associations have adopted the Code,

or more detailed codes, and some national organizations have their own adjudicating committees

to address complaints (285). If the complaint is

made directly to the IFPMA, the IFPMA contacts

the appropriate member association in the country of the company’s headquarters and, if applicable, the member association in the country in

which the violation occurred. (In cases involving

nonmember companies, IFPMA makes informal

contact, whenever possible, encouraging them to

follow the IFPMA Code.) (109) The member association refers the matter to the company concerned, and the company’s response is sent back

to IFPMA through the member association.

The response is reviewed by the IFPMA

“President’s Committee,” consisting of the presi-
Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information 137

dent, two vice-presidents, and an executive vicepresident. The Code also notes that the committee is counseled by three independent reviewers

(1 11); however, the Ten Year Report on the

IFPMA Code (1 10) makes no mention of the independent reviewers and the executive director of

the IFPMA has stated it is not feasible to have

outsiders review the complaints (187). When the

President Committee has reviewed a case, a formal reply is sent to the complainant. The IFPMA

states that no member company or member association has failed to take corrective action when

found to be in violation of the Code (1 10).

Because the Code is voluntary, IFPMA relies

on adverse publicity as a “stick” to keep members in compliance. Status reports on the Code

(the list of all complaints made, the companies

involved, and the actions taken) are public and

can be obtained from IFPMA, though they are

not distributed widely. Code-related activities are

also summarized (by number and type of complaint, and by action taken) in the IFPMA

newsletter, Health Horizons, and certain international pharmaceutical publications also report on

complaints brought under the IFPMA Code (e.g.,

SCRIP World Pharmaceutical News).

 Reporting and Resolution of IFPMA

Code Violations

The IFPMA complaint procedure has been

used by consumer groups, WHO, and by individuals. Between 1982 and 1991, the IFPMA received 72 complaints, comprising 926 separate

cases. Forty percent of the complaints (accounting for 86 percent of the cases) were brought by

consumer groups, with WHO accounting for another 35 complaints (involving 100 cases) (1 10).

In 1987, 13 complaints involving 509 separate instances were filed. The majority of these complaints were filed by the Medical Lobby for

Appropriate Marketing (MaLAM), an international doctors lobbying network (See ch, 7.)

(130). Most of their complaints referred to advertisements in prescribing guides (1 10).

Approximately 56 percent of complaints (535

citations) concern Section IV of the IFPMA

Code. In particular, these complaints have focused on the lack of full disclosure of active

ingredients, the nature of indications and the disclosure of side effects, precautions, and contraindications. Many of the complaints have focused

on reminder advertisements, which need not

carry complete information unless the pharmaceutical’s use entails specific precautionary measures (1 10). MaLAM, one of the groups whose

complaints have focused on reminder advertisements, claims that the IRMA has refused to clarify the exact definition of a reminder or the

phrase “specific precautionary measures.” According to MaLAM, IFPMA has permitted relatively long advertisements (more than 200

words) to be classified as reminders, exempting

them from the more inclusive requirements for

full advertisements. MaLAM also cited examples

of reminders that, as required, state “further information is available on request,” but either fail

to provide an address, or refer readers to information available only if the drug is purchased

(130,196).

From August 1989 through August 1990, over

half of the 34 breaches of the Code (out of 74

cases resolved) were for failure to adequately

support claims for a product with scientific evidence, or for making claims not in accordance

with “needs of public health.” Six advertisements

were cited for using the word “safe” without

proper qualification. Twelve other advertisements failed to include all the information required by the Code (109). U.S. pharmaceutical

companies were responsible for six of the 34

breaches: one for failing to use the non-proprietary name, three for failing to include complete

information in advertisements, one for including

advertising claims that were stronger than justified, and one for using the word “safe” in an unqualified manner (109).

Not all complaints are found by the President’s

Committee to violate the Code. Of the 926 cases

resolved between 1982 and 1991, approximately
138 I Drug Labeling in Developing Countries

56 percent were declared by the IFPMA to be

breaches; 21 percent were not breaches; 10 percent were declared invalid because the complaint

was based on false or out-of-date information, or

was a repeat complaint about the same advertisement; and 13 percent did not involve member association companies.9

 Criticisms of the Code

The IFPMA Code has been criticized by both

pharmaceutical associations and health activists

because its requirements lack specificity and are

prone to subjective interpretation (103,196,223).

The Code requires, for instance, that information

on products conform to “ethical standards and

standards of good taste” (111), without further

explanation. On another point, the Code states

that a product should not be promoted as safe and

effective for a particular indication before it has

been approved officially for that indication, but

also states that the scientific community and the

public have a right to be “fully informed” of the

results of investigational studies (111). So while

the Code does not permit a company to market a

drug for indications not approved by a regulatory

authority, the company may disseminate the results of studies that support unapproved indications.

With respect to pharmaceutical sales representatives, the Code does not define what constitutes

“sufficient training” or the type of information

sales representatives must provide, and it does

not provide guidance on what might be a reasonable amount of free samples. According to one

activist, the only provision that is not ambiguous

is the requirement that the word “safe” be qualified (103).

IFPMA has also been criticized for the amount

of time it takes to make a determination on alleged infractions; MaLAM has claimed that the

delays permit companies to continue running

advertisements that violate the Code (130).

MaLAM filed 208 complaints in January 1987,

and the IFPMA responded with an interim report

on 165 of them 7 months later. This interim report listed 89 infringements, and 28 “invalid

complaints.” The remaining 43 complaints were

not acted on because the companies involved

were not members of IFPMA associations.

In April 1987, MaLAM filed another 254

complaints, and the IFPMA responded to 111 of

them almost a year later, in March 1988, leaving

143 complaints unresolved. This response included findings of 44 new breaches and 42 repeat

advertisements from the first submission by

MaLAM (130). IFPMA classified these 42 repeat

submissions as invalid complaints, rather than

continued infractions, as MaLAM contended

they were (130). One activist, who filed 259 complaints between November 1985 and April 1988,

reported that the average time taken to resolve

222 of his complaints was about 7 months (195).

IFPMA explains that the large number of complaints received in 1987 could be interpreted as

an attempt to “break the system,” as many of

them did not include documentation, making resolution of those cases more difficult (1 10).

IFPMA also points out that a delay in issuing a

decision does not necessarily delay remedy of a

breach. IFPMA claims that companies often take

remedial action soon after being informed of a

complaint, before the IFPMA decision is made.

Perhaps the most controversial aspect of the

Code is IFPMA’s interpretation of provisions requiring deference to national laws. IFPMA acknowledges that it would be desirable for labeling, packaging, leaflets, and data sheets used in

developing countries to be consistent with the

ones used in industrialized countries. However, it

recognizes that a company ultimately must follow the regulations of the country in which the

drug is marketed. According to IFPMA, regulato9 ~~ough tie IFPMA may con~ct the membr association in the country where the company k hxated, tie compltit is not a ~mch ~-

less the company is part of a member association of the IFPMA (1 10).
Codes of Conduct and Voluntary Guidelines for Pharmaceutical Information 1139

ry requirements differ among countries for good

reasons (11 1):

. . .[t]he decision of a national authority with regard to the permitted indications and precautionary information to be provided about the

product must take precedence.

Furthermore, when a product has been evaluated

and registered by an established regulatory authority, the approval by itself is accepted as adequate evidence of the product’s efficacy. IFPMA

does not challenge the decisions or judgments of

national regulatory agencies in any country (9).

MaLAM asserts that the IFPMA position is

flawed, noting that the Code recognizes that

“Third World countries are not aware of the indications, contra-indications, side-effects, etc. of

individual drugs that have been adopted in developed countries” (11 1), yet IFPMA advocates deferring to regulatory bodies of developing countries on those issues. MaLAM contends that the

point of self-regulation is to develop a voluntary

standard that is compatible with, but different

from, the government standard. According to

MaLAM, industry standards should meet or exceed those of the government, especially when

the government agency has limited resources for

drug regulation (139).

Despite the criticisms of the Code, it remains

one of the few formal mechanisms for challenging specific advertisements. The complaint procedure has been responsible for at least some improvements in pharmaceutical promotion. In the

past 2 years, IFPMA has received only 17 complaints involving 34 different instances (1 10).

Consumer groups, however, still report violations

of the Code and continue to push for stronger

mechanisms for controlling promotion of pharmaceutical products (39).

SUMMARY

Codes of conduct offer a possible means of

setting international standards for drug labeling

without compromising the sovereignty of individual countries. However, even though the codes

are voluntary, they are not necessarily easy to develop, as the Translational Code demonstrates.

While not binding legally, they are formal pronouncements and will not be endorsed by governments that do not agree with their provisions.

The most relevant precedent for a pharmaceutical

labeling code is the Breast-Milk Substitutes

Code. That Code was devised at a time of public

outrage at the behavior of certain MNCs, however, and addressed a less complex issue than that

of drug labeling.

Codes of conduct provide general guidance

and principles for behavior. A code of conduct

for pharmaceutical labeling might define the categories of information that should be on a label

and create some uniformity in labeling format. It

could also address the type of information that

should be presented to a developing country regulatory body with an application for registration.

A code would not, however, define the content or

wording of the label for each individual product.

The overall impact of such a code would depend

to a great extent on how it was implemented and

monitored over the long term.
Efforts to Improve

Drug Information

In Developing

Countries 7

D

rug labeling is not the only, or necessarily the most important, pharmaceutical issue facing developing countries, but it is recognized as an essential component of

effective drug regulation. The World Health Organization (WHO), national governments, and private organizations

have made efforts to promote the rational use of drugs, and within that broad objective, to improve the prescribing information

available in developing countries. The activities of WHO, the

U.S. Food and Drug Administration (FDA), and private groups

related to drug labeling are discussed in this chapter.

THE WORLD HEALTH ORGANIZATION

In the past decade, pharmaceutical programs of the World

Health Organization (WHO), in conjunction with other donors,

have assisted developing countries in formulating comprehensive national drug policies (135). The focus of many national

programs is pharmaceutical supply and consumption in the public sector, but strengthening regulation has been another priority.

The following discussion covers briefly the main WHO activities directed specifically at improving drug regulation and prescribing information for physicians.

 Action Program on Essential Drugs

WHO direct country support for pharmaceutical issues is provided primarily through the Action Program on Essential Drugs

(APED). APED promotes the rational use of drugs all over the

world, especially in developing countries. 1 The core of the

1

‘ For an overview of the history of the APED and the political constraints on WHO’s

efforts in this area, see reference number 183.

141
142 I Drug Labeling in Developing Countries

Action Program is WHO’s “Model Essential

Drug List,” which can be adopted by countries,

modified to fit their health needs, and used to

promote the rational use of a limited number of

pharmaceuticals. APED also promotes improved

registration systems to better ensure that only

safe, effective, and properly labeled products

enter the market.

WHO provides training materials and seminars to achieve its goals. Among the publications

relevant to drug labeling are: the Model Guide to

Good Prescribing (286), developed in conjunction with the Groningen University in the

Netherlands, and designed to be used in undergraduate medical education; the Manual for

Rural Health Workers: Diagnosis and Treatment

with Essential Drugs (47); and The Essential

Drugs Monitor, a quarterly newspaper that discusses all aspects of essential drug programs, focusing on existing programs in developing countries. The Essential Drugs Monitor is distributed

to 28,000 subscribers and is read by 180,000

people worldwide (286). APED also has a

Documentation Center that distributes more than

20,000 publications a year and issues a periodically updated bibliography of available materials

(on diskette and in printed form) (286).

 Drug Management and Policies

WHO’s Division of Drug Management and

Policies (DMP), which is independent of the

Action Programme on Essential Drugs, is responsible for a number of functions involving

pharmaceutical issues. The DMP’s units include

Biological Standardization, Drug Regulatory

Support, Drug Safety and Efficacy, and Quality

Assurance. The DMP develops the Mode l

Prescribing Information used by APED and coordinates the exchange of information on safety

and efficacy of pharmaceuticals. In addition, the

DMP is responsible for monitoring and further

developing WHO’s Certification Scheme on the

Quality of Pharmaceutical Products Moving in

International Commerce, which is discussed

below.

 WHO Certification Scheme

In 1969, WHO endorsed requirements for

“Good Practices in the Manufacture and Quality

Control of Drugs” (Guidelines on Good Manufacturing Standards) (285). These guidelines

were the starting point for the “Certification

Scheme on the Quality of Pharmaceutical

Products Moving in International Commerce,”

which was adopted in 1975 (275). The Certification Scheme was designed to assist countries

lacking a comprehensive or effective drug control or registration system to ensure the safety

and quality of imported drugs. Under the Certification Scheme, an importing country may request that the regulatory authority of the country

in which the drug is manufactured provide a cerSample of WHO essential drugs.
Efforts to Improve Drug Information In Developing Countries 143

tificate assuring that it was manufactured in accordance with good manufacturing practices. As

originally designed, the certificate included the

name and dosage form of the drug, the active ingredients, and either certified that the product

was approved for marketing in the country of origin, or explained why it was not. In addition, the

Drug prescribing by village health worker in

Bangladesh.

regulatory authority certified that the factory producing the drug was inspected regularly and

complied with WHO guidelines on good manufacturing practices,

In 1984, the Third International Conference of

Drug Regulatory Authorities (cosponsored by

WHO and the U.S. FDA) recommended that the

product labeling information approved in the

country of origin be submitted with the certificate. They also recommended that the

Certification Scheme be broadened to include

imports of raw materials and unfinished products

(275). These recommendations were adopted in

1988 (277). The new certificates require copies

of all labeling supplied with the product in the

country of origin, including approved packaging

materials and package inserts (277).

WHO recently issued proposed new guidelines for the Certification Scheme, which were

endorsed by the World Health Assembly (266).

The new guidelines call for the issuance of one of

three different certificates: certificate of a pharmaceutical product (see figure 7-1), statement of

licensing status of a pharmaceutical product, and

batch certificate of a pharmaceutical product

(285). The certificate of a pharmaceutical product is used by an importing country when: 1) the

country is evaluating whether to approve a product for import and sale and 2) when administrative action is required to renew, extend, vary, or

review an existing license for import and sale

(285). The company exporting the product is responsible for requesting that a certificate be issued. So, if OTA, Inc. wished to export a drug to

Thailand, and the Thai regulatory authority

wanted a WHO certificate of a pharmaceutical

product, OTA, Inc. would ask the FDA to issue a

certificate to Thailand. Under WHO’s Guidelines, the certificate is considered a confidential

document.

Man purchasing low-priced essential drugs in Nepal,
Figure 7-l—Facsimile of WHO Certification Program Certificate

Exporting (certifying) country

lmporting (requesting) country:

Certificate of a Pharmaceutical Product

Proprietary name (if applicable) and dosage form:

Active ingredient(s) and amount(s) per unit dose:

1. Is this product licensed to be placed on the market for use in the exporting country? If yes, complete box A; if no, complete box B

A

Product Iicence holder:

Status of Iicence holder:* aD ba cCI da

Number of product Iicence and date of issue:

is an approved technical summary appended? yes ❑ n o

Is the attached product information complete and consonant with the Iicence?

y e s n o n not provided

Applicant for certificate if different

from the licence holder.

B

Applicant for certificate:

status of applicant:” an bu CO d ❑

Why is authorization lacking?:

not ❑ n o t Undercl refused

required required consideration

Remarks:

2. Does the certifying authority arrange for periodic inspection of the manufacturing plant in which the dosage form is produced?

• l

y e s If No, proceed to

no ❑ question 3

Periodicity of routine inspections (years):

Has the manufacture of this type of dosage form been inspected? yes ❑ non

Do the facilities and operations conform to GMP as recommended by the World Health Organization?

• l

y e s non

—

3. Does the information submitted by the applicant satisfy the certifying authority on all aspects of the manufacture of the product undertaken by another party?

yesn non If no, explain:

Address of certifying authority: Name of authorized person:

Signature:

Stamp and date:

Telephone/fax numbers:

This certificate conforms to the format recommended by the World HeaIth Organization.

● Specify whether the person responsible for placing the product on the market;

(a) manufactures the active ingredients and the finished dosage form;

(b) manufactures the finished dosage form;

(c) packages and/or labels a finished dosage form manufactured by an independent company;

(d) is involved in none of the above.

SOURCE: World Health Organization, Implementation of WHO’s Revised Drug Strategy-Safety and Efficacy of Pharmaceutical Products, Progress Report of the Director General, A45/13

(Geneva, Switzerland: WHO, 1992).
Efforts to Improve Drug Information In Developing Countries I 145

The statement of licensing status of a product

attests that the product has been licensed for sale

in the country of export. The statement is intended to be used by importers considering bids made

in response to an international tender for drugs

(285). The batch certificate of a pharmaceutical

product provides information on the quality and

expiration date of a specific batch of the product,

including results of any analyses undertaken on

the batch. For most products, the batch certificate

is issued by the manufacturer. For vaccines, sera,

and other biological products, the certificate is issued by the regulatory authority (285).

By 1990, 129 countries had notified WHO that

they intended to use the Certification Scheme;

however, most of the countries opted to use it as a

means of controlling imports, not as a means to

support exports (52), Countries were regularly

requesting certificates for imports, but did not

have a policy of providing certificates with exports. This is not surprising because in order to

issue a certificate a country must ensure that:

●

●

●

●

It is

the authorization for sale or distribution is

subject to appropriate testing,

its pharmaceutical industry conforms with

recommended standards for the manufacture

and quality control of pharmaceuticals,

the competent authority is given the authority to carry out complete inspections of the

pharmaceutical manufacturing facilities, and

the country’s inspectors are qualified and

experienced.

likely that only those countries with develDonated drugs or drugs procured from wholesalers and brokers with a wide variety of sources

may not be easily certified. Products manufactured specifically for a foreign agency or government may differ from the manufacturer’s standard products and labeling from the standard

product may not be appropriate for the special

product (275). If a country requests a certificate

only at the time of frost import or when a drug is

reregistered, the country may not obtain updated

oped drug regulatory bodies could provide certificates that meet these criteria (285). In addition, evidence suggests that the Scheme is not

used optimally by developing countries, particularly in Africa, which relies heavily on imported

pharmaceuticals (275,200).

The Certification Scheme has limitations.

Certificates may be difficult to obtain for drugs

manufactured in more than one country or manufactured in one country and packaged in another.

Transport of essential drugs in Latin America

information about the drug (164). Countries with

inadequate administrative or legal infrastructure

for drug regulation may be unable to use the

Certification Scheme effectively (164).

APED and DMP have initiated activities to

improve the Certification Scheme and expand its

adoption. The United States Agency for International Development (USAID) is supporting a

WHO evaluation of the Certification Scheme in
146 I Drug Labeling in Developing Countries

developing countries and the DMP is carrying

out field trials in a number of countries (259,

286).

 Distribution of Prescribing Information

In addition to labeling provided with a drug,

compendia of pharmaceutical information from

industrialized countries are useful sources of prescribing information for officials and physicians.

WHO is working to provide national drug regulatory authorities in developing countries with

three of these compendia, which contain information approved by the regulatory authorities in

those countries: the Dictionnaire Vidal (249) (information approved by the French Ministry of

Health); Association of the British Pharmaceutical Industry Data Sheet Compendium (10) (information in compliance with the regulations of

the United Kingdom), and the Physicians’ Desk

Reference (information in compliance with regulations of the U.S. FDA) (258).

DMP has also begun work on a series of publications entitled WHO Model Prescribing

Information for those drugs on the essential

drugs list that are of particular interest to developing countries. The first one, Drugs Used in

Anesthesia (280), was published in 1989; Drugs

Used in Parasitic Diseases (282) was released

during 1990; and Drugs Used in Mycobacterial

Diseases (284) in 1991, with more in preparation.2

 Access to New Information on

Safety and Efficacy of Pharmaceuticals

Most industrialized countries have formal programs for monitoring adverse reactions associated with pharmaceuticals. Developing countries

typically do not have the resources to do this in

their own countries, and as a result, may not be

able to respond to the need to revise labeling, or

even withdraw a drug from the market. One

WHO priority is to secure the regular exchange

of information on the safety and efficacy of pharmaceuticals and to promptly transmit new information on serious side effects to national health

authorities (258). The DMP receives information

regularly on decisions of regulatory authorities

and voluntary decisions of manufacturers related

to the safety of pharmaceuticals. During 1986,

for example, WHO received information on decisions about 360 pharmaceutical products from 35

countries (258). This information is disseminated

monthly to the drug regulatory authorities of

member countries through the WHO Pharmaceutical Newsletter (285). DMP also produces

WHO Drug Information, a quarterly journal that

provides discursive commentaries on the more

important actions of national drug regulatory

bodies (258,285).

WHO has established collaborating centers in

each of its five regions for the purpose of information dissemination, training, and operational

research. The most recent collaborating center

was established in India in 1988 to serve 11

countries in Southeast Asia (131,274).

These collaborating centers are distinct from

the WHO Collaborating Centre for International

Drug Monitoring in Uppsala, Sweden, which is

an international center for monitoring adverse

drug reactions. Thirty-three countries, including

the United States, provide case reports on adverse drug reactions to the Uppsala Centre where

the data are combined and analyzed to detect relationships between drugs and rare adverse reactions (290). The information in the database at

Uppsala, which as of 1991 contained 950,000 individual case reports (290), is available only to

the countries that participate in reporting.

Nonparticipating countries may learn about the

adverse reactions through medical journals or

through the regulatory actions of participating

z w() is Cmentiy wor~g on pre~ribing gUMW for drugs used in treating sexually transmitted diseases, including ~S, ad o~er ~cterial diseases, and in neurology and dermatology (285).
Efforts to Improve Drug Information In Developing Countries I 147

countries, but there is no guarantee that they, in

fact, will (290).

THE U.S. FOOD AND DRUG

ADMINISTRATION

The FDA is primarily a domestic agency, but

being the regulatory agency for one of the largest

pharmaceutical markets in the world, it is also involved in international pharmaceutical issues.

The FDA is not a development agency and it does

not generally help other countries with projects

specifically designed to improve the marketing

and labeling of drugs, but it does assist developing countries by sharing its expertise with their

drug regulatory personnel.

Most of FDA’s international activities are coordinated by its International Affairs Staff (IAS)

under the Associate Commissioner for Health

Affairs. The IAS is principal FDA contact point

and liaison with foreign counterpart agencies,

foreign embassies, international regional organizations, U.S. Government agencies (e. g., the

Office of International Affairs, U.S. Public Health

Service; USAID, the U.S. Trade Representative),

and U.S. embassies. IAS arranges the participation of FDA officials in U.S. delegations to international meetings, such as those held by WHO.

Four IAS officials are responsible for bilateral liaison within broad geographic regions.

One of FDA’s most visible international activities is the dissemination of information about

regulatory actions. FDA sends monthly updates

to WHO and representatives of the European

Community on important regulatory developments, including proposed regulations and policies; reports of serious adverse reactions from

pharmaceuticals; the monthly list of approvals

for new drugs, medical devices, and biologics;

and other public information. WHO may incorporate this information in its newsletters, which

are distributed internationally.

The FDA also sends its Medical Bulletin (see,

e.g., ref. 150) to more than 800 government and

academic organizations around the world. Many

of these institutions are in industrialized countries (e.g., more than 129 Canadian institutions

are on FDA’s mailing list), but a number are in

developing countries. The Medical Bulletin focuses on new FDA policies and findings on particular drugs and devices, For example, a recent

issue discussed the dangers of angiotensin converting enzyme (ACE) inhibitors during the second and third trimesters of pregnancy, allergic reactions with dialysis and ACE inhibitors, new

Halcion labeling, warnings about sporicidin

products, FDA proposed food labeling reforms,

recommendations on silicone breast implants,

and foodborne diseases in nursing homes (150).

Until the end of 1991, the FDA sent quarterly

information packets to WHO, the Pan American

Health Organization (PAHO), and approximately

70 drug regulatory authorities throughout the

world (95). This policy has now modified to

sending important policy papers to WHO and to

62 foreign embassies located in Washington, DC.

The material sent by FDA does not necessarily

focus on labeling for specific drugs but instead

highlights regulatory decisions that U.S. regulators believe are important (32).

The FDA also has a special procedure for notifying foreign purchasers that a drug or medical

device has been withdrawn from the U.S. market

for safety reasons. FDA contacts the U.S. company for a list of foreign individuals, institutions,

and government agencies that have imported the

product. The IAS works with the U.S. Department of State to provide the U.S. embassies

in the countries in which the product is sold with

a list of the purchasers so that the purchasers can

be notified (168). FDA provides a summary o f

the reasons for withdrawal, and encourages the

U.S. company to provide foreign purchasers with

complete information. FDA may evaluate the

effectiveness of the company’s notice by requesting that the U.S. embassies follow up with foreign purchasers to see whether information was

provided. If the company has not provided adequate information, FDA may ask them to send it

but does so without legal authority. There have
148 I Drug Labeling in Developing Countries

been few drug withdrawals in which FDA has

used this special notification procedure (31).

FDA also responds to requests for information

from other countries. FDA is currently setting up

an electronic bulletin board that will contain all

public information issued by the FDA including:

Enforcement Report (weekly recall list), a drug

and device product approval list, Medical

Devices and Radiological Health news, FDA

Medical Bulletin, FDA Consumer Information,

FDA’s Federal Register summaries, speeches by

FDA officials, FDA congressional testimony,

special AIDS information, Veterinary Medicine

news, and notice of upcoming FDA public meetings. The electronic information will be available

through INTERNET, a worldwide research computer network of government, military, academic,

and other organizations (32).

The IAS administers the FDA International

Visitors Program. In the year ending September

1991, FDA was visited by 603 representatives

from 61 countries. In 1990, the IAS arranged visits to the FDA by 789 foreign officials representing 65 countries and multinational organizations

(168).

FDA cooperates with WHO in various activities. In 1980, the FDA and WHO cosponsored

the first International Conference of Drug Regulatory Authorities, held biannually since then,

bringing together regulatory authorities from all

over the world. FDA representatives have provided advice and other assistance to various WHO

programs including the Action Program on

Essential Drugs, WHO’s Management Advisory

Committee, the Certification Scheme, the Ethical

Criteria for Medicinal Drug Promotion, the preparation of Model Drug Prescribing Information,

the Model Lists of Essential Drugs, and the

Global Program on AIDS (166). FDA is also a

WHO Collaborating Center for Monitoring of

Adverse Drug Reactions, providing WHO with a

monthly accounting of all serious adverse reaction reports (168).

FDA staff have also assisted WHO with drug

regulation projects in developing countries (17).

In 1988, for example, the FDA provided a drug

specialist for 2 years to PAHO, a regional office

of WHO, to assist with formal training programs

designed to strengthen national drug agencies

and improve pharmaceutical manufacturing (57).

Most recently, the FDA agreed to assist USAID

in its support of a WHO evaluation of the

Certification Scheme (see above) (24,259), and

USAID and the FDA will assist in a WHO evaluation of its “Guiding Principles for Small National Authorities” (24, 278).

THE U.S. AGENCY FOR INTERNATIONAL

DEVELOPMENT

Until recently, USAID was not involved directly with WHO’s pharmaceutical work, but has

just begun funding a WHO evaluation of both the

Certification Scheme and the “Guiding Principles for Small National Authorities.” USAID is

also supporting a WHO project to develop country-specific research on current pharmaceutical

use in developing countries. The research will be

carried out by the International Network for the

Rational Use of Drugs (INRUD) (see below for

description of INRUD), which will develop a

Drug Use Indicators Manual. The manual will

include background, definitions, methodologies

for collecting drug use indicators,3 and extensive

appendices containing data collection methods,

drug and problem lists, and data collection forms

(24,113). A report on these activities should be

available by the end of 1992.

USAID is also engaged in a 5-year cooperative

agreement with the U.S. Pharmacopoeia to assess

and facilitate the distribution of pharmaceutical

3 Dmg USC ~di@tom ficlude: ~v~age n~~r of tigs used per facility; percent of antibiotics or injections; l=cent of patients not provided drugs; number of essential drugs in stock patients reporting correct dosing, etc. (1 13).
Efforts to Improve Drug Information In Developing Countries I 149

information in developing countries, including

both information provided to the drug regulatory

authorities and to health workers (24). Finally,

US AID has requested proposals for a 5-year contract addressing three areas of pharmaceutical

distribution in developing countries: drug regulation and registration; rationalization of procurement strategies; and the development of pharmaceutical information for prescribers, consumers,

and drug regulatory authorities (24).

CONSUMER HEALTH ADVOCATES

A variety of organizations and individuals address themselves to pharmaceutical issues in developing countries. This section concentrates on

groups that act as advocates for political change

or focus on the role of multinational pharmaceutical companies in the area of drug information.

The many organizations that provide health care

or focus on health issues other than pharmaceuticals are not discussed here.

Public health advocacy may take several

forms. The most common form is the dissemination of information to the public and the press

about actions of industry, international organizations, or governments, that are inconsistent with

consumer interests. Consumer boycotts, while

difficult to organize, can also be powerful. In addition, public interest organizations may operate

as information clearinghouses and many provide

educational programs in developing countries.

Numerous public interest groups operate in individual countries. Many of the individual health

and consumer groups in both developing and industrialized countries are part of a larger international network, Health Action International

(HAI), which itself works closely with the

International Organization of Consumers Unions,

an umbrella group that helps promote consumer

issues and consumer advocacy in many countries,

These two groups and selected smaller consumer

groups are discussed below.

 The International Organization of

Consumers Unions

The International Organization of Consumers

Unions (IOCU) was formed in 1960 as a multipurpose resource for its membership of 130 consumer groups in 51 countries. IOCU’s central office is in the Hague, and its two regional offices

are in Penang, Malaysia, and Santiago, Chile.

IOCU acts as an information network, coordinates consumer activities, holds a triannual world

congress, and organizes international seminars

and workshops. In 1973, IOCU published one of

the frost studies on drug labeling in developing

countries (see app. A) (61,116) and it continues

to be active in drug information as well as other

issues of pharmaceutical distribution. In August

1990, IOCU sponsored an International Workshop on Consumer Health and Drug Information

and Education in Penang, Malaysia. The major

objective of the workshop was to determine how

media could be used effectively to communicate

information to parents about children’s health

and the rational use of drugs (54),

IOCU drug labeling activities include collecting relevant information (e.g., general prescribing information, lists of banned or restricted

pharmaceuticals, reports of adverse effects) and

passing this information on to developing countries. IOCU also publishes reports related to the

pharmaceutical industry and rational drug use. In

1981, IOCU published a Consumer Action and

Resource Kit on Pharmaceuticals, which focused

on 44 “problem” drugs, that could be used by

groups in developing countries to lobby against

the sale of dangerous drugs (154).

IOCU also maintains a network called Consumer Interpol, consisting of approximately 260

correspondents in 79 developing and developed

countries (117). The correspondents monitor information on newly discovered or newly regulated hazardous consumer products, including pharmaceuticals, such as notifications of banning,

restriction, withdrawal, or nonapproval of products. This information is received by the Con-
150 I Drug Labeling in Developing Countries

sumer Interpol office in Penang and may become

the basis for Consumer Alerts sent to all members of the network. As of March 1991, 85

Consumer Alerts had been sent out, covering

hazardous toys, cosmetics, pharmaceuticals,

electrical goods, food products, pesticides, and

other items (4). Consumer Interpol also distributes a Consumer Interpol Memo, relating selected articles and news briefs on consumer issues,

and a quarterly Consumer Interpol Focus, with

feature stories on specific safety problems or

major international initiatives to restrict global

trade in hazardous products (3).

IOCU has published many books and pamphlets on technical aspects of pharmaceutical

use. In 1988 it published several short pamphlets

written by it pharmaceutical adviser, K.

Balasubramaniam, including: Policy Options in

Pharmaceutical Patents for Developing Asian

Countries (14); The Rational Use of Drugs: A

Universal Concept (15); Global Marketing of

Pharmaceuticals: Prescription for Disaster (12);

and Policies and Strategies On Drug Pricing

Regulations: International Experiences (13).

IOCU also supports publications by other consumer organizations.

With respect to pharmaceutical issues, IOCU

plays a major role in one of the primary international consumer health organizations, Health

Action International.

 Health Action International

In 1981, 50 consumer organizations and individuals founded Health Action International

(HAI) as an “international antibody” to the adverse effects of pharmaceutical marketing. HAI

has coordinating offices in Europe, Asia, and

Latin America. HAI’s original agenda included

(102):

1.

2.

3.

developing an information clearinghouse;

responding to the IFPMA Code of Pharmaceutical Marketing Practices;

coordinating activist campaigns regarding

specific drugs and companies;

4.

5.

6.

promoting full implementation of WHO’s

Action program on Essential Drugs;

pressuring industry to market drugs that

meet “real medical needs,” have “significant medical value,” and are acceptably

safe and efficacious; and

supporting nondrug solutions to health

problems.

HAI has coordinated international advocacy

for essential drug policies in lobbying WHO,

UNICEF, the European Parliament, and other international and regional bodies (16,97).

For a number of years, HAI lobbied WHO to

pass a code of pharmaceutical marketing. In

1982, HAI published its own code of conduct

that it hoped would be the basis for a U.N. or

WHO international code. The HAI code demonstrates the degree of specificity that consumer

groups seek. With respect to labeling, HAI’s code

calls for package labels with:

1.

2.

3.

4.

5.

specific information on whether the product is for prescription or OTC use;

the non-proprietary name for all active ingredients printed in equal or greater size

than the print used for the manufacturer’s

name;

information on the class and category of

therapeutic use;

an explanation of all contraindications that

may endanger life or severely endanger

health; and

a list of all active ingredients.

HAI also would limit claims about efficacy,

safety, or potency of the product unless they were

qualified. In addition, the HAI Code would require that package inserts include: 1) only those

indications approved by public health authorities

or generally endorsed by reputable and independent scientific publications, 2) all contraindications that are not included on package label, and

3) a list of active and inactive ingredients (84).

Finally, HAI would require graphic warning

symbols on all promotional material indicating
Efforts to Improve Drug Information In Developing Countries 151

products that should be avoided during pregnancy or lactation, on all prescription-only products

to indicate changes in product information, and

on new products for which reports of any adverse

reactions or events are required (86).

HAI has published a detailed critique of the

IFPMA Code and WHO’s Ethical Criteria for

Medicinal Drug Promotion (see ch. 6) (86).

Another report by HAI presents evidence that the

IFPMA Code is not effective in controlling advertising (39). In 1992, HAI carried out the first

phase of an international survey of pharmaceutical marketing standards that will evaluate the implementation of WHO’s Ethical Criteria for

Medicinal Drug Promotion (97). Initial results indicate that the Ethical Criteria have not been effective because they have not been implemented

at the national level (89).

HAI member groups also focus on problems

with specific products or categories of product,

trying either to have the products removed from

the market or to change their labeling or promotion. Their campaigns usually consist of documenting problems with drug products, challenging the companies involved to respond to their

criticisms and, if the company responses are not

satisfactory, using public education campaigns

“built on solid information and powerful emotional pleas” (102)0 The organization communicates through an international newsletter, HAI

News.

One HAI international campaign was directed

at removing inappropriate antidiarrheals from the

market. Following a WHO paper on the limited

efficacy of antidiarrhea drugs, HAI members in

Latin America published a survey of antidiarrhea

drugs marketed in Bolivia, Brazil, Chile,

Colombia, Costa Rica, Ecuador, Guatemala,

Mexico, Peru, Uruguay, and Venezuela. A number of products that WHO said were not efficacious, and potentially harmful, were widely

available in those countries (87).

HAI has published various resource books on

pharmaceuticals. Problem Drugs (38), a HAI “information and campaign pack” on various categories of “problem” pharmaceuticals, was first

published in 1986. It has since been translated

into 8 languages and a new edition is scheduled

for release in 1993 (97). Other publications include: Peddling Placebos: An Analysis of Cough

and Cold Remedies (36), Antibiotics: The Wrong

Drugs for Diarrhoea (35), Cleared for Export

(33), The Provision and Use of Drugs in

Developing Countries (71), Drugs and Primary

Health Care (63), Promoting Health or Pushing

Drugs? A Critical Examination of Marketing of

Pharmaceuticals (39), A Question of Control

(261), and Bitter Facts About Drugs (5). Andrew

Chetley, a prominent consumer advocate who has

worked with a number of consumer groups, is the

author of several of these publications and has recently written a book analyzing the role the pharmaceutical industry has played in health care in

the developing world (37).

In addition to its publications and lobbying,

HAI groups help promote and develop national

drug policies and sponsor a wide variety of training and education programs. HAI seeks to promote the WHO Ethical Criteria for Medicinal

Drug Promotion, and continues to expand and

strengthen its ties to local consumer organizations in developing countries (88).

SOCIAL AUDIT

Social Audit, based in the United Kingdom, is

an active HAI member. It has concentrated on the

marketing practices of British multinational

pharmaceutical corporations in developing countries, but it also has examined their activities in

industrialized countries. In 1979, Social Audit

published Insult or Injury? An Enquiry into the

Marketing and Advertising of British Food and

Drug Products in the Third World (142), a work

funded largely by IOCU. In 1982, the group published Drug Diplomacy: Decoding the Conduct

of a Multinational Pharmaceutical Company

(148). This book chronicles Social Audit’s campaign against the marketing claims made by

Searle Pharmaceuticals for its antidiarrhea drug

330-065 0 - 93 - 6 QL 3
152 I Drug Labeling in Developing Countries

Lomotil, a campaign that Social Audit maintains

resulted in changes in the labeling (154).

In 1980, Social Audit published Dru g

Disinformation: What British and Multinational

Drug Companies Tell Doctors About Their

Products, At Home and Abroad (143). This book

compared the information for about 900 drugs

listed in MIMS prescribing guides in England

and Ireland. Although over half of the entries

were identical, the study found what they believed to be significant discrepancies for the prescribing entries for over 200 products.

The main force behind Social Audit is its

Director, Charles Medawar. He continues to publish books and articles that keep the work of

Social Audit visible. In addition to the titles listed

above, he has written: The Wrong Kind of

Medicine? (144), Drugs and World Health (146),

“International Regulation of the Supply and Use

of Pharmaceuticals” (145), and with the support

of IOCU, One Drug at A Time: A Report on the

Limitation of Fixed Ratio Combination Drugs

(149). In 1991, Social Audit published Power

and Dependence (147), an examination of the

history of benzodiazepine (a class of sedatives

that includes diazepam) marketing, focusing on

the problems of dependence.

BUKO

BUKO (the Federal Congress of Development

Action Groups), one of the founding members of

HAI, is a West German network of approximately 200 consumer groups that focuses on “global

malpractice in drug marketing by the multinational pharmaceutical companies” (62), in particular Swiss and German companies. In 1987, it

published a short report on Hoechst, a German

pharmaceutical company, with evidence that

Hoechst was marketing drugs in developing

countries that had potentially severe side effects,

or which had been banned in developed countries, often without complete warnings (62). The

study also attacked Hoechst’s practices in

GermanY, such as the delay of a warnin g letter to

German doctors about several reported adverse

reactions (including six deaths) caused by one of

its antidepressant products (62).

In 1990, BUKO, together with HAI, helped

disseminate a study by two German physicians

that examined more than 2,000 German and

Swiss pharmaceutical products marketed in 26

developing countries. The majority of these products were marketed by large multinational corporations. The authors determined whether these

drugs met the health needs of the countries in

which they were marketed by comparing the

sample drugs to those on WHO’s Essential Drug

List. The authors also evaluated the efficacy and

safety of the drugs using authoritative pharmaceutical reference books from several countries

(7,28,30,75). They reported significant problems

in all areas. (See app. A, “The Hartog and

Schulte-Sasse Study.”)

In addition to its publications, BUKO produces a monthly newsletter Pharma-Brief. The

newsletter contains summaries of research on

pharmaceutical issues in developing countries

and reports on consumer activities (64). BUKO

also helps facilitate dialogue on pharmaceutical

policies in developing countries. In 1987, for example, BUKO held a conference in Germany that

brought together representatives of nongovernmental organizations from various developing

countries, academia, and industry. The conference focused on the relationship among the number of pharmaceuticals on the market in a country, the quality of those products, and the need for

essential drug policies in countries with limited

budgets for health care (85).

 Medical Lobby for Appropriate

Marketing (MaLAM)

MaLAM is an international network of physicians that acts as a watchdog for advertising by

pharmaceutical companies (199). MaLAM works

to encourage companies to provide what they

consider “sufficient, consistent, and accurate information” about their products, and primarily
— 

Efforts to Improve Drug Information In Developing Countries I 153

targets marketing claims made in developing

countries (254).

Each month, MaLAM’s approximately 700

subscribers in more than 40 countries receive a

draft letter addressed to a senior executive in a

pharmaceutical company questioning a particular

marketing practice. MaLAM subscribers are

asked to sign the letter and return it to MaLAM.

A final letter is sent after review by an international editorial board (153,254), The letters ask

the company to provide evidence supporting the

contested advertising claim. MaLAM publishes

the responses it receives from industry in its

newsletter. (Results of some of MaLAM’s work

are discussed in ch. 4 and 6.)

 International Network for the Rational

Use of Drugs (INRUD)

Developing countries typically lack the resources needed to evaluate national programs, including drug policies, An organization that provides support for evaluative research is the

International Network for the Rational Use of

Drugs (INRUD), a nonprofit group based in

Boston, INRUD is a cooperative organization of

health professionals, administrators, and researchers from developing countries who are interested in implementing new, innovative programs to improve the use of pharmaceuticals, and

is supported by the development agencies of a

number of countries (including USAID) and private foundations (127).

INRUD’s strategy is to first engage in research

designed to clarify the “dynamics of drug use

and, . the underlying motivations, expectations.

and incentives of providers and consumers”

(128). According to INRUD, although a number

of countries have tried to improve drug use by developing standard treatment protocols, providing

drug information, drug bulletins, implementing

changes in health training curricula, restricting

drug advertising, and using public education,

there has been little evaluation of these strategies;

they are assumed to have a positive impact.

However, studies in industrialized countries have

revealed that some of these same interventions

have not been very effective (127).

The initial INRUD network is limited to seven

countries that have demonstrated a commitment

to the rational use of essential drugs: Bangladesh,

Ghana, Nigeria, the Sudan, Tanzania, Indonesia,

and Nepal. Each country has a “Country Core

Group” of four to eight people representing various professional disciplines and organizations, A

“Central Support Group” is staffed by Management Sciences for Health and the Harvard

Medical School in Boston. INRUD anticipates

that other individuals and organizations interested in the program will become affiliate members

and share in information gathering, training, and

other activities (128).

INRUD also is developing a number of indicators of drug use to facilitate comparisons of drug

use among countries and identify drug use problems, The study involves field work in Indonesia,

Bangladesh, Nepal, Nigeria, and Tanzania. WHO

plans to publish a manual on standard drug use

indicators based on the results of this study (1 15),

INRUD recently received a grant from US AID to

conduct country-specific research with WHO on

current pharmaceutical use in developing countries (see section on USAID, above).

INRUD publishes a newsletter, INRU D

NEWS, reporting on its own activities and on

other recent drug utilization studies, and has developed a computerized bibliography of published and unpublished literature relating to drug

use in developing countries (114), In addition,

NRUD has developed training materials to promote rational drug use, which it has used in

Nepal and will use in Zimbabwe in 1993.

INRUD’s future plans include studies of the factors that influence drug prescribing behavior

(129).

SUMMARY

Developing countries face many obstacles to

maintaining effective pharmaceutical programs,
154 I Drug Labeling in Developing Countries

including lack of political commitment, poor programs and private groups have attempted to

planning capabilities, lack of trained personnel, help countries by providing information and

inadequate financial resources, irrational pre- other services to improve drug regulation, includscribing and dispensing practices, and lack of ing the regulation of drug labeling.

public awareness of the problems (286). WHO
Appendix A: Major

Studies of

Pharmaceutical Labeling

in Developing Countries

T

he 1970s marked the rise of the consumer

movement and a time of increased attention to

the operations of multinational corporations

(MNCs) in developing countries. Concern

was growing that many .MNCs operated in a virtually

unregulated environment in developing countries, in

some cases to the detriment of consumers. A number

of consumer groups, health care workers, and representatives from international organizations raised concerns about certain corporate practices in developing

countries. One issue raised with respect to pharmaceutical companies was the quality of their prescribing information, Small studies began to disclose that a number of pharmaceutical MNCs had labeling standards

for developing countries that differed from those for

industrialized nations. These studies are discussed

below.

 IOCU: The Chloramphenicol Study

The first comprehensive study of pharmaceutical

labeling in the developing world was carried out by

member groups of the International Organization of

Consumers Unions (IOCU) in 1972 (1 16). IOCU examined 55 packs of chloramphenicol marketed by

MNCs in 21 countries. Chloramphenicol is an antibiotic that can cause aplastic anemia, a serious blood

condition. Although aplastic anemia is rare, when it

does occur it has a fatality rate of 40 percent or more

(210). Since the discovery of this connection in the

1950s, use of chloramphenicol has been limited in the

United States and other industrialized countries to

treating serious infections when alternative treatments

failed. IOCU did not find a single label that included

all the necessary contraindications, and they found

wide variation in the warnings given with identical

brands sold in different countries (34,61).

 IOCU: The Clioquinol Study

A larger study was done during 1974 and 1975 on

clioquinol, a drug originally introduced for treatment

of amoebic dysentery, but often used for treatment of

traveler’s diarrhea (53). By the early 1970s, clioquinol

was implicated in an epidemic of subacute myelooptic neuropathy (SMON), an often fatal condition

that causes blindness and paralysis. The epidemic

claimed the lives of about 10,000 people in Japan. As

a result, where it was still available, clioquinol was

recommended only for treating acrodermatitis enteropathica, a serious chronic condition affecting the skin

and bowels of young people.

At the time of the study, clioquinol had been

banned in the United States and Japan, and was available only from a pharmacy in Norway, Sweden,

Austria, Finland, France, Iceland, Italy, the Netherlands, Yugoslavia, New Zealand, some places in

Australia, the Philippines, and Denmark. It was available without prescription, but in most cases only from

a pharmacy, in the United Kingdom, Belgium, Ireland, Guatemala, Ghana, South Africa, Tanzania,

Egypt, Lebanon, Zambia, Malaysia, Mexico, Sri

Lanka, Israel, Greece, Tunisia, Thailand, Taiwan,

Iraq, and Brazil,

The IOCU researchers obtained 107 drugs containing clioquinol from 39 countries, of which 83 samples

from 34 countries included package inserts. Almost

all of the package inserts recommended the drug for

155
156 I Drug Labeling in Developing Countries

the treatment of diarrhea and 50 of them recommended it as a prophylactic. The indications were often

vague, e.g., “for specific medically indicated prophylactic use. ” The dosage recommendations on 63

leaflets ranged from 400-1,500 mg per day for 3 to 28

days, despite the fact that the clinical literature recommended an adult dose of only 750 mg a day for 14

days (169). Twenty of the leaflets had no recommended dosage, Thirty-two leaflets mentioned the most important contraindications: hyperthyroidism, iodine allergy, and malfunctioning of the liver or kidneys;

however, 37 leaflets listed no contraindications, including those from the United Kingdom, New

Zealand, Belize, Brazil, Tanzania, Taiwan, Kenya,

Spain, Malaysia, and Singapore. One explanation offered for the lack of contraindications on certain of

these package inserts was that the insert recommended a maximum treatment of 3 days, after which it recommended consulting a doctor if the diarrhea was not

cleared up. The risk of an adverse effect from clioquinol was relatively small if used in low dosage for a

few days.

Information on side effects was also analyzed.

Forty-five leaflets listed the major side effect, peripheral and optic neuropathy, but only 34 recommended

stopping the drug at the first sign of peripheral neuritis or optic neuritis. The researchers concluded that

warnings were deficient on inserts from the United

Kingdom, Bahamas, Belize, New Zealand, Brazil,

Indonesia, Thailand, Tanzania, Taiwan, Iraq, Kenya,

Malaysia, and Singapore. However, the lack of complete warnings in the United Kingdom, Belize,

Bahamas, and New Zealand was tempered by the fact

that there were instructions that the drug be taken for

no more than 3 days,

The study also looked at four other halogenated

hydroxyquinoline drugs (the same chemical class as

clioquinol) because there was some evidence that

these drugs also could cause neurological illness. The

researchers examined 44 leaflets from 24 countries.

Again, there were many differences in indications,

contraindications, and warnings on the package

leaflets. There were differences among labels within

the same country and among labels provided by the

same manufacturer for a drug marketed in different

countries. Some of the differences might have been

attributable to different national regulations, but the

differences within countries indicated that differing

regulatory requirements were probably not the sole

explanation. A number of lawsuits were brought

against MNCs that marketed products containing clioquinol (primarily Ciba-Giegy, a Swiss company, and

Takeda and Tanabe from Japan), Damage awards

eventually reached almost $900 million.

Today, clioquinol is banned in the United States

and United Kingdom, and in other industrialized and

developing countries. However, a recent study found

many products containing clioquinol in India,

Indonesia, Thailand, the Middle East, Egypt, Mexico,

Central America, Colombia, Venezuela, and Brazil, A

number of these products are marketed by domestic

companies and their labeling carries little or no warning of possible neurological damage. Despite clioquinol’s history, it is considered safe and effective in

a number of developing countries, and in India is considered an essential drug (212).

 IOCU: The Anabolic Steroid Study

In 1983, IOCU released a study about the marketing of anabolic steroids in Germany, Australia, the

United Kingdom, the United States, and a number of

Asian countries (118),1 According to the cited clinical

literature, anabolic steroids were recommended only

for treatment of certain serious anemias resulting

from bone marrow failure, and for treating osteoporosis in the elderly. Anabolic steroids were also recommended for children with certain growth disorders,

but because they can cause subsequent infertility, precocious or abnormal sexual development, and stunt

growth, this indication was very limited. Other known

side effects of anabolic steroids include irreversible

symptoms of masculinization in women (deepening

of voice, body hair growth, male-pattern baldness),

and in men, atrophy of the testicles, inhibition of

sperm development, and impotence, Anabolic steroids were also linked to liver tumors, jaundice, acne,

and nausea.

IOCU examined 38 anabolic steroid products marketed in Indonesia, Bangladesh, the Philippines,

1 This was not the fiist study to e xamine the labeling and marketing of anabolic steroids in developing counties. See also references

134,163,208,
Major Studies of Pharmaceutical Labeling in Developing Countries 157

Thailand, Mexico, Malaysia, the United States, and

West Germany. Fifteen samples came from a single

Dutch company, Organon, and the remaining drugs

were marketed by Winthrop, a U.S. company, and

Schering, a West German company, Package inserts,

advertisements, and other promotional literature were

examined.

The study found examples of these companies marketing the same product with complete warnings in

developed countries and less-than-complete warnings

in developing countries, Anabolic steroids were promoted in the developing countries for poor appetite in

children, poor weight gain, listlessness, and lack of

energy, sometimes using pictures of healthy, wellnourished children. In a number of countries, the

drugs were available in easy-to-take drops and syrups,

often flavored to make them more palatable to children. Package inserts in Bangladesh and the Philippines stated specifically that there were no contraindications in children. Another 16 package inserts failed

to caution against use in children or to recommend

that skeletal maturation be checked periodically by xray. A majority of the package inserts also failed to

warn against use in patients with kidney or liver disease.

Side effects were also minimized. Nine package inserts from developing countries listed no side effects.

The majority of products that did include warnings

about side effects failed to warn against impotence,

enlargement of breasts, liver damage, jaundice, or the

more common side effects found in children,

 The Yudkin Study

In the late 1970s, a British physician, J.S. Yudkin,

compared the prescribing information in the African

Monthly Index of Medical Specialties (MIMS)2 with

information on the same drugs in the British MIMS

(292). He found significant discrepancies in indications and warnings. For example, tetracycline was

marketed in Africa with no warning about the risk of

tooth discoloration in children. In Britain, anabolic

steroids, whose side effects include stunting of growth,

virilization (appearance of secondary male sexual

characteristics in women) and liver tumors, were recommended only to treat osteoporosis, renal failure,

terminal malignancies, and aplastic anemia. In Africa

they were also indicated for treatment of malnutrition,

weight-loss, as appetite stimulants, and for excessive

fatigue. In the African MIMS several different brands

of liothyronine, a drug recommended for “severe thyroid deficiency” in Britain, were marketed for “lowered metabolic states. ” Methadone, which was recommended in Britain for severe pain, was marketed in

Africa as a cough suppressant.

 The Social Audit Studies

A 1978 study by the British consumer group,

Social Audit, funded principally by IOCU, focused on

products of the major British pharmaceutical MNCs:

Beecham, Boots, Fisons, Glaxo, ICI, Reckitt and

Colman, and Wellcome (142). The study compared

the information from British MIMS with MIMS

guides from Africa, the Caribbean, and the Middle

East. When available, the researchers also looked at

detailed prescribing instructions in India and Malaysia. They found that dosage recommendations in developing countries tended to be greater, even double

the dosages recommended in the United Kingdom.

The study also found a marked lack of detail about

contraindications. For example, the British official

prescribing information for Ancoloxin (meclizine), an

antiemetic, warned against use in pregnant women except in cases of severe vomiting. U.S. labeling also

warned against use during pregnancy because animal

studies had indicated the drug might cause birth defects. However, in Africa and some developing countries in other areas, it was indicated specifically for the

treatment of nausea and vomiting in pregnancy, Even

the detailed prescribing information in India did not

contain warnings about potential birth defects.

Another example was the painkiller, Paramol 118 (dihydrocodeine). In Britain this drug required warnings

against use by children, people with impaired liver or

kidney function, or during an asthma attack. This

same drug was marketed in Africa without these

warnings.

In contrast, indications were often more expansive

in the developing country guides than in the U.K.

2 MIMS are commercial prescribing guides distributed free to physicians. Their prescribing information is supplied by the pharmaceutical manufacturers and edited by the publishers. Production of the guides is paid for by advertisements.
158 I Drug Labeling in Developing Countries

MIMS. For example, a painkiller marketed in the

United Kingdom for “persistent pain, particularly

muscle pain, headache, neuralgia,” was indicated in

Africa and the Caribbean also for “fibrosis, lumbago,

back pain, sprains, strains, dysmenorrhoea, dental

pain, bursitis, trauma, and chronic rheumatic pain.”

While this detail was not necessarily misleading, the

researchers concluded that the emphasis in indications

coupled with deficient warnings demonstrated that the

companies were more interested in drug promotion

than in providing objective prescribing information.

The researchers found that the quality of information

did vary by prescribing guide and by company, but

because no attempt had been made to obtain a representative sample from each company, no comparative

analysis could be carried out.

 Silverman, Lydecker, and Lee’s Studies

Some of the most comprehensive and influential

research on drug labeling in developing countries was

carried out by U.S. researchers. In 1974, Silverman

and Lee, of the University of California in San

Francisco, published Pills, Profits and Politics (209),

which focused on the policies of both U.S. and foreign

pharmaceutical manufacturers and included evidence

that these companies provided irrational prescribing

information. Further work was published by

Silverman in The Drugging of the Americas (208),

which examined the prescribing information for 26

single-drug entities or fixed combinations, marketed

by 23 MNCs as 147 different products in 12 countries

in Central and South America (212).

The drugs in this study included antibiotics, oral

contraceptives, nonsteroidal antiinflammatory drugs,

steroid hormones, antipsychotic tranquilizers, antidepressants, and anticonvulsants. Each drug selected

met the following criteria:

● it was a valuable and widely used drug;

● it had well-established clinical usefulness and

known hazards;

• it was marketed in the United States and Latin

America by the identical company, its foreign

subsidiaries, or affiliates; and

● it was described in the U.S. Physicians’ Desk

Reference (PDR) and selected prescribing guides

in Mexico, Central America, the Dominican

Republic, Ecuador, Colombia, Brazil, and

Argentina.

The PDR, which contains the labeling information

approved by the U.S. FDA, was used as a standard.

The researchers concluded that “with few exceptions,

the indications included in the Latin American] reference books are far more extensive, but the listings of

hazards are curtailed, glossed over, or totally omitted”

(208). There also were examples of the same drug

marketed by the same company with different information in different countries. One of these was chlorarnphenicol. The PDR recommended chloramphenicol for acute typhoid fever only, and to treat serious

cases of salmonella, hemophilus influenza, some

types of meningitis, and some forms of cystic fibrosis.

In addition, the drug was not recommended for infants, pregnant women, or in patients in whom there

was evidence of hypersensitivity, depression of bone

marrow, signs of blood dyscrasia (abnormalities in the

production of blood cells), or impaired liver or kidney

function, Potential adverse reactions included aplastic

anemia (which may be fatal), blood dyscrasias, nausea, vomiting, headache, mild depression, mental confusion, and other necrologic reactions. The PDR also

recommended that periodic blood studies be done on

patients taking the drug to avoid the most serious reactions.

The study examined five brands of chloramphenicol marketed by four companies in Latin America, including one brand that was removed from all markets

in 1973, All the prescribing entries evaluated included

broader indications than those in the PDR. The antibiotic was recommended for dysenteric infections, tonsillitis, colitis, whooping cough, and as a broad-spectrum antibiotic. The prescribing guides for Central

America, Argentina, and Ecuador contained no contraindications or warnings. In other prescribing

guides, the warnings and contraindications were limited. Listings for three of the brands, taken from four

different prescribing guides, failed to warn against

aplastic anemia or other blood dyscrasias.

Oral contraceptives were also examined. The PDR

lists many contraindications, the most important being

thrombophlebitis, impaired liver function, known or

suspected estrogen-dependent malignancies, and unexplained abnormal genital bleeding. Many adverse

reactions were also presented, including changes in li-
Major Studies of Pharmaceutical Labeling in Developing Countries I 159

bide, nervousness, dizziness, loss of hair, and skin

changes.

Again, Silverman found prescribing guide entries

with far more indications than in the PDR. Entries for

seven different oral contraceptives, marketed by five

multinational corporations, recommended oral contraceptives for premenstrual tension, uterine bleeding,

and various menstrual disorders. Thrombophlebitis

was included as a contraindication in 14 out of 20 entries; suspected hormonal neoplasms in 4 out of 20;

undiagnosed abnormal vaginal bleeding in 4 out of 20;

emotional disease in 2 out of 20; and caution in cases

of epilepsy, migraine, asthma, or cardiac or renal dysfunction was included in only one entry, Eleven entries listed no potential adverse reactions,

In Prescriptions for Death: The Drugging of the

Third World (210), Silverman, Lee, and Lydecker returned to Latin America, but expanded Silverman’s

earlier work to include Central Africa (15 countries),

Southeast Asia (4 countries), and the United Kingdom. The researchers examined 515 prescribing guide

entries for 34 drug entities or fixed combinations marketed by more than 149 companies (46 were products

of U.S. multinationals or their affiliates) (21 1). They

examined many of the same drugs they had looked at

in The Drugging of the Americas. This 1980 study

again showed that certain prescription drugs were promoted in developing countries for more indications

than had been approved in the United States and that

mention of serious adverse reactions had been minimized or omitted from the labeling.

In Indonesia, Singapore, the Philippines, and

Central America, chloramphenicol was still recommended for minor infections such as bronchitis, vaginal infections, and throat infections, and that almost

all of the chloramphenicol products marketed in

Indonesia had no warning about aplastic anemia. A

number of products marketed in the Philippines,

Malaysia, and Singapore also failed to mention aplastic anemia or had no warnings at all. In the African

MINIS, however, which had been critiqued just a few

years earlier by Yudkin, the authors found information almost identical to the PDR.

The authors looked again at tetracycline drugs,

which are not recommended for most patients with

impaired liver or kidney function. In infants and

young children, tetracycline may discolor teeth and

interfere with bone growth, so it is not usually recommended for women in the last half of pregnancy or for

children under the age of 8 or 12. Of the 90 tetracycline products examined from developing countries,

warnings about use in patients with kidney disease

were given for 13; warnings about use with liver disease, for 9; and about use during pregnancy, for 9.

Thirty-five products had no specific warnings, though

some included vague warnings or referred the prescriber to the literature (210).

The study also analyzed prescribing information

for certain combination antibiotics, clioquinol, dipyrone, and oral contraceptives. The investigators found

that the dangers of serious or lethal side effects were

frequently minimized or totally ignored, and claims of

effectiveness often “wildly exaggerated” (210).

In 1984, Silverman, Lee, and Lydecker published

the results of another survey. The 1984 study examined information from prescribing guides for 63 drug

entities or fixed combinations, marketed as 1,069 different products by 303 drug companies in 15 countries

(211). The study revealed that a number of pharmaceutical companies had made a “marked improvement” in their promotional and labeling practices in

developing countries. The authors examined 103 chlorarnphenicol products and found that 93 carried warnings against use in trivial infections, for prophylaxis,

or in prolonged therapy. They also examined the prescribing entries for 117 tetracycline products, and

found that 109 carried suitable warnings, including

contraindications for kidney and liver disease.

With respect to dipyrone, a pain reliever that was

withdrawn from the U.S. and British markets because

it could cause agranulocytosis, a fatal blood condition,

the authors found that 119 out of 155 (76 percent)

contained warnings of serious or possibly fatal agranulocytosis. In 1980, only half of the dipyrone products

studied warned about agranulocytosis.

Clioquinol and the related halogenated hydroxyquinolines, which had previously been promoted as

antidiarrhea agents, were also studied. Twenty-two

out of 61 prescribing entries for products containing

clioquinol failed to include warnings of severe and

possibly fatal neurological damage. They concluded

that most cases of irrational promotion (60 percent)

involved domestic firms in developing countries.

They cautioned that the “problem of irrational, inaccurate, or even dishonest promotion has not been

solved” (21 1).
160 I Drug Labeling in Developing Countries

During 1987 and 1988, at approximately the same

time OTA gathered its labeling material, Silverman,

Lydecker, and Lee revisited the issue of drug labeling

in developing countries, this time with partial financial support from 10 pharmaceutical companies. The

researchers examined 40 single-drug entities or fixed

combinations marketed as 1,500 products in the

United States, the United Kingdom, and 74 developing countries-28 countries in Africa (both English

and French speaking), 12 countries in Latin America,

11 countries in the Caribbean, and 6 countries in

Southeast and southern Asia (212). The products were

marketed by more than 400 companies, both MNCs

based in industrialized countries and domestic companies in the developing countries.

The drugs chosen for the study were in the following categories, including many of the same drugs they

had examined in previous studies: analgesics, antiarthritis drugs, antidiarrheals, antibacterial, appetite

stimulants, cardiovascular drugs, cerebral vasodilators, psychoactive agents, major and minor tranquilizers, antidepressants, anabolic steroids, female sex hormones, and sex potions. As in their previous studies,

prescribing guide entries were analyzed. Unlike the

OTA study, Silverman and his colleagues focused on

certain indications or warnings for each drug, rather

than examining the entire label. The results of their

study were published in the spring of 1992.

The authors concluded that most multinational corporations were willing to disclose major hazards and

to limit their indications to those based on sound scientific evidence; there were, however, “glaring exceptions.” They found that the total amount of misinformation presented to physicians had not changed

because the improvements made by the multinational

corporations appeared to be offset by the misleading

labeling presented by the increasing number of local

or domestic firms (212).

 The UNCTC Study

In 1984, the U.N. Centre for Translational Corporations published a study that included a section on

drug marketing by MNCs in developing countries, examining 12 products marketed in 12 countries. Each

drug selected had some significant side effect or contraindication, The review found “significant discrepanc[ies]” between the information provided in the

PDR and the information provided in the prescribing

guides of Brazil, Colombia, Ecuador, Mexico, Venezuela and Central America. For example, clofibrate, a

cholesterol-lowering drug, has some serious side effects, including gallstones, leukopenia (decreased production of white blood cells), and cardiac arrhythmias.

In Brazil, Ecuador, and Mexico, the prescribing guide

did not mention any of these effects. In Argentina, one

MNC marketed 17 varieties of clofibrate with no mention of side effects, although the same firm sold the

drug in the United States with complete side effect

and warning information (223).

The study also looked at prescribing guide entries

for five drugs containing dipyrone, a pain reliever that

can cause a fatal blood disease. The United States had

banned the drug, as had Australia, Sweden, and the

United Kingdom, but it was still on the market in

some European countries as an analgesic, antipyretic,

and antispasmodic, The study found that dipyrone was

widely used as a general painkiller in Brazil and

Argentina, often without prescription or proper warning. In Thailand, the drug was dispensed over-thecounter more often than aspirin. In Costa Rica and

Kenya, it was an ingredient in many popular medicines. A review of the prescribing guides found a

number of entries promoting the drug for treatment of

headaches, common cold, pneumonia, and rheumatoid

arthritis, In some cases, the risk of the fatal blood disease was mentioned, but no mention was made of the

need for hematologic tests to detect its onset early,

Other entries mentioned no side effects. The U.N.

study also cited a review by two researchers of 110

antibiotic preparations marketed in Central America.

According to that study, prescribing guide entries for

40 of the preparations had no information on contraindications and 66 had no information on adverse

reactions (79).

The U.N. study concluded that in most of the countries studied there were no limits on the amount of information that could have been provided. However,

the study also noted that some companies had begun

to respond to the criticisms with promises to dispense

uniform labeling information and to support standard

international drug prescribing information (223).

 The Osifo Study

In the early 1980s, a small study was carried out in

Benin City, Nigeria, to determine whether Nigeria’s

new labeling regulations altered the content of pack-
Major Studies of Pharmaceutical Labeling in Developing Countries 161

age inserts (171). Nosakhare Guy Osifo, a pharmacologist, examined package inserts for 28 prescription

drugs marketed by 15 U.S. MNCs or their subsidiaries, Osifo found that the four package inserts supplied with products exported directly from the United

States were identical or very close to the U.S. labeling.

The remaining package inserts, included with 18 different products distributed by U.S.-controlled foreign

subsidiaries, contained more indications and fewer

warnings than appeared in U.S. labeling. Inserts for

drugs specifically for use in critically ill patients,

which were generally more dangerous products, tended to be more complete and accurate than those accompanying products for less serious conditions.

 The Hartog and Schulte-Sasse Study

Hartog and Schulte-Sasse, two German physicians

working with the support of BUKO-Pharmakampagne

(a German public interest group that focuses on pharmaceutical issues) reported on more than 2,000

German and Swiss pharmaceutical products marketed

in 26 developing countries (81).3 The study, published

in 1990, evaluated whether these drugs, mostly products of MNCs, met the health needs of the countries

where they were marketed by comparing them with

WHO’s Essential Drug List. They also evaluated the

efficacy and safety of all the drugs and examined labeling and advertising.

Drugs were classified as inappropriate if:

1.

2.

3.

Even

there were no efficacy data to support the labeling or advertising claims;

the available data had been criticized as scientifically inadequate by a substantial number of experts; or

different researchers reported contradictory results.

if a drug was found efficacious, it was deemed

inappropriate if there was a more effective or less dangerous alternative. Finally, a drug was considered inappropriate if the amount of active ingredients was too

low at the recommended dose, or the drug would fail

to be effective as administered (e.g., the oral form of

an antispasmodic, butylscopolamine, which is effective only as an injection). Using these criteria, the researchers concluded that more than 60 percent of the

drugs evaluated were inappropriate.

The WHO Essential Drug List includes only drugs

that are of “utmost importance and are basic, indispensable and necessary for the health needs of the

population.” The drugs also are selected on the basis

of cost and the practicality of prescribing a particular

medicine under a variety of medical situations (e.g., in

situations where there is little likelihood the patient

would be monitored). Hartog and Schuhe-Sasse compared the products in their sample to therapeutic

agents on the WHO list, looking specifically at ingredients, concentration, and dosage form. They concluded that less than 20 percent of their sample drugs

would meet the criteria for inclusion in an essential

drug list.

In the analysis of labeling, the study reported deficiencies in information in MIMS prescribing guides

for English-speaking Africa and the Middle East, the

Philippines, and India. They compared information in

the Swiss pharmaceutical compendium with the developing country prescribing guides. They concluded

that the prescribing guide entries typically included

more indications and less information on adverse effects and contraindications than did the Swiss compendium.

 The Industry Response

Industry responses to these studies have varied.

The International Federation of Pharmaceutical

Manufacturers Associations claims that companies

quickly responded to The Drugging of the Americas

by developing internal corporate policies to guarantee

that claims about efficacy and disclosures about side

effects were consistent worldwide (37). Some companies blamed MIMS editorial policies for discrepancies

between the official drug datasheets and MIMS entries. Companies also noted that MIMS guides were

not the sole source of information for physicians, and

that their company representatives did provide complete information, or that information was available

from the company on request (210).

3 The study looked at 1,312 German products marketed in 1984/1985, 1,273 German products marketed in 1988, and 1,084 Swiss products marketed in 1988.
162 I Drug Labeling in Developing Countries

The primary explanation offered by companies for

the differences between the information given in developing and developed countries was that developing

countries had different laws and regulations. As a former President of the U.S. Pharmaceutical Manufacturers Association (PMA) explained shortly before

the release of Prescriptions for Death: The Drugging

of the Third World, “our foreign labels conform to the

labeling regulations of the importing country which

may forbid the sorts of disclosure required by the

FDA” (148). Another PMA representative stated that

it would be arrogant and paternalistic to insist that one

nation’s decision in the area of drug regulation was

superior to another’s (165),

Critics pointed out that regulatory policies were not

responsible for the labeling differences between industrialized and developing countries. As evidence of

this, they noted several examples where, in a single

country, the same chemical entity was marketed by

different companies with substantially different labeling. Also, since the information in most of the prescribing guides was not regulated by the host governments, the critics contended that regulatory policies

were not responsible for the differences found in the

guides. 4

4 See, e.g., references 62,134,142,148,154,260.
T

he following sections describe the legal requirements for drug registration and labeling

in Brazil, Kenya, Panama, and Thailand, the

four countries of the OTA survey. OTA did

not evaluate how well these requirements are met in

practice. There is considerable evidence in the literature, however, that in many developing countries limited resources and personnel make full implementation of the requirements virtually impossible.

Appendix B: Drug

Registration and

Labeling in Brazil,

Kenya, Panama,

and Thailand

 Brazil

DRUG REGISTRATION

At the time of the OTA

survey, the Division of Drugs

of the Ministry of Health

(DIMED) had primary responsibility for drug regulation and enforcement, Since

then, the Ministry of Health

has been reorganized (under the Collor government)

and DIMED no longer exists as a distinct entity. Its

functions have been taken over by the Division of

Products (DIPROD) of the National Secretariat for

Sanitary Surveillance (Vigilancia Sanitaria) (207).

All drugs not included in the Brazilian Pharmacopoeia are considered “new drugs”l and must be registered with the Ministry of Health (this excludes raw

materials, which are regulated under other legislation)

(106). To register a drug for marketing in Brazil, a

company must submit an application that includes:

1.

2.

3.

4.

5.

6.

7.

a drug registration petition;

a report on the experimental therapeutics (preclinical and clinical trials) of the proposed drug,

in conformity with detailed rules issued by the

National Health Council in Resolution No. 1 of

1988;

a technical report on the product, including

chemical and pharmaceutical detail, principal

indications, method of use, complementary indications, contraindications, side effects, adverse reactions, restrictions or precautions, expiration period, storage conditions, and instructions

for use, when applicable;

pharmacodynamic data, including method of

action and dosing information with justifications;

report on production and quality control, including full details of the production process and

proposed quality control mechanisms for all

stages;

models of labels and packaging; and

bibliography, including translations of original

papers, if foreign.

Brazilian law states that an application for registration must be processed in 90 days. In the past, delays

were common and the average processing time was 2

1 A new product is considered any type of new molecular substance; new salt of previously approved ingredient modifkation in the quantity, number, or identity of active ingredients or pharmacokinetic characteristics of an existing medication or any new combination of registered substances.

163

330–065 O - 93 - 7 QL 3
164 I Drug Labeling in Developing Countries

to 3 years (192). The type and urgency of the registration may affect its handling. According to a former

DIMED director, some petitions took as long as 6-8

years to process while others were handled rapidly

(206). Registration is valid for 5 years, but if new information about adverse reactions, precautions, or

contraindications for the product becomes known, it

must be reported to the Ministry of Health. For renewal, a simplified application form with recent analytical, preclinical, and clinical data, along with a renewal fee, must be submitted.

In August 1990, the Ministry of Health began restructuring the SNVS (National Secretariat for Health

Monitoring), including a new program called “INOVAR,” to streamline the registration system and handle the backlog of approximately 18,000 product approval applications (197). With about half a dozen

professionals working on drug regulation, the following approvals were granted in a period of 7 months

(September 1991 through March 1992): 425 petitions

to change the composition (active ingredients) of

drugs already on the market, without changing the

name of the drug; 455 registrations of drugs that are

similar to others already approved; 293 transfers of

registry from one producer to another, and 457 registrations of new commercial presentations (207).

DRUG LABELING

Brazilian labeling requirements are the same for

over-the-counter (OTC) and prescription drugs (106).

As a general rule, neither labeling nor advertisements

may include geographic names, symbols, figures, designs, or other indications that might be misleading.

In addition, any unauthorized modification of the

label is punishable by cancellation of the registration.

Preclearance of labeling is required as part of the

registration procedure. The package label must include the following (106):

1. name of product (trademark or generic);

2. pharmaceutical form;

3. number of units in package;

4. active ingredients;

5. complete formula of the product with quantitative composition;

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

name and address of manufacturer;

responsible pharmacist;

license number and date of issue;

batch number;

expiration date and date of manufacture;

storage instructions;

for prescription products, statement that it is

supplied on prescription only;

indications;

side effects; and

precautions, if any.

Package inserts are not compulsory for all products, but if the company intends to include a package

insert, it must be approved in advance. Inserts are usually physician-oriented (201). Once labeling is approved, all changes must be submitted for review, including a technical justification for the proposed

change,

r——————————

I I

products from around

 Kenya

DRUG REGISTRATION AND

LABELING

At the time of Kenyan independence in 1963, almost

all available pharmaceuticals

were imported from Great

Britain, and there was no formal registration system. As

the world began to enter the

country in the 1970s, the government instituted import permits. The primary purpose of the permit system is to control the amount of foreign currency moving out of the country, rather than specifically to

control the flow of drugs. The need to assert some

control over the drug supply itself led to the passage

in 1981 of laws governing drug registration.2 The

statutes do not define the registration process in detail,

but authorize the Ministry of Health to develop detailed guidelines (40). The Pharmacy and Poisons

Board of the Ministry of Public Health has the responsibility to review drug registration applications and

product advertisements.

A drug may be registered for 5 years in Kenya,

after which the company must apply for renewal.

2 The requirements for registration are provided for in the Pharmacy and Poisons Act and the Pharmacy and Poisons (Regulation of

Drugs) Rules of 1981.
Drug Registration and Labeling in Brazil, Kenya,

Initial applications for drug registration are assessed

on grounds of safety, efficacy, and quality. Each registration application must include the following information (106):

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

administrative data;

pharmaceutical formula;

name and structural formulae of the active ingredients;

specifications of ingredients (active and excipient);

analytical control of ingredients;

analytical control procedures during manufacture;

shelf life;

summary of the method of manufacture and

assembly;

summary of the experimental tests for pharmacological effects;

summary of tests for physiological availability; and

summary of clinical tests for efficacy.

In addition, the application must include labels,

package inserts, and any promotional literature. The

label

1.

2.

3.

4.

5.

6.

7.

8.

9.

should include the following (106):

therapeutically active substances, specified by

name, qualitatively and quantitatively, per suitable unit;

inactive ingredients, which may be specified

under a common term such as “excipients” unless such ingredients may be of some special

significance in the use of the product;

name and percentage of any bactericidal or bacteriostatic agent;

expiration date;

batch number;

where necessary, directions of a technical nature for the use of the product;

particulars on the normal dose and indications;

name and business address of manufacturer;

and

registration number of the product.

Kenya does not require package inserts, but if a

company chooses to include one, it must be approved

by the Ministry of Health. All changes to the approved labeling must also be reviewed by the Ministry.

Panama, and Thailand 165

 Panama

DRUG REGISTRATION AND

LABELING

According to Decree 93 of

February 16, 1972, the Regulation on Registration of

Pharmaceutical Specialties,

almost all pharmaceuticals

must be registered in Panama,

The Ministry of Health controls the registration

process and works in conjunction with the National

University of Panama and specialized laboratories to

review applications. In evaluating an application, the

Ministry compares the safety and therapeutic advantages of the drug with similar products, and bases its

decision on these comparisons.

The following information must be included in a

registration application (106):

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

trade mark or generic name of product;

name and address of manufacturer and distributor;

dosage form and route of administration;

name of the responsible pharmacist;

details of therapeutic class;

a sample of the container

complete formula of finished dosage;

draft of proposed packaging copy and package

insert;

active ingredients;

indications;

contraindications;

warnings, precautions;

recommended route of administration;

draft outline of proposed information to the

medical profession;

recommended dosage: usual dose, frequency,

range;

summary of pharmacological data and data

relevant to proposed use;

summary Of all clinical trials; and

data on adverse reactions and drug interactions.

Panama also requires that any “physician-oriented”

information be included with the registration application.

It takes an average of 2 years for a full registration

application to be approved. Drugs that are not new
166 I Drug Labeling in Developing Countries

chemical entities and that already are listed in locally

approved pharmacopoeias are subject to lesser requirements, which include provision of a Free Sale

Certificate, a Certificate of Analysis, the product formula, and samples of the product (106).

Printed packaging copy and package inserts also

must be reviewed at the time of registration. The following information, in Spanish, is required on the

package label (106):

1. qualitative and quantitative formula;

2. strength and pack size (contents);

3. registration number;

4. trademark;

5. manufacturer’s name and address;

6, statement that dose must be as prescribed by

physician, and that sale is subject to prescription; and

7. expiration date and batch number.

Package inserts are not required for all products.

The decision to include a package insert is left to the

discretion of the manufacturer (106), but there are

legal requirements for their content if an insert is included. Inserts usually are physician oriented. Companies are not required to notify the government of

changes in labeling for registered products.

 Thailand

DRUG REGISTRATION AND

LABELING

Thailand’s pharmaceutical

market is actually two markets that exist side by side: a

public market, supplying government health centers and

hospitals, and a large private

market, The regulation of these two markets differs.

Regulation of the Private Market

As established by the Drug Act of 1967, the main

legislation affecting the pharmaceutical industry in

Thailand, every pharmaceutical product intended for

sale must be granted a marketing approval by the Thai

Food and Drug Administration (TFDA) of the Ministry of Public Health (MOPH) (193). The Drug Act

applies to the private market, but since 1986 has not

applied to the Governmental Pharmaceutical Organization (GPO), the

company (272).

At the time of

government’s own drug production

OTA’s survey, a company was required to submit a registration application containing

some or all of the information in the list that follows

(in Thai or English). Since that time, more specific

regulations have been issued, requiring more types of

information.

In 1989, the following information was required

for registration (272):

1.

2.

3.

4.

5.

6.

7.

8.

9.

10,

11.

12,

13,

14.

15.

product name and formulation;

dosage form and regimen;

origin and background of discovery;

conditions of use in foreign countries;

properties and comparative studies with other

drugs;

physiochemical properties;

standards and method of product analysis;

long-term storage tests;

pharmacological and toxicological data;

data to support efficacy;

general pharmacology;

biological data;

data on clinical trial results;

label claims and package insert; and

existence of registration from the country of

origin for imported drugs (WHO certification

scheme form may be used).

Applications are evaluated on the basis of safety,

efficacy, and quality. Registration officials are required to consider the product safety and therapeutic

advantages compared with similar products. According to the law, all products must be analyzed before registration (106), The Division of Drug Analysis

(DDA) in the Department of Medical Sciences is responsible for conducting quality assurance tests, but

due to limited manpower, is able to test only about

one-fourth of the products (272). Approval of applications takes 6-18 months.

Thailand registers a few thousand formulations a

year including many locally produced combination

products (272). Since 1985, registrations are permanent and do not require renewal (106).

Regulation of the Public Market

In 1981, the Thai Government announced a National Drug Policy. The main goals of the new pro-
Drug Registration and Labeling in Brazil, Kenya, Panama, and Thailand 167

gram were to provide an adequate supply of safe and

good quality drugs, to reduce drug waste by using the

essential drug strategy, to strengthen drug quality assurance, to develop pharmaceutical raw material production capability, and to explore the potential of traditional medicines (272). This national drug strategy

was included in the government’s Fifth Five-Year

Plan (1982-1986). The Sixth Five-Year Plan (1987-

1991) focuses on rationalizing drug use and strengthening ongoing activities.

Thailand published its first national list of 372 essential drugs in 1981. A 1982 revised list increased

the number to 450 essential drugs in 30 therapeutic

categories (272). The most recent revision, in 1992,

reduced the list to 348 items in 29 therapeutic categories (179). In university hospitals and in institutions

such as the Ministries of Defense, Interior, and

Education, drugs from the essential drug list must account for 60 percent of the drug budget. Community

and provincial hospitals in each of Thailand’s 72

provinces must select 80 percent of their pharmaceuticals from the essential drug list (272). Local health

centers are also required to stock a certain percentage

of essential drugs (272), The Government Pharmaceutical Organization (GPO) is one of the largest manufacturers of essential drugs in Thailand and it accounts

for 11 percent of the prescription drug market (193).

Labeling and Promotional Regulation in Thailand

The Drug Act of 1967, as amended in 1988, contains labeling requirements. Printed packaging material, including package inserts, must be submitted for

approval. The following information must appear on

the package label (106):

1.

2.

3.

4,

5.

6.

7.

8.

9.

product name;

registration certificate number;

content;

composition or active ingredient with quantity/

potency;

batch number;

name of manufacturer with country of origin;

date of manufacture;

where applicable and on a red label: “Ya

Antarai (Dangerous Drug)” in Thai, “Special

Control” in Thai, “External or Topical Use” in

Thai; and

the word “expiry” in Thai and expiration date of

drug.

Package inserts also are required and are expected

to contain the product name; active ingredients; indications; instructions for use, including warnings, precautions, adverse drug reactions, and contraindications; dosage, and storage information (272).

All labeling information must be in Thai or English. Thailand also requires that all other information

companies intend to send to doctors, such as reminder

advertisements or other promotional material, be included with the registration application. Any changes

in labels for products already registered must be approved by the government (106).

The Thai Government limits advertising of prescription products. Promotion is limited to medical

and pharmaceutical journals or through direct contact

with the prescribers or dispensers. The agency requires that advertisements not exaggerate efficacy or

broaden indications beyond those approved in labeling (106).
Appendix C:

Acknowledgments

OTA would like to express its appreciation to the following individuals.

Maryanne Anderson

U.S. Agency for Intemational

Development

Washington, DC

K. Balasubramaniam

International Organization of

Consumers Unions

Penang, Malaysia

Mark Banks

Blue Cross/Blue Shield of

Minnesota

St. Paul, MN

Wilbert Bannenberg

International Organization of

Consumers Unions

Amsterdam, The Netherlands

Muriel Bell

Bristol-Myers Squibb

Pharmaceutical Group

Princeton, NJ

Patty Benson

PATH

Seattle, WA

William J. Bicknell

Boston University

Boston, MA

Anthony Boni

U.S. Agency for International

Development

Washington, DC

Ian C. Boulton

Smith, Kline, & French, Ltd.

Bangkok, Thailand

George A. Braun

Johnson & Johnson International

New Brunswick, NJ

Pascale Brudon

World Health Organization

Geneva, Switzerland

Karta Bundittanugul

Lemya Pharmacy

Bangkok, Thailand

Alfonso Carbonar

Embassy of Brazil

Washington, DC

Phillip C. Carra

The Upjohn Co.

Kalamazoo, MI

John F. Chappell

SmithKline & French

Laboratories

Philadelphia, PA

George A. Clay

G.D, Searle & Co.

Skokie, IL

Rungpetch Charoenvisuthiwongs

College of Pharmacy, University

of Iowa

Iowa City, IA

Preecha Cheranavanich

Payathai Hospital I

Bangkok, Thailand

Vanida Chitman

Pharmaceutical Products

Association

Bangkok, Thailand

Thomas Christie

Wyeth International Ltd.

Philadelphia, PA

Supawat Chutivongse

Thai Red Cross Society

Bangkok, Thailand

169
170 I Drug Labeling in Developing Countries

Bernard J. Clark

American Cyanamid Co.

Wayne, NJ

Sister Joan Devane

MEDS

Nairobi, Kenya

Gary Gereffi

Duke University

Durham, NC

Gloria Coe

Pan American Health

Organization

Washington, DC

Robert Ducan

American Embassy

Bangkok,Thailand

James K. Githaiga

Warner Lambert (E..A.) Ltd.

Nairobi, Kenya

J.F. Dunne

World Health Organization

Geneva, Switzerland

Dr. Henry Grabowski

Duke University

Durham, NC

Peter Collins

U.S. Trade Representative

Washington, DC

Alberta R. Edwards

Schering-Plough Corp.

Kenilworth, NJ

John M. Graves

Syntex

Palo Alto, CA

John E. Condon

Abbott Laboratories

Abbott Park, IL

Jim Entwistle

U.S. Department of State

Washington, DC

Jim Hamilton

Food and Drug Administration

Rockville, MD

Paul Coppinger

Food and Drug Administration

Rockville, MD

Robert Eshelman

Food and Drug Administration

Rockville, MD

Martha Hanson

University of Pennsylvania

Philadelphia, PA

Daniel P. Cronin

Pfizer International

New York, NY

Michael D. Fenoglio

Alcon Laboratories, Inc.

Fort Worth, TX

Elizabeth Hayes

Health Action International

Amsterdam, The Netherlands

Marjory Darn

Pan American Health

Organization

Washington, DC Sev S. Fluss

World Health Organization

Geneva, Switzerland

George Heinze

Johnson & Johnson International

Gabriel Daniel Raratan, NJ

Africare

Washington, DC Michael J. Foley

Abbott Laboratories

Abbott Park, IL

Thiravat Hemachudha

Chulakmgkom Hospital

Mitchell E. Daniels, Jr. Bangkok, Thailand

Eli Lilly and Co.

Indianapolis, IN Colin Forbes

Nairobi, Kenya

Julia Ho

Food and Drug Administration

William G. Davidson Rockville, MD

Marion Merrell Dow

Kansas City, MO

Allan M. Fox

Fox, Weinberg & Bennett

Washington, DC

Catherine Hodgkin

Health Action International

Amsterdam, The Netherlands Diana Davis

SIMBA

Washington, D.C.

John Gammon

Sterling Products International,

Ltd.

Nairobi, Kenya

William H. Hubregs

Alcon Laboratories, Inc.

Fort Worth, TX Edgar G. Davis

Eli Lilly and Co.

Indianapolis, IN
Acknowledgments 171

U.S. Inyang

West African Pharmaceutical

Federation

Yaba, Lagos, Nigeria

Jerry Lanier

U.S. Embassy, Kenya

New York, NY

Peter Mansfield

MaLAM

Adelaide, Australia

Philip Lee

University of California

San Francisco, CA

Harsh Maroo

Pfizer Corporation

Nairobi, Kenya

Prance Jaiarj

Mahidol University

Bangkok, Thailand

Ulit Leeyavanija

Ministry of Public Health

Bangkok, Thailand

James Marttila

Mayo Medical Ventures

Rochester, MN

Sumlee Jaidee

Chulalongkom University

Bangkok, Thailand

Sanguan Lekeithbundit

Chulalongkom University

Bangkok, Thailand

G.S. Masafu

Kenya Pharmaceutical Industry

Association

Nairobi, Kenya

D.C. Jayasuriya

Nawala, Sri Lanka

Gregory L. Johnson

Warner Lambert Co.

Morns Plains, NJ

Ann Lewis

Bristol-Myers Squibb

Pharmaceutical Group

Princeton, NJ

Robert McDonough

The Upjohn Co.

Kalamazoo, MI

Marion T. Jones

Devitt Jones Productions

Washington, DC

Edward R. Leydon

Rhone-Poulenc Rorer Inc.

Fort Washington, PA

Leo McIntyre

U.S. Department of Commerce

Washington, DC

Michael Jordan

U.S. Agency for International

Development

Washington, DC

Jiraporn Limpanont

Chulalongkom University

Bangkok, Thailand

Win McKeithan

U.S. Agency for International

Development

Washington, DC

Preeya Kashemsant

Ministry of Public Health

Bangkok, Thailand

Klaus P. Lippold

SmithKline Beecham

Philadelphia, PA

John McMurdo

Sterling International

New York, NY

John Kline

Georgetown University

Washington, DC

David Long

Warner-Lambert Co.

Morris Plains, NJ

Charles Medawar

Social Audit Ltd.

London, England

Ramona Lunt

World Health Organization

Geneva, Switzerland

Peter Kowey

Medical College of Pennsylvania

Philadelphia, PA

M. Alex Michaels

Wyeth-Ayerst Laboratories

Philadelphia, PA

Judith Krieger

University of Kentucky

Lexington, KY

Mia Lydecker

Palo Alto, CA Lawrence Miike

Papa Ola Lokahi

Honolulu, HI Charles Maitai

University of Nairobi

Nairobi, Kenya

Richard O. Laing

Management Sciences for Health

Boston, MA

Kathy Moore

World Health Organization

Geneva, Switzerland
172 I Drug Labeling in Developing Countries

Steve Moore

Food and Drug Administration

Rockville, MD

Andreas Plei1

University of Texas

Austin, TX

Suely Rosenfeld

Fundacao Oswaldo Cruz

Rio de Janeiro, Brasil

Lou Morris

Food and Drug Administration

Rockville, MD

Michael Pollard

Michaels & Wishner, M.C.

Washington, DC

Robert G. Ruark

Merck, Sharpe & Dohme

Rahway, NJ

George Nakitare

The University

Glasgow, Scotland

Panyarak Poolthup

Royal Thai Embassy

Washington, DC

Sara E. Sa’adah

University of Pennsylvania

Boonardt Saisom

Chulalongkom University

Bangkok, Thailand

Goy E. Navas

Estafeta Univeritaria

Panama, Rep. de Panama

Lane Porter

Washington, DC

James Post

Boston University

Boston, MA

Tony Santopolo

Johnson & Johnson International

New Brunswick, NJ

John Nelson

University of Texas

Dallas, TX

Sompol Prakongpan

Mahidol University

Bangkok, Thailand

Santong Sawasdiphab

Ministry of Public Health

Bangkok, Thailand

Stuart L. Nightingale

Food and Drug Administration

Rockville, MD

Kuntira Punyathikun

Lerdsin General Hospital

Bangkok, Thailand

Herbert J. Schnieder

Rorer International

Pharmaceuticals

Fort Washington, PA

Tom North

Food and Drug Administration

Washington, DC

P. Rees

AMREF

Nairobi, Kenya

S.J. Noumoff

McGill University

Montreal, Canada

Claudio Sepulveda-Alvarez

UNICEF

Bangkok, Thailand

Mary Richardson

Food and Drug Administration

Rockville, MD

E.B. Nyanusi

Ministry of Health

Nairobi, Kenya

S. Douglas Sheldon

Pfizer International Corp. (S. A.)

Bangkok, Thailand

Judith Richter

DIAC

Bangkok, Thailand

Thomas Ogada

Ministry of Health

Nairobi, Kenya

Milton Silverman

Menlo Park, CA

Jim Robb

U.S. Department of Commerce

Washington, DC

Kanawar Singh

Bangkok General Hospital

Bangkok, Thailand

Tamas L. Paal

National Institute of Pharmacy

Budapest, Hungary

Susan Robertson

World Health Organization

Geneva, Switzerland

Thipaporn Sitprija

Chulalongkorn Hospital

Bangkok, Thailand

Patipan Panomwannayuthaya

Chulalongkom University

Bangkok, Thailand
Acknowledgments 173

Craig Smith

Johns Hopkins University

Baltimore, MD

Gwen Solan

Danbury, CT

Payuree Sorasuchart

Pfizer International Corp.

Bangkok, Thailand

Walter Spath

G.D. Searle & Co.

Skokie, IL

Stephen Spielberg

The Hospital for Sick Children

Toronto, Ontario, Canada

Cecilia Stalsby

National Corporation of

Pharmacies

Stockholm, Sweden

Matej Stepita-Klauco

Syntex

Palo Alto, CA

Suthee Sunthorntham

Chulalongkom University

Bangkok, Thailand

Lee Tavis

University of Notre Dame

Notre Dame, IN

Nopdol Thongnopnua

Police General Hospital

Bangkok, Thailand

Becky Van Doren Shulkin

U.S. Department of State

Washington, DC

Praves Vasi

Mahindol University

Bangkok, Thailand

Marcelo Vemengo

OPAS/OMS

Rio de Janeiro, Brazil

Suntharee Vijayanatpaisan

Chulalongkom University

Bangkok, Thailand

Sharon Villa

Washington, DC

Sandeep Wadhwa

Columbia University School of

Medicine

Cynthia D. Wallace

Center for Strategic and

International Studies

Washington, DC

Don Wallace, Jr.

Arnold & Porter

Washington, DC

Agathe Wehrli

World Health Organization

Geneva, Switzerland

Henry Wilde

Thai Red Cross Society

Bangkok, Thailand

Linda Willett

Pfizer Inc.

New York, NY

Karen Williams

Pharmaceutical Manufacturers

Association

Washington, DC

Don G. Wright

Abbott Laboratories

Abbott Park IL

Sam Young

Food and Drug Administration

Rockville, MD

Antonio Carlos Zanini

Universidade de Sao Paulo

Sao Paulo, Brazil
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237. U.S. Congress, Library of Congress,

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Index

Action Program on Essential Drugs, 18,20,141-142

Adverse reactions section of label, 5,43-44

Advertising, pharmaceutical

codes of conduct and, 131-139

detail men, 111

in developing countries, 110-112

fairness and balance test, 95

medical journals, 111-112

over-the-counter drugs, 11, 95-96

prescription drugs, 11,95-96

reminder advertisements, 18, 137

WHO ethical criteria, 16-17, 133-135

Alcohol as an ingredient, 41

AMA. See American Medical Association

AMA Drug Evaluations, 32, 106

American Hospital Formulary Service, 106

American Law Institute, 13, 118

American Medical Association, 32, 106

Anabolic steroid study, 156-157

Antibiotics: The Wrong Drugs for Diarrhoea, 151

Antidepressant drugs, 152

Antidiarrhea drugs, 151-152, 155-156

Antitrust laws, 120-121

APED. See Action program on Essential Drugs

Argentina, drug advertising, 111

Association of the British Pharmaceutical Industry,

146

Bad Medicine: The Prescription Drug Industry in the

Third World, 42

Balasubramaniam, K., 150

Batch certificates, 19, 145

Bitter Facts About Drugs, 151

Boycotts, 13, 117, 123, 131

Brazil

drug advertising, 111

drug labeling, 164

drug registration, 163-164

obtaining product labels, 28-29

package inserts, 29

sample product selection, 28

selection for study, 27

Breast-Milk Substitutes Code. See International Code

of Marketing of Breast-Milk Substitutes

Bristol-Myers Squibb Co., 115

BUKO, 152

Bush, George, economic sanctions against Iraq, 122

Cancer treatment, off-label prescribing and, 105-106

Carter, Jimmy, freezing of Iranian assets, 122

Certificates for pharmaceutical products, 19

Certification Scheme on the Quality of

Pharmaceutical Products Moving in

International Commerce, 19,20, 142-146

Chetley, Andrew, 151

Chloramphenicol study, 155

CIOMS. See Council for International Organizations

of Medical Sciences

Clayton Act, 120

Cleared for Export, 151

Clinical pharmacology section of label, 4,40

Clioquinol study, 155-156

Code of Conduct for Companies Operating in South

Africa, 15

Code of Conduct for Translational Corporations, 15-

16,23,24, 128, 130-131

187
188 I Drug Labeling in Developing Countries

Code of Pharmaceutical Marketing Practices, 9, 17-

18

criticisms of, 138-139

description, 135-136

implementation, 136-137

reporting and resolution of violations, 137-138

Codes of conduct, 15-18,23-24

under international law, 128-135

Collaborating Center for Monitoring of Adverse

Drug Reactions, 20

Collaborating Centre for International Drug

Monitoring, 146-147

Combination drugs, 103-104

Comity principle of international law, 118-119

Consumer Action and Resource Kit on

Pharmaceuticals, 149

Consumer Alerts, 150

Consumer groups

health advocates, 149-153

IFPMA ethical criteria and, 134-135

infant formula and, 132

international programs and, 21

Consumer Interpol, 149-150

Contraindications section of label, 5,4243

Council for International Organizations of Medical

Sciences, 24, 135

Data Sheet Compendium, 146

DEACs. See Drug Export Act countries

Description section of label, 4,40

DESI. See Drug Efficacy Study Implementation

Detail men, 111

Dictionaire Vidal, 146

Dingell, John, 2

DMP. See Drug Management and Policies Division,

World Health Organization

Dosage and administrative section of label, 5-6,44

Drug Diplomacy: Decoding the Conduct of a

Multinational Pharmaceutical Company, 151

Drug Disinformation: What British and

Multinational Drug Companies Tell Doctors

About Their Products, At Home and Abroad,

152

Drug Efficacy Study Implementation, 95

new drug review, 103-104

Drug Export Act countries, 45,49

Drug Export Act of 1986,2,6-7,45,96-98

Drug Facts and Comparisons, 32

Drug Information for the Health Care Professional,

32,106

Drug Labeling studies, 155-162

Drug Management and Policies Division, World

Health Organization, 18-19, 142, 146

The Drugging of the Americas, 158, 159, 161

Drugs and Primary Health Care, 151

Drugs and World Health, 152

Drugs Used in Anesthesia, 146

Drugs Used in Mycobacterial Diseases, 146

Drugs Used in Parasitic Diseases, 146

EAA. See Export Administration Act

Economic sanctions, 121-123

Effects principle of international law, 13, 14, 117-

118, 125

Enforcement Report, 148

The Essential Drugs Monitor, 18, 142

“Ethical and Scientific Criteria for Pharmaceutical

Advertising,” 16, 133

“Ethical Criteria for Medicinal Drug Promotion,” 16-

17, 18,24, 133-135

European Community, codes of conduct, 15

Expert Advisory Panel on Drug Evaluation, 7,49

Expert Review Group

first review, 31-32

medical importance standard, 30

original label examination, 29

scoring review, 36

Export Administration Act, 13, 121-123

Exported drugs

FDCA and, 11

labeling, 11,96-98

tropical disease drugs, 12,98

unapproved drugs, 11, 96

Extraterritorial jurisdiction

antitrust laws, 120-121

health and safety of foreign nationals and, 14-15,

125-126

international law principles, 12-13, 117-119, 125-

126

U.S. laws allowing, 13-14

Fairness and balance test, 95

FCPA. See Foreign Corrupt Practices Act

FDA. See Food and Drug Administration

FDA Consumer Information, 148

FDA Medical Bulletin, 148
Index 189

FDCA. See Food, Drug, and Cosmetic Act

Federal Congress of Development Action Groups.

See BUKO

Federal Register, 148

Federal Trade Commission, 23

Federal Trade Commission Act, 120

Food, Drug, and Cosmetic Act, 9,91

export of pharmaceuticals, 11

1962 amendments, 95

Food and Drug Administration

cooperation with WHO programs, 148

exported pharmaceuticals labeling, 11

extraterritorial jurisdiction, 12-15

FDCA and, 91

international activities, 20, 143, 147-148

labeling standard, 3

tropical disease drug export, 12

unapproved drug export, 11

unlabeled indications, 104

U.S. drug labeling, 9-11

Foreign Corrupt Practices Act, 13-14,22-23, 123-

125, 126

Foreign relations law, 118-120

France

drug approval process, 107

drug efficacy standards, 107

GAIT. See General Agreement on Tariffs and Trade

General Accounting Office

export of unapproved drugs, 96

off-label prescribing study, 105

General Agreement on Tariffs and Trade, 15

Germany

drug approval process, 107

labeling, 107

Global Marketing of Pharmaceuticals: Prescription

for Disaster, 150

“Good Practices in the Manufacture and Quality

Control of Drugs,” 142

Guidelines for Multinational Corporations, 15, 128

“Guiding Principles for Small National Authorities,”

20, 148

HAI. See Health Action International

HAI News, 151

“The Hartog and Schulte-Sasse Study,” 152, 161

Harvard Medical School, 153

Health Action International

code of conduct, 150-151

description, 21, 149, 150

ethical criteria critique, 151

IFPMA critique, 151

Health Horizons, 137

Hoechst, 152

House Subcommittee on Health and the Environment

of the Committee on Energy and Commerce,

98

IBFAN. See International Baby Food Action

Network

IEEPA. See International Emergency Economic

Powers Act

IFM, See International Association of Infant Food

Manufacturers

IFPMA. See International Federation of

Pharmaceutical Manufacturers Associations

ILO. See International Labour Office

India

multinational corporations and, 116

WHO collaborating center, 146

Indications section of label, 4-5,41-42

Indonesia, multinational corporations and, 116

IND. See Investigational new drug exemption

Inert ingredients, 41

Infant formula, 16,23-24, 125, 131-133

Ingredients section of label, 4,4041

INRUD. See International Network for the Rational

Use of Drugs

INRUD News, 153

Institutional Review Boards, 100

Insult or Injury? An Enquiry into the Marketing and

Advertising of British Food and Drug Products

in the Third World, 151

Interfaith Center on Corporate Responsibility, 131

International Affairs Staff, Food and Drug

Administration, 147

International Association of Infant Food

Manufacturers, 16, 132

International Baby Food Action Network 131, 132

International Chamber of Commerce, 15, 128

International Code of Marketing of Breast-Milk

Substitutes, 16,23-24, 128

description, 131-132

implementation, 132-133

International Conference of Drug Regulatory

Authorities, 20
190 I Drug Labeling in Developing Countries

International Emergency Economic Powers Act, 13,

122-123

International Federation of Pharmaceutical

Manufacturers Associations

codes of conduct, 16, 17-18.24, 128, 133, 135-

139

drug advertising, 111

product promotion guidelines, 9

International Labour Office, 15, 128

International law

codes of conduct, 15-18, 128-135

foreign relations law, 118-120

multinational corporations, 116-120

principles, 12-13, 117-119, 125-126

rule of reasonableness and, 119

International Network for the Rational Use of Drugs,

21, 148, 153

International Non-proprietary Name, 136

International Organization of Consumers Unions, 21,

132, 149-150

labeling studies, 155-162

International Pharmaceutical Federation, 49

International programs for labeling improvement

consumer groups, 21, 149-153

FDA international activities, 20, 143, 147-148

prescribing information distribution, 7, 18-19,49,

146

safety and efficacy information access, 19-20

USAID programs, 20-21, 145-146, 148-149

WHO Certification Scheme, 19,20, 142-146

“International Regulation of the Supply and Use of

Pharmaceuticals,” 152

International Union of pharmacology, 49

International Workshop on Consumer Health and

Drug Information and Education, 149

Investigational new drug exemptions

application, 99-100

exemption for clinical trials in human beings, 96

IOCU. See International Organization of Consumers

Unions

IRBs. See Institutional Review Boards

Italy, bribery of officials, 124

Japan

bribery of officials, 123-124

inert ingredients database, 41

Journal of the American Medical Association, 106

Kennedy, Edward, 2

Kenya

drug registration and labeling, 164-165

obtaining product labels, 29

package inserts, 29

sample product selection, 28

selection for study, 27

Labeling changes, prescription drugs, 94

Laws. See specific laws and regulations by name;

U.S. drug labeling laws and regulations

Lee. See Silverman, Lydecker, and Lee, labeling

studies

Lockheed Corp., 123-124

Lydecker. See Silverman, Lydecker, and Lee, labeling studies

MaLAM, See Medical Lobby for Appropriate

Marketing

Management Sciences for Health, 153

Manual for Rural Health Workers: Diagnosis and

Treatment with Essential Drugs, 18, 142

Marketing. See Advertising

Medawar, Charles, 152

Medical Bulletin, 20, 147

Medical Devices and Radiological Health, 148

Medical importance standard, 3,30-31,32,35,4049,

104

Medical Lobby for Appropriate Marketing, 21, 137-

139, 152-153

Medicines Control Agency, 107

Merck & Co., 115

MNCs. See Multinational corporations

Model Guide to Good Prescribing, 18, 142

“Model List of Essential Drugs,” 7,49, 142, 161

Model Prescribing Information, 142

Moscow Olympics boycott, 123

Multinational corporations

bribery of foreign officials, 13-14, 123-125, 126

codes of conduct and, 15, 114, 128-139

description, 113-114

drug advertising, 111

drug labeling influences, 8

extraterritorial jurisdiction and, 120-126

growth of, 114-115

health and safety of foreign nationals, 14-15, 125-

126

host country laws, 106
international law, 116-120

joint venture arrangements, 115

labeling studies, 155-162

legal control, 8-9

markets, 7-8

proprietary products licensing to foreign companies, 116

structure, 8, 115-116

trade embargoes and economic sanctions, 121-123

U.N. standards for, 9, 130-131

—. 

Index 191

NAS. See National Academy of Sciences

National Academy of Sciences, new drug review,

103-104

Nationality principle of international law, 12, 13,

117, 125-126

NDA. See New Drug Application

Nestle Corp., 131-133

Nestle Infant Formula Audit Commission, 132

New Drug Applications, 91,99, 101-102

over-the-counter drugs, 95

New drug approval

clinical trials, 100-101

definition of “new,” 98-99

Investigational New Drug exemption, 99-100

NDA review, 101-102

preclinical research, 99

Nigeria, labeling study, 160-161

OECD. See Organization for Economic Co-operation

and Development

Off-label prescribing, 104-106

Office of International Affairs, U.S. Public Health

Service, 147

One Drug at a Time: A Report on the Limitation of

Fixed Ratio Combination Drugs, 152

Options for Congressional action, 21-24

Organization for Economic Co-operation and

Development, 14, 15, 124-125, 128

Osifo, Nosakhare Guy, 160-161

OTA Labeling evaluation process

analysis and final results, 37

company response evaluation, 32-34

Expert Review Group reviews, 31-32,36

interim and revised overall scores, 37

medical importance standard, 30-31, 32, 35, 40-49

preliminary screening, 31

provision of scoring sheets to companies, 34-36

queries to companies, 32

scoring of labels, 34-36,4049

summary sheets for additional responses, 36-37

OTC. See Over-the-counter drugs

Over-the-counter drugs

advertising, 11,95-96

classes, 95

labeling, 10-11,94-95

package inserts, 29

Overdosage section of label, 6,44

Package inserts, 10,29-30,92-93, 107

in developing countries, 109-110

Package labels for prescription drugs, 92-93

PAHO. See Pan American Health Organization

Pan American Health Organization, 147, 148

Panama

drug registration and labeling, 165-166

obtaining product labels, 28-29

package inserts, 29

prescribing guides, 3

sample product selection, 28

selection for study, 27

PDR. See Physicians’ Desk Reference

Peddling Placebos: An Analysis of Cough and Cold

Remedies, 151

Pediatric drug prescribing, 105-106

Pfizer, Inc., 115

Pharma-Brief, 152

Pharmaceutical labeling studies, 155-162

Pharmaceutical Manufacturers Association, 7,28,45,

135

Physicians’ Desk Reference, 31, 146

Physicians’ Desk Reference for Nonprescription

Drugs, 31

Pills, Profits and Politics, 158

PMA. See Pharmaceutical Manufacturers Association

Policies and Strategies on Drug Pricing Regulations:

International Experiences, 150

Policy Options in Pharmaceutical Patents for

Developing Asian Countries, 150

Post-marketing surveillance, 102-103

Power and Dependence, 152

Precautions section of label, 5,43

Prescribing guides, 3, 30

in developing countries, 110

Prescription drugs

advertising, 11,95-96
192 I Drug Labeling in Developing Countries

labeling changes, 94

labels, 10,92-93

package inserts, 29,92-93

standards of evidence, 94

Prescription for Death: The Drugging of the Third

World, 159, 162

Problem Drugs, 151

Product documents, 107-108

Promoting Health or Pushing Drugs? A Critical

Examination of Marketing of Pharmaceuticals,

151

Protective principle of international law, 117

The Provision and Use of Drugs in Developing

Countries, 151

Qualitative results of OTA survey, 3940,54-91

Quantitative results of OTA survey

company analysis, 6,44

country analysis, 6,44-54

labeling category analysis, 40-44

other industrialized country comparison, 6-7,45-

49

overall analysis, 40

WHO model prescribing information, 7,49

Queries to companies, 32-34

A Question of Control, 151

The Rational Use of Drugs: A Universal Concept,

150

Reagan, Ronald, Breast-Milk Substitutes code and,

133

Reminder advertisements, 18, 137

Reporting requirements, new drugs, 102-103

Restatement (Third) of the Law: The Foreign

Relations Law of the United States, 13-15,118

Rhodesia, economic sanctions against, 123

Rule of reasonableness, 119

Sample selection, OTA Survey

company identification, 28

country selection, 27-28

label translations, 30

sample products, 28-30

Schulte-Sasse. See “The Hartog and Schulte-Sasse

Study”

SCRIP World Pharmaceutical News, 137

Searle Pharmaceuticals, 151-152

export of unapproved drugs, 96

Sherman Act, 120-121

Silverman, Lydecker, and Lee, labeling studies, 42,

158-160

Social Audit, 151-152

labeling studies, 157-158

Statements of licensing status, 19, 145

Survey, OTA

category of information analysis, 4-6

company analysis, 6,44

country analysis, 6,4445

labeling evaluation process, 30-37

other industrialized country comparison, 6-7,45-

49

process, 2-3,27-37

qualitative results, 39-40,54-91

quantitative results, 40-54

results, 3-7

sample selection, 27-30

scoring categories, 3-6, 34

WHO model prescribing information and, 7,49

Syntex Corp., 116

Ten Year Report on the IFPMA Code, 137

Territorial principle of international law, 12-13, 117

Thailand

drug registration and labeling, 166-167

obtaining product labels, 29

package insets, 29-30

sample product selection, 28

selection for study, 28

Third International Conference of Drug Regulatory

Authorities, 143

Trade embargoes, 13, 117, 121-123

Translation of foreign language labeling, 30

Translational Code. See Code of Conduct for

Transnational Corporations

Treaties, codes of conduct and, 129

Tropical disease drugs, 98

export, 12

U.N. Centre on Translational Corporations, 130-131

labeling studies, 160

U.N. Conference on Trade and Development Code of

Conduct on Restrictive Business Practices, 15,

128

U.N. Council for Trade and Development, 133

Unapproved drugs, 96-98

export, 11,96-98
lndex 193

United Kingdom

drug approval process, 107

sales representatives, 111

United Nations. See also specific divisions by name

codes of conduct, 15-16, 23, 24, 128, 130-131

standards for MNCs, 9

United Nations International Court of Justice, 116

United Nations Participation Act, 123

United States Pharmacopeial Convention, 106

U.S. Agency for International Development, 19

cooperative agreement with U.S. Pharmacopoeia,

20-21, 148-149

WHO and, 20, 145-146, 148

U.S. Department of State, 147-148

U.S. drug labeling laws and regulations. See also specific laws and regulations by name

DESI review, 103-104

exported drugs, 96-98

new drug approval, 98-102

off-label prescribing, 104-106

over-the-counter drugs, 94-96

post-marketing surveillance, 102-103

prescription drugs, 92-94

U.S. Pharmacopoeia, 148-149

agreement with USAID, 20-21

U.S. Public Health Service, 147

U.S. Securities and Exchange Commission, 123

U.S. Senate Committee on Labor and Human

Resources, 105

U.S. Trade Representative, 147

USAID. See U.S. Agency for International

Development

USP DI. See Drug Information for the Health Care

Professional

Veterinary Medicine, 148

Warnings section of label, 5,43

Waxman, Henry, 2

WHO. See World Health Organization

WHO Drug Information, 20, 146

WHO Model Prescribing Information, 18-19, 146

WHO Pharmaceutical Newsletter, 20, 146

World Federation of Proprietary Medicine

Manufacturers, 49

World Health Assembly, 135, 143

World Health Organization

Action Program on Essential Drugs, 18,20, 141-

142

Certification Scheme, 19,20, 142-146

codes of conduct, 16, 128

collaborating centers, 20, 146-147

Division of Drug Management and Policies, 18-

19, 142, 146

drug advertising, 111

ethical criteria for drug promotion, 16-17, 24

Expert Advisory Panel on Drug Evaluation, 7,49

FDA and, 20

infant formula hearings, 125

prescribing information, 7, 18-19,49, 146

The Wrong Kind of Medicine?, 152

Yudkin, J. S., 157

U . S . GOVERNMENT PRINTING OFFICE : 1993 0 330–065 QL 3

ISBN 0-16 -041628-0