Technology Transfer at the National

Institutes of Health

March 1982

NTIS order #PB82-202904
Library of Congress Catalog Card Number 82-600529

For sale by the Superintendent of Documents,

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

The quality and efficiency of health care and, ultimately, improved health of the

population depend substantially on the timely and appropriate transfer of medical

technologies from the research setting into medical practice. This spreading of technologies must be fast enough so that significant potential benefits are not denied to the

population and yet sufficiently paced to assure that enough is known about the safety

and appropriate conditions of use of the emerging technologies.

The flow of technologies from research and development (R&D), through evaluation, to their adoption and diffusion in health care settings is thus a crucial aspect of the

lifecycle of technology. Congress and many other parties are concerned with how to

blend accelerated transfer with informed transfer.

As background to an effort to develop improved policies toward the transfer of

medical technologies, the House Committee on Energy and Commerce requested OTA

to prepare an examination of current technology transfer and assessment activities of

the National Institutes of Health (NIH). This technical memorandum is the result of

that examination. It presents general information on biomedical R&D and its relationship to technology transfer, and on the processes of transferring medical technology

and of assessing that technology. It discusses the current technology transfer activities

of NIH and contains detailed looks at two specific institutes.

The National Cancer Institute has been the focus of substantial congressional concern, particularly over its research directions and its activities in bringing technologies

to medical practice. OTA conferred with a large number of academic and other experts

regarding these issues.

The National Heart, Lung, and Blood Institute (NHLBI) is also covered in depth.

NHLBI has been the single most active institute in terms of an organized approach to

technology transfer and the level of such activities.

The main finding of this study is that despite some problems in timely transfer of

technologies the most critical problems are: 1) insufficient attention to the development

of the basic science base necessary for development of effective technologies; and 2) insufficient attention to the careful, scientific evaluation of the potential benefits, risks,

and costs of medical technologies.

Director

. . Ill
Health Program Advisory Committee

Sidney S. Lee, Chairman

Vice President, Michael Reese Hospital and Medical

Stuart H. Altman Joyce C. Lashof

Dean, Florence Heller School

Brandeis University

Robert M. Ball

]nstitute of Medicine

National Academy of Sciences

Lewis H. Butler

School of Medicine

University of California, San Francisco

Kurt Deuschle

Mount Sinai School of Medicine

Rashi Fein

Center for Community Health

and Health Care

Harvard Medical School

Melvin A. Glasser

Committee for National Health lnsurance

Patricia King

Georgetown Law Center

Center

School of Public Health

University of California, Berkeley

Mark Lepper

Vice President for InterInstitutional Affairs

Rush Presbyterian-St. Luke’s Medical Center

Margaret Mahoney

President

The Commonwealth Fund

Frederick Mosteller

School of Public Health

Harvard University

Mitchell Rabkin

Beth Israel Hospital

Frederick C. Robbins

Institute of Medicine

National Academy of Sciences

Rosemary Stevens

Department of History and

Sociology of Science

University of Pennsylvania

Kerr L. White

Rockefeller Foundation

iv
OTA Technology Transfer at NIH Project Staff

H. David Banta, Assistant Director, OTA

Health and Life Sciences Division

Clyde J. Behney, Health Program Manager and Project Coordinator

Anne Kesselman Burns, Analyst

Hellen Gelband, Analyst

Michael Gough, Senior Analyst

Lawrence Miike, * Senior Analyst

Kerry Britten Kemp, * Editor

Mary E. Harvey, Secretary

Pamela J. Simerly, Secretary

Virginia Cwalina, Administrative Assistant

OTA Publishing Staff

John C. Holmes, Publishing Officer

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

OTA would like to thank the following individuals for their assistance during this project.

Lynne Alexander

Office of Technology Assessment

Harold Amos

Harvard Medical School

David Baltimore

Massachusetts Institute of Technology

James Bowen

M. D. Anderson Hospital and Tumor Institute

Lester Breslow

UCLA School of Public Health

Irwin Bross

Roswell Park Memorial Institute

Louis Carrese

National Cancer Institute

Bruce Chabner

National Cancer Institute

Sir Richard Doll

Oxford University

Pony Feigl

Fred Hutchinson Cancer Research Center

Leonard Fenninger

American Medical Association

James Fries

Stanford University Medical Center

Peter Greenwald

National Cancer Institute

Maureen Henderson

University of Washington

Harry Holmes

M. D. Anderson Hospital and Tumor Institute

Anne Stuart Houser

National Institutes of Health

Douglas Hussey

National Institutes of Health

Itzhak Jacoby

National Institutes of Health

Rose Kushner

Kensington, Md.

Joshua Lederberg

Rockefeller University

Mark Lepper

Rush-Presbyterian-St. Luke’s Medical Center,

Chicago

Charles Lowe

National Institutes of Health

David McCallum

Consultant in Health Policy

Jay Moskowitz

National Heart, Lung, and Blood Institute

Norton Nelson

New York University

Guy Newell

M. D. Anderson Hospital and Tumor Institute

Richard Peto

Oxford University

Donald Pitcairn

National Cancer Institute

Henry Pitot

McArdle Laboratory for Cancer Research

Nathaniel Polster

M. D. Anderson Hospital and Tumor Institute

David Rail

National Institute of Environmental Health Sciences

Benno Schmidt

J. H. Whitney & Co.

Marvin Schneiderman

Clement Associates, Inc.

Irving Selikoff

Mt. Sinai School of Medicine

Charles Smart

American College of Surgeons

Howard Temin

McArdle Laboratory for Cancer

William Terry

National Cancer Institute

Arthur Upton

New York University

Ernst Wynder

American Health Foundation

John Young

National Cancer Institute

Marvin Zelen

Sidney Farber Cancer Institute

Research

vi
Contents

Chapter Page

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2. Biomedical Research and Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

3. The Process of Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

4. Evaluation of Medical Technologies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

5. Technology Transfer at the National Institutes of Health. . . . . . . . . . . . . . . . . 37

6. Technology Transferal the National Cancer Institute. . . . . . . . . . . . . . . . . . . . 57

7. Technology Transfer at the National Heart, Lung, and Blood Institute. . . . . 93

8. Findings and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........115

Appendixes

A. Glossary of Acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . ....................121

B. Background Material: Grants, Contracts, and Peer Review . ..............123

C. NHLBI Clinical Trials Briefing Document . . . . . . . . . . . . . . . ...............129

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......185

vii
Chapter 1
Chapter 1

Introduction

The ultimate goal of biomedical research is a

healthier population. The road to this end result,

though, is made up of a great many intermediate

goals: for example, improved understanding of

basic biological processes; identification of the

nature and causes of specific diseases and disabilities; development of ways to identify, prevent, diagnose, or treat diseases; exchange of

relevant information; and delivery of services.

One important characteristic that most of the

intermediate goals and objectives have in common is their dependence on science and technology. The Office of Technology Assessment

(OTA) defines technology as the practical application of organized knowledge. Medical technology is defined as including drugs, devices,

and medical and surgical procedures, and the

systems in which such technologies are delivered

(85). For example, prevention of disease is both

a technology in itself and also depends on effective technologies (such as vaccination or public

education) for its attainment. Thus, one of the

principal outcomes of health-related research is

the development and subsequent use of medical

technologies.

The process through which technologies are

brought to existence and employed in everyday

medical practice is not a simple one. It involves,

as will be covered later, a series of overlapping

and often cyclical stages. For purposes of analysis, OTA divides the process into research and

development (R&D), evaluation, diffusion, and

use (delivery, financing, etc.).

Technology transfer is often thought of as

involving primarily the diffusion stage—the

spread of a new technology into common use.

However, the success and appropriateness of

any technology’s transfer or diffusion is heavily

dependent on all the stages that precede use.

Thus, technology truansfer-related activities are

viewed in this report as involving R&D, evaluation, dissemination of pertinent information,

and technology transfer (or diffusion) itself.

The timely and appropriate transfer of technologies from a research setting into medical

practice has important implications for the quality of health care, access to care, and the cost of

care. For this reason, the transfer of biomedical

knowledge into technologies, the assessment of

the resulting technologies, and their spread into

health care settings continue to be areas of congressional concern.

The National Institutes of Health (NIH) is the

primary institution in the United States for the

first two of the above processes (the development and the assessment of technologies) and

one of the key actors in the third. Because NIH

plays such a large and critical role in the substance and the quality of technology transfer, it

exerts a powerful influence on the priority given

to technology transfer by other groups, on the

state of the art of assuring effective transfer, and

on the generation and flow of information about

technologies, especially their benefits, risks,

costs, and readiness for widespread use.

The House Committee on Energy and Commerce requested that OTA examine the role of

NIH in assessing and transferring medical technology. This technical memorandum, Technology Transfer at the National Institutes of

Health, presents the results of that examination.

It was prepared during February and March of

1982. As with all OTA technical memoranda, it

contains no policy options for congressional

consideration. In response to the committee’s

primary concerns, it covers NIH in regard to its

R&D activities as they relate to the development

of medical technologies, its demonstration and

control programs and other activities related to

transfer of technologies, its efforts to disseminate information on medical technology, and

the extent and form of its assessment activities.

It draws heavily on earlier OTA studies, especially Assessing tile Efficacy and Safety of Medical Technologies (85), The Implications of CostEffectiveness Analysis of Medical Technology

(89), Development of Medical Technology A s -

sessment: Opportunities for Assessment (88),

Strategies for Medical Technology Assessment

(92), and Technologies for Determining Cancer

Risks From the Environment (86).

3
4

ORGANIZATION OF THE REPORT

Chapters 2 through 5 cover NIH in general.

Chapter 2 discusses biomedical R&D, providing

background information on the process of biomedical science and its relation to technology

development and transfer, on the Nation’s and

NIH’s investment in biomedical research, and on

the organization of NIH.

The third chapter presents a description of the

process of technology transfer. It is designed to

provide a context for the later examinations of

current technology transfer activities at NIH.

Chapter 4 highlights the role of evaluation of

medical technologies as part of the R&D and

transfer processes.

Chapter 5 presents and examines the current

technology transfer activities engaged in or supported by NIH.

Because of their size, importance, and levels

of relevant activities, the National Cancer Institute (NCI) and the National Heart, Lung, and

Blood Institute (NHLBI) have been highlighted.

A major share of attention has been devoted to

NCI because of continuing congressional concern over the conflicting pressures on NCI related to transfer and assessment of technologies

for preventing, diagnosing, and treating cancers.

Chapter 6, therefore, is on NCI. NHLBI has been

focused on because it is probably the single most

active institute in technology transfer. It has

devoted considerable thought and funds to such

activities. Thus, chapter 7 covers NHLBI and its

transfer and assessment activities.

Chapter 8 presents the findings and conclusions of the study.

Appendix A is a glossary of acronyms. The

second appendix contains background material

on NIH’s process of awarding grants and contracts, including a discussion of peer review. Appendix C is on NHLBI clinical trials.
Chapter 2

Biomedical Research

and Development
Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Form and Results of R&D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Basic Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Applied Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Development .,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical Technology: Definition and Classification . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical Technology: Its Lifecycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Assessments and Expectations of Biomedical R&D . . . . . . . . . . . . . . . . . . . . . . . . . .

The Role of NIH in Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Federal Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Agencies Participating in Health R&D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Growth of the NIH Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organization of NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Extramural Research Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Intramural Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

List of Tables

Table No.

‘7

8

8

9

10

10

10

11

12

12

13

13

16

17

17

l. Federal Health R&D as a proportion of Total U.S. Funded Health R&D,

1960-80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. U.S. Health R&D as a Proportion of Total U.S. R&D, 1960-80 . . . . . . . . . . . . . . . .

3. Federal Health R&D as a Proportion of Total Federal R&D, Fiscal Years

1960-80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Federal ObligationsforHealth R&D by Agency, 1980 . . . . . . . . . . . . . . . . . . . . . . .

5. Number and Amount of Research Grants Awarded by the National

Institutes of Health, Fiscal Years 1938-80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6. NIH Obligations by NIH Component, Fiscal Years 1969-80. . . . . . . . . . . . . . . . . . .

7. 1982 Continuing Budget Resolution for NIH by Funding Mechanism . . . . . . . . . . .

Page

List of Figures

12

13

14

14

15

15

18

Figure Page

l. The Organization of the National Institutes of Health . . . . . . . . . . . . . . . . . . . . . . . 16
Chapter 2

Biomedical Research and Development

INTRODUCTION

Even in this era of increasing disagreement

over the allocation of shrinking resources, there

is general agreement that a healthy population is

the overall goal of efforts in the health sphere.

These efforts include a range of activities, from

biomedical or health-related research* through

the development, application, production, delivery and use of medical technologies. The efforts in these areas are undertaken by the public

sector (including Federal, State, and local governments) as well as by the private sector (including nonprofit organizations, universities, industries, and individuals).

Federal participation in the attempts to assure

a healthy population have been increasing.

Total national health expenditures in 1965 were

$42.0 billion; the public share** was $11.0 billion, or 26.1 percent. In 1979, total national

health expenditures were $247 billion, with the

public share at 42.2 percent (31). Likewise, Federal support for health research and development (R&D) has been increasing, from $1.67 billion in 1970 to $4.93 billion in 1981*** (49). One

of the clearest of the Federal responsibilities in

health has been to support biomedical research

(114).

Health-related research has been defined by

the National Institutes of Health (NIH) as follows:

Health-related research involves systematic

study directed toward the development and use

of scientific knowledge in the following areas:

(1) The causes, diagnosis, treatment, control,

prevention of and rehabilitation relating

to the physical and mental diseases and

other crippling impairments of mankind;

*In this paper, biomedical and health-related research are used

synonymously.

**Of the public share, the Federal share has always been the

largest. For example, in 1980, of total public expenditures for personal health care of $77,3 billion, 555.3 billion (71 .S percent) was

Federal and $22.1 billion (28.5 percent) was State and local (31).

● * ‘Estimated.

(2)

(3)

(4)

The origin, nature and solution of health

problems not identifiable in terms of disease entities;

Broad fields of science important to or

underlying disease and health problems;

and

Research in nutritional problems impairing, contributing to, or-otherwise affecting optimum health. (114).

The concepts were recently summarized eloquently by Handler who wrote:

It is no longer known who first used the term

“biomedical science"—perhaps an early clinical

investigator desiring to cloak his relatively

crude arts with the mantle of precise science, or

maybe a fundamental biologist seeking to attract funds more readily available for distinctly

medical research. Be that as it may, this is a

testimonial to the vitality and enormous utility

of “biomedical science”--a spectrum of research

extending from the most esoteric explorations of

the diverse manifestations of life to astute observations made at the bedside, (30).

The Federal Government supports a range of

health-related R&D activities. The basic objective of all of these activities is the production of

knowledge (89,114). This knowledge may be in

the form of information on health itself, on diseases and disabling conditions, or on environmental influences which impinge on health.

Knowledge, in turn, results in new tools and

technologies to intervene in the disease process,

or to counteract the effects of disease. Some research evaluates the products of previous research while other research investigates the use

of technology and other aspects of the health

care delivery systems. Perhaps most important,

though, is the fact that much of the existing research serves multiple purposes, and some yields

results that are more valuable to solve problems

in fields other than the field in which the research originated (89).

Health-related R&D have given the health

care system and this country much beneficial in7
8

formation and many effective technologies, but tential benefit to all of society and not just to

they are activities necessarily full of uncertain- specific individuals or groups. Thus, although a

ties. These activities may also be expensive— rationale and a precedent for Federal involveclose to $5 billion was spent on health-related ment in biomedical R&D exist, it is important

R&D in 1981 by the Federal Government alone that those moneys be spent as wisely as possible

(49). At the outset, the expenditure of Federal and in accord with a balance between public and

funds for R&D is clearly an investment in the scientific priorities (89,114).

future. Much of this investment represents a poTHE FORM AND RESULTS OF R&D

Ultimately, the desired result of health-related

R&D is a healthier population, However, there

are a number of diverse activities and intermediate results which occur after a new discovery but

before a change in health status is seen. The

range of activities is often broken down into

loosely defined categories:

1. basic research,

2. applied research,

3. targeted development of technologies,

4. evaluation of technologies, and

5. diffusion and use of technologies.

In general, the first three categories of activities

are forms of R&D which result in medical technologies. Medical technologies, then, may be

termed the intermediate result of R&D. The last

two categories are the utilization of the intermediate results in the refinement and application

of those technologies. *

The demarcations between the categories are

not clearly defined. Nevertheless, the classifications play an important role in the process of setting health care research priorities, allocating

and distributing funds, and evaluating the outcomes or products of R&D efforts. The intended

purpose of any given research effort is important

at several levels in the health care decisionmaking and policy process. There is constant tension

in the decisionmaking process between those

who advocate increased funds for basic research, those who feel more work is needed in

applying more fully the knowledge and technol-

● Another form of research is research on the process involved in

performing all of these activities. When this research is done on the

use of medical technologies, it is often referred to as health services

research.

ogies that exist, and those who believe that it is

most important to examine what is already in

place to determine how it is working and how to

make it work better. An important result of

these different perceived research needs is that

the “label” that is affixed to a given health care

program or initiative can be quite important to

its ultimate success (89).

The discussion that follows describes the

forms of biomedical R&D—basic research, applied research, and development of medical

technologies—and defines the immediate result

of these activities—medical technology. A brief

description of the lifecycle of medical technologies is then included for perspective, but the activities concerned with the evaluation, diffusion

and use of the technologies will not be discussed

until future chapters.

Basic Research

There are numerous definitions of basic (biomedical) research found in the literature

(82,97,98,114). The National Science Foundation (NSF) states that, “In basic research the objective . . . is to gain fuller knowledge or understanding of the fundamental aspects of phenomena and of observable facts without specific

applications toward processes or products in

mind” (82). The President’s Biomedical Research

Panel (98) did not formulate a precise definition,

but instead suggested characteristics of basic research—that it is an exploring activity, that it requires an atmosphere of uncertainty, and that it

must rely heavily on the initiative of the individual investigator or group of investigators.

Viewed still another way, basic research pro-
9

duces the fundamental science base on which to

build improved technologies to prevent and

treat disease (97).

There is agreement among biomedical researchers that basic research is essential to the

ultimate goal of a healthier population. Comroe

and Dripps cited the following examples of the

value of basic research:

When Roentgen discovered X-rays, it was not

to enable a cardiologist to visualize the coronary arteries of a patient suffering from angina

pectoris; he was studying a basic problem in

physics to determine the electrical nature of

matter.

When Carl Landsteiner discovered blood

groups, it was not part of a program to make

blood transfusions safe; he was investigating

basic problems in immunology.

When Cournand and Richards passed a catheter into the heart of man, it was not to develop

a new method of diagnosing heart disease; they

were attempting to measure the oxygen content

of mixed venous blood in the right atrium of the

heart.

When Shackell developed a technique of

freeze drying in 1909, it was not to preserve

plasma or its fractions; he was studying a basic

problem of the water content of liver and muscles.

When Clarke, collector and amateur breeder

of butterflies, studied variations in the color of

butterfly wings, he had no idea that it would

lead to the discovery of the Rh factor in human

blood.

When Davies and Brink devised an electrode

for measuring the partial pressure of oxygen, it

was not to monitor blood-oxygen in the intensive care unit; they were carrying out basic research (16).

The principle illustrated in these examples were

summarized by Handler:

What stands out in such histories is that each

new major technique or procedure enables a

leap to unanticipated new understandings and

insights, that each new broad biological understanding illuminates a host of pathological circumstances never even considered by the original investigators (30).

Numerous other examples of unanticipated

clinical applications from basic research could be

cited. In addition, there have been studies of the

cost-benefit of basic research (114). For example,

Fudenberg (24) estimated that in the 6-year period from 1955 to 1961, monetary savings resulting from the prevention of poliomyelitis cases

were $6 million. Savings in 1975 were estimated

at $2 million per year, the approximate amount

of the total NIH appropriation that year.

If called upon to prove the value of its work,

the basic research community can always provide examples. However, these examples can

only be compiled retrospectively. Because of its

nature, the future outcome of basic research is

unknown and speculative.

Applied Research

As with basic research, there are numerous

definitions of applied (biomedical) research.

NSF (82) states that, “In applied research the objective . . . is to gain knowledge or understanding necessary for determining the means by

which a recognized and specific need may be

met.” Characteristics of appIied research include

a high degree of certainty about the outcome of

the research, the use of facts in the research

which are sufficiently abundant and tested so

that the outcome can be predicted, a relatively

fixed protocol, and carefully planned sequential

work schedules (98).

The value of applied research, because its

results are more closely linked to treating or

preventing disease, is not an issue. Instead, attention has focused on two questions. First,

what is the appropriate amount of resources to

be spent on applied research in relation to those

spent on basic research? Although this question

has been answered by numerous researchers and

policymakers, others note that it is difficult to

see how fixed percentages of future budgets can

be set, since ideally the need to do applied research, at a particular time in a particular area of

science, depends on what knowledge is available

to be applied (98). Second, how can the lag time

between the discoveries of basic research and
10

their application in applied research be shortened?’ This lag was a striking problem around

the beginning of the century, but seems to be less

of one currently (114).

Development

The distinction between development and applied research is even fuzzier than the one between basic and applied research. Indeed, there

are those who do not make one at all. However,

development can be defined as “systematic use

of the knowledge or understanding gained from

research, including design and development of

prototypes and processes. It excludes quality

control, routine product testing, and production” (98).

While there are many examples of Federal

support for development (i. e., the artificial

heart), the area is one in which the private sector, and particularly private industry, provides

significant funding. This is especially true when

the object of the development process is a physical technology, such as a drug or device, and

there is a perceived potential for profit (88).

Medical Technology: Definition and

Classification

As noted earlier, one of the primary intermediate results of the entire biomedical R&D

process is the creation of medical technology.

OTA defines technology broadly—as the practical application of organized bodies of knowledge. Medical technology, then, can be defined

as the drugs, devices, and medical and surgical

procedures used in medical care, and the organizational and supportive systems within which

such care is provided.**

Although medical technologies are of many

different types and serve a variety of functions,

they can be classified into sets. A useful system

*This lag does not refer to the lag between basic research and

adoption of technology in clinical practice. As will be discussed

further, the lag between these events has been found too long for

some technologies and too short for others.

**This discussion is drawn from two previous OTA reports—

Assessing the Efficacy and Safety of Medical Techno!~gies (85) and

Development of Medical Technology: Opportunities for Assessment (88). For an expanded discussion, see those reports.

for classifying medical technologies distinguishes

these technologies according to two dimensions

—medical purpose and physical nature. Each of

these dimensions—medical purpose and physical nature—can be broken down further:

Medical purpose: 1) A diagnostic technology

helps in determining what disease processes occur in a patient; 2) A preventive technology

protects an individual from disease; 3) A therapeutic or rehabilitative technology relieves an

individual from disease and its effects; 4) An

organizational or administrative technology is

used in management and administration to ensure that health care is delivered as effectively as

possible; and 5) A supportive technology is used

to provide patients, especially those in hospitals, with needed services (e.g., hospital beds

and food services).

Physical nature: 1) A technique is a purposive

application of skills or knowledge, or both, by a

health care provider to a patient; 2) A drug is

any chemical or biological substance that may

be applied to, ingested by, or injected into

humans in order to prevent, treat, or diagnose

disease or other medical conditions; 3) A device

is any physical item, excluding drugs, used in

medical care, and may range from a machine requiring large capital investment to a small instrument or implement; and 4) A procedure is a

combination, often quite complex, of provider

skills or abilities with drugs, devices, or both.

With procedures, the predominant factor may

be either the product (drug or device), the technique, or the skills of the individual provider

performing the procedure.

Medical Technology: Its Lifecycle

In order to place in perspective the role of

biomedical R&D in the ultimate application of

medical technologies to improve the health of individuals and to set the stage for the discussion

of technology transfer, it is useful to briefly

describe the lifecycle of medical technologies. * * *

The development, diffusion, and use of medical technologies is a process that has been described as including at least seven steps (85):

● * *As in the previous section, this discussion is drawn from previous OTA reports, particularly Assessing the Efficacy and Safety

of Medical Technology and Development of Medical Technology.
11

1.

2.

3.

4.

5.

6.

7.

Discovery, through research, of new

knowledge, and relation of this knowledge

to the existing knowledge.

Translation of new knowledge, through applied research, into new technology, and

development of a strategy for moving the

technology into the health care system.

Evaluation of the safety and efficacy of new

technology through such means as controlled clinical trials.

Development and operation of demonstration and control programs to demonstrate

feasibility for widespread use.

Diffusion of the new technology, beginning

with the trials and demonstrations and continuing through a process of increasing acceptance into medical practice.

Education of the professional and lay communities in use of the new technology.

Skillful and balanced application of the

new developments to the population.

This sequence is attractive, because it offers a

logical, linear model for understanding the

development process and categorizes activities

for discussion purposes. In addition, it highlights the fact that it is usually possible to identify a medical innovation prior to widespread

diffusion, and thus intervene in the process—either to assure that technologies not properly evaluated for safety and efficacy (at a minimum) are not widely disseminated for clinical

use or to speed the process for proven new technologies. Thus, like other models, it represents a

desirable order for its component events.

However, medical technologies, like others, in

fact emerge from a process that is far less systematic and certainly less linear than implied by the

model. Certain steps in the process, especially

those concerned with evaluation and demonstration, have often been skipped entirely. An additional weakness of the model is the absence of an

acknowledged place for epidemiologic research,

Epidemiologic methods have been used in testing

efficacy and safety of medical technologies, and

they have led to the discovery of causes of disease. For example, epidemiological research has

shown that cigarette smoking is the major cause

of lung cancer, and thus, control programs for

this disease are now possible even though basic

research has not as yet discovered the biological

mechanism by which smoking causes cancer.

Obviously, biomedical R&D is an important

component of the Iifecycle of medical technologies. Other important, and overlapping, components include evaluation and technology

transfer. These additional components and their

interrelationships will be discussed further in

chapters 3 through 5.

Assessments and Expectations of

Biomedical R&D

Assessment of the performance of biomedical

R&D involves one of two kinds of review—

review of the individual steps in the R&D process or review of the final results of the R&D,

changes in health status. The first kind is an

assessment of how well each specific project met

its goals. In the case of basic research—where

the goal of the study is the production of new

knowledge—the measurement of attaining the

goal is often the publication output. For applied

R&D, production of the targeted product is the

measurement of goal achievement. This kind of

assessment is also conducted at the organizational level. For example, NIH has conducted

studies that measure the correlation between

their support effort and biomedical publication

output (89).

The second kind of assessment of healthrelated R&D is concerned with measuring the

changes in mortality and morbidity. In this area,

the expectations of health research often seem

unrealistic. Great cures or changes in health

statistics, particularly mortality, can no longer

be expected in the short run (114). From 1900 to

1975, the increase in life expectancy at birth was

greater than 20 years (56). There is no doubt that

medical advances in antibiotics and vaccines and

the resulting control of infectious diseases are

strongly related to this dramatic increase. In the

current era, however, chronic diseases dominate

the causes of morbidity and mortality, These

diseases are not likely to lend themselves as easily to molecular solutions, since we do not yet

understand their mechanisms. Factors difficult

to control such as environment, genetics, and
12

personal health habits play a role. And since

chronic diseases generally become evident late in

life, gains in life expectancy from their control

THE ROLE OF NIH IN BIOMEDICAL

The Federal Role

It is estimated that national support for

health-related research in fiscal year 1981 totaled

$8.47 billion. Of that amount, 58.3 percent, or

$4.93 billion, came from the Federal Government. Industry expended $2.7 billion, or 32.0

percent of the total. The remainder, in decreasing order of percent of the total, was spent by

State and local governments, voluntary health

agencies, other private nonprofit organizations,

and private nonprofit foundations (49).

As indicated in table 1, the Federal share of

the national support for health R&D has generare likely to be small compared to the years of

life saved in children cured of an acute disease

(56).

RESEARCH

ally decreased over the past decade. The Federal

Government has continued to provide the majority of support since 1960, however. Industry’s

share of the total health R&D effort has steadily

increased—in 1960, industry supported 28.6 percent of the total compared with 32.0 percent in

1981 (101). Most expenditures by industry for

health-related R&D represent studies relating to

drug development (114).

The national support for health R&D as a

percentage of all R&D increased rapidly during

the 1960’s and has remained fairly constant at

around 12.4 percent since 1976 (see table 2). A

Table 1.— Federal Health R&D as a Proportion of Total U.S.-Funded Health R&D,

1960-80a (dollars in millions)

Health R&D Federal health R&D as a

percent of total

Year Total b

Federal Non-Federal health R&D

1960 . . . . . . . . . . . . . . $ 8 8 4 $ 448 $ 436 50.7 ”/0

1961 . . . . . . . . . . . . . .

1962 . . . . . . . . . . . . . .

1963 ., . . . . . . . . . . . .

1964 . . . . . . . . . . . . . .

1965 . . . . . . . . . . . . . .

1966 . . . . . . . . . . . . . .

1967 . . . . . . . . . . . . . .

1968 . . . . . . . . . . . . . .

1969 ..., . . . . . . . . . .

1970 . . . . . . . . . . . . . .

1971 . . . . . . . . . . . . . .

1972 . . . . . . . . . . . . . .

1973 . . . . . . . . . . . . . .

1974 . . . . . . . . . . . . . .

1975 . . . . . . . . . . . . . .

1976 C 

. . . . . . . . . . . . .

1977 . . . . . . . . . . . . . .

1978 C 

. . . . . . . . . . . . .

1979 . . . . . . . . . . . . . .

1980 (est.)c 

. . . . . . . . .

1981 (est.) . . . . . . . . .

1,085

1,330

1,523

1,695

1,890

2,111

2,345

2,568

2,785

2,846

3,167

3,527

3,735

4,431

4,688

5,084

5,594

6,249

7,097

7,894

8,456

574

782

919

1,049

1,174

1,316

1,459

1,582

1,674

1,667

1,877

2,147

2,225

2,754

2,832

3,059

3,396

3,811

4,325

4,726

4,932

511

548

604

646

716

795

886

986

1,111

1,179

1,290

1,380

1,510

1,677

1,856

2,205

2,198

2,438

2,772

3,168

3,524

52.9

58.8

60.3

61.9

62.1

62.3

62.2

61.6

60.9

58.6

59.3

60.9

59.6

62.2

60.4

60.2

60.7

61.0

60.9

59.9

58.3

aExclude5 research tratning and construction Includes U. S-funded health R~D support SPent abroad.

bflewsed.

c Beg, nnlng ~lth fiscal year IW5, Federal health R&D data are collected biennially. For iW?tW2ifM other than f++fi HCFA VA,

and the Consumer Product Safety Commission, health R&D figures are estimated by NIH for intervening years.

SOURCES. 1980-80 Data, National Institutes of Health, 1981 N/l/ A/rnanac, NIH publication no, 81-5, 1981.

1981 Data, National Institutes of Health, E?as/c f)afa Re/at/rrg to the Naf/orra/ /rrsfitufes of Hea/th 1981, May 1981.
Table 2.—U.S. Health R&D as a Proportion of Total U.S. R&D, 1960-80a

(dollars in millions)

Health R&D as a percent

Year Total U.S. R&D U.S. health R&D of total R&D

1960 . . . . . . . . . . . . . $13,523 $ 863 6.4%

1961 . . . . . . . . . . . . . 14,316 1,058 7.4

1962 . . . . . . . . . . . . . 15,394 1,289 8.4

1963 . . . . . . . . . . . . . 17,059 1,475 8.6

1964 . . . . . . . . . . . . . 18,854 1,645 8.7

1965 . . . . . . . . . . . . . 20,044 1,833 9.1

1966 . . . . . . . . . . . . . 21,846 2,050 9.4

1967 . . . . . . . . . . . . . 23,146 2,276 9.8

1968 . . . . . . . . . . . . . 24,604 2,488 10.1

1969 . . . . . . . . . . . . . 25,631b

2,697 10.5

1970 . . . . . . . . . . . . . 25,910b

2,765 10.7

1971 . . . . . . . . . . . . . 26,604 b

3,063 11.5

1972 . . . . . . . . . . . . . 28,426b

3,418 12.0

1973 . . . . . . . . . . . . . 30,631 b

3,587 11.7

1974 . . . . . . . . . . . . . 32,768b

4,236 12.9

1975 . . . . . . . . . . . . . 35,256b

4,478 12.7

1976 C 

. . . . . . . . . . . . 38,960b

4,848 12.4

1977 . . . . . . . . . . . . . 43,013b 5,318 12.3

1978 C 

. . . . . . . . . . . . 48,286 b

5,942 12.3

1979 . . . . . . . . . . . . . 54,296b

6,732 12.4

1980(est.). . . . . . . . . 60,375 7,468 12.4

aExcludes research training and construction. Also excludes U.S -funded R&D Support spent abroad.

bRev!sed

Ceeglnnlngwlth ftscalyear1975, Federal health R&Ddata are collected bienmally. For agencies other than PHS,HCFA.VA,

and the Consumer Product Safety Commission, health R&D figures are estimated by NIH for Intervening years.

SOURCE. Natlonallnstltutes of Health, 7981 fV/HA/rnanac, NIHpublication no. 81-5, 1981.

similar trend for Federal health R&D expenditures as a proportion of total Federal R&D expenditures can be seen in table 3.* In contrast,

the percentage of the Federal health dollar spent

on R&D activities has decreased. In 1974, approximately 10 percent of the Federal health

dollar supported R&D (l14), but in 1980, only

7.9 percent did.**

Agencies Participating in Health R&D

Federal funds for health-related R&D are

channeled primarily through NIH. In 1980, NIH

support for health R&D accounted for 67.3 percent of the Federal support (48). However, a

number of other Federal agencies participate in

health R&D. Their contributions are shown in

table 4.

———. -——-—

‘The drop in 1981 may appear because the fi~ures come from

budget authority rather than actual expenditures,

‘ ‘The 7.9 percent figure is derived as follows: 1980 Federal persona] health expenditures were $55,3 billion (31 ). Federal health

R&D expenditures were ~4.726 million (49). The R&D expenditure> as a percent of the sum c~f the two figures (representing total

Federal health expenditures) is 7.9 percent.

Growth of the NIH Program

Prior to World War II, biomedical research in

the United States was a small activity, primarily

academically based. During the 20-year period

following World War II, the field of biomedical

research experienced very rapid growth (114).

This growth can be seen in table 5. The National

Cancer Institute (NCI), authorized in 1973,

awarded its first research grants in 1938. At that

time, NIH was a separate organization conducting intramural research. The Public Health Service Act of 1944 consolidated and revised existing

legislation, making NCI a division in NIH and

authorizing NIH to expand its research programs through an extramural grants program. In

December 1945, 44 wartime research contracts

were transferred to the Public Health Service

(PHS) jurisdiction, giving sufficient funds for a

general extramural research program. A research grants office was created at NIH in early

1946 to administer these projects and to operate

a program of research grants and fellowship

awards. This office became the Division of Research Grants (DRG) later that year, and the

number and amount of grants began to climb.
—

14

Table 3.—Federal Health R&D as a Proportion of Total Federal R&D, Fiscal Years

1960-80a’ b (dollars in millions)

Federal health R&D as a

Total Federal percent of total Federal

Year Federal R&D health R&D R&D

1960 . . . . . . . . . . . . . .

1961 . . . . . . . . . . . . . .

1962 . . . . . . . . . . . . . .

1963 . . . . . . . . . . . . .

1964 ......, . . . . . . .

1965 . . . . . . . . . . . . . .

1966 . . . . . . . . . . . . . .

1967 ......, . . . . . . .

1968 . . . . . . . . . . . . . .

1969 . . . . . . . . . . . . . .

1970 . . . . . . . . . . . . . .

1971 . . . . . . . . . . . . . .

1972 . . . . . . . . . . . . . .

1973 . . . . . . . . . . . . . .

1974 . . . . . . . . . . . . . .

1975 . . . . . . . . . . . . . .

1976 C 

. . . . . . . . . . . . .

1977 . . . . . . . . . . . . . .

1978 C 

. . . . . . . . . . . . .

1979 . . . . . . . . . . . . . .

1980(est.) c 

. . . . . . . . .

1981 . . . . . . . . . . . . . .

$ 7,552

9,059

10,290

12,495

14,225

14,614

15,520

16,529

15,921

15,641

15,339

15,543

16,496

16,800

17,411

19,039

20,780

23,984

26,388

28,978

31,878

35,523

$ 448

574

782

919

1,049

1,174

1,316

1,459

1,582

1,674

1,667

1,877

2,147

2,225

2,754

2,832

3,059

3,396

3,811

4,325

4,726

4,932

5.9%

6.3

7.6

7.4

7.4

8.0

8.6

8.8

9.9

10.7

10.9

12.1

13.0

13.2

15.8

14.9

14.7

14.2

14.4

14.9

14.8

13.8

aExcludes research training and construction, Includes U.S.-funded health R&D support spent abroad.

bRevised.

cBeginning with fiscal year 1975, Federal health R&D data are collected biennially.Foragencies other than PHS, HCFA, VA,

and the Consumer Product Safety Commission, health R&D figures are estimated by NIH for intervening years

SOURCES: 1980-80 Data, Nat!onallnstitutes of Health, 198f N/H Ahrrarrac, NIH publication No. 81-5,1981.

1981 Data, National Science Foundation, “Total Federal R&C) Funding Estimated To Increase 7 Percent In 1982

After September Revisions, ” Sc/errce Resources Stud/es” H/g/r//ghts, publication No. NSF 81-321, Dec. 15, 1981.

National Institutes of Health, Basic Data Re/at/rrg to the fVat/onal lnst~tutes of Health: 1987, May 1981

Table 4.–Federal Obligations for Health R&D by

Agency, 1980a (millions of dollars)

Department of Health and Human Services (total). . . . . . .

National institutes of Health . . . . . . . . . . . . . . . . . . . . .

Other Public Health Service agencies . . . . . . . . . . . . . . .

Other DHHS agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other agencies (total) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Department of Agriculture . . . . . . . . . . . . . . . . . . . . . . . .

Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . .

Department of Education , . . . . . . . . . . . . . . . . . . . . . . . .

Department of Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Environmental Protection Agency , . . . . . . . . . . . . . . . . .

Agency for International Development . . . . . . . . . . . . . .

National Aeronautics and Space Administration. . . . .

National Science Foundation. . . . . . . . . . . . . . . . . . . . .

Veterans Administration. . . . . . . . . . . . . . . . . . . . . . .

Other agencies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

($3,694.7)

3,181.9

458.6

54.3

(1,028.6)

147.3

211.0

32.1

210.9

78.1

13.4

71.8

75.7

133.4

54.9

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $4,723.4

a Estimated

The end to the rapid growth period occurred

in the late 1960’s, when biomedical research support faced competition with other Federal health

programs, especially medicare and medicaid,

and with the Vietnam War. Table 5 shows that

the dollar amount of research grants dropped in

1967, rose again in 1968 and 1969, and dropped

again in 1970 before climbing continuously from

1971 on. However, the rise in dollars during the

1970’s did not herald the start of a new growth

period. Table 6 shows NIH obligations from

1969 through 1980 in actual and constant

dollars. When inflation is taken into account,

there has been fluctuation throughout the

decade ending in a real drop for 1980.

SOURCE: National Institutes of Health, Bas/c Data Re/at/rrg to the Nat/orra/ /rrstltutes of Health 1981, May 1981.
15

Table 5.—Number and Amount of Research Grants

Awarded by the National Institutes of Health,

Fiscal Years 1938-80

Amount Amount

(dollars in (dollars in

Year Number thousands) Year Number thousands)

1938 . . . . . . . . . 9 11,571 $ 198,757

10

13

12

12

9

5

9

79

335

1,042

1,130

1,529

1,695

1,798

2,084

2,855

3,256

3,430

6,186

7,028

9,056

$ 91

68

61

78

78

49

53

85

890

3,458

10,152

11,274

13,670

17,130

18,597

20,936

29,950

35,162

40,520

80,906

99,480

141,419

1960 . . . . . . . . .

1961 . . . . . . . . .

1962 . . . . . . . . .

1963 . . . . . . . . .

1964 . . . . . . . . .

1965 . . . . . . . . .

1966 . . . . . . . . .

1967 . . . . . . . . .

1968 . . . . . . . . .

1969 . . . . . . . . .

1970 . . . . . . . . .

1971 . . . . . . . . .

1972 . . . . . . . . .

1973 . . . . . . . . .

1974 . . . . . . . . .

1975 . . . . . . . . .

1976a . . . . . . . . .

1977 . . . . . . . . .

1978 . . . . . . . . .

1979 . . . . . . . . .

1980 . . . . . . . . .

13,534

14,975

15,233

15,242

15,183

15,153

13,937

13,120

12,435

11,339

11,063

11,524

11,317

13,400

13,430

14,260

14,429

15,431

17,744

18,511

272,941

372,098

430,899

497,924

538,763

600,974

593,312

626,019

627,580

602,177

676,245

805,041

815,195

1,070,563

1,116,301

1,239,657

1,386,460

1,577,504

1,883,224

2,086,302

1939 . . . . . . . . .

1940 . . . . . . . . .

1941 . . . . . . . . .

1942 . . . . . . . . .

1943 . . . . . . . . .

1944 . . . . . . . . .

1945 . . . . . . . . .

1946 . . . . . . . . .

1947 . . . . . . . . .

1948 . . . . . . . . .

1949 . . . . . . . . .

1950 . . . . . . . . .

1951 . . . . . . . . .

1952 . . . . . . . . .

1953 . . . . . . . . .

1954 . . . . . . . . .

1955 . . . . . . . . .

1956 . . . . . . . . .

1957 . . . . . . . . .

1958 . . . . . . . . .

1959 . . . . . . . . .

aExcludes transition quarter.

SOURCE National Institutes of Health, 1981 NIH Almanac, NIH publication No 81.5,1981

— —. .- .-—- —-- Table 6.—NlH Obiigations by NIH Component, Fiscal Years 1969-80a

(in current and constant dollars (millions~ excluding programs that have been transferred out)

Fisc~

year Total b NIA NIAID NIADDK NCI NICHD NIDR NIEHS NEI

Current dollars

29.6 17.9 $ 21.5

28.7 17.3 22.8

35.2 20.1 30,0

43.3 26.4 36.9

40.9 26.1 34.4

50.0 32.1 45.2

50.0 35.9 43.7

50.7 36,8 50.1

55.4 50.9 63.7

61.7 63.9 85.2

65.0 77.5 104.9

67.6 83.6 1096

Constant dollars

29.6 17.9 21.5

27.0 16.3 21.5

31.3 17.9 26.7

36,7 22.4 31.3

33.1 21.1 27.8

38.0 244 34.4

34.3 24.7 30.0

32.4 23.5 32,0

32.8 30.1 37,7

34,0 35.2 46.9

33.1 39.4 53.4

315 39.0 511

-—

NIGMS NHLBI NINCDS DDRC FIC NLM

$161.9

160,3

194.8

232.6

255.7

327.3

327.8

368.6

396.5

447.8

510.0

527.1

161.9

150.8

173.2

197.1

206.8

248,9

225.1

235.6

234.7

246.7

259.6

2458

$160.1

148.1

159,8

173.3

154.0

188,6

189.5

1869

204.8

230,4

277.3

3123

160.1

139,3

142.1

146.8

124.5

143.4

130.2

119.4

121,2

126.9

141.1

1457

$104.6

972

103.4

116.4

107,4

1435

1424

1404

154.6

1773

212.1

241.4

104.6

91.5

92.0

98.6

86.8

109.1

97.8

89.7

91.5

97.7

107,9

112.6

$ 653

62.6

662

750

728

1301

127,1

1303

137,4

144.8

1541

1691

$13.1

2.7

3 4

4 2

3 9

5.0

5.7

5 7

77

8.3

8 9

8.7

$21.7

19.8

214

23.9

25.0

29,2

28.8

270

34.5

360

405

439

Index

217 100.0

21.7 1063

19.0 112.5

20.2 118.0

20.2 1237

222 131 5

198 145 6

173 1565

20.4 1689

19.8 181.5

20.6 196.5

20.5 214.4

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1960

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1980

$1,087.7

1,057.8

1,212.0

1,505.8

1,523.1

1,994.4

2,106.9

2,238.4

2,582.0

2,828.0

3,184.6

3,428,8

$ 92.8

97.1

102.1

109.0

103.0

120.8

119.4

125.6

140.4

161.8

191 1

214.7

$140,3

131.5

137.9

153.3

142.8

177.4

173.6

174.9

219.4

259.9

302.7

340.1

140.3

123.7

122.8

129.9

115.5

134.9

119.2

111.8

129.9

143.2

154.1

158.6

$182.4

181.3

232.9

378.6

431.2

581.0

699.3

760.5

814.9

872.4

936.7

998.0

182.4

170.6

207.1

320.7

348.7

441.7

480.3

486.0

482.4

460.6

476.7

465.5

$ 71.2

76.0

94.7

116.5

111.2

144.1

142.4

135.9

145.1

165.8

197.3

208.3

—

19.2

29.9

37.1

56.5

69.7

92.6

91.4

90.8

92.3

83.3

91.6

82.0

80.3

83.1

89.1

97.3

1001 —

71.2

71.5

84.2

987

89.9

109.5

97.8

86.8

85.9

91.3

100.4

97.2

653

58.9

58.9

63.5

589

98.9

87.3

83.3

813

798

784

78.9

131

2 5

3 0

3.6

3.2

3.8

3 9

3.6

4 6

4 6

4 5

4.0

1,087.7

995.3

1,077.8

1,275.7

1,231.6

1,516.2

1,446.4

1,430.5

1,528.4

1,558.0

1,620.8

1,599.3

————

——

12.3

17.7

20.4

28.8

32.5

aOD buildlngs and facilities, are included in totals only. Excludes Foreign Currency Programs. Constant dollars are based On biomedical R&D Price Index

bED for 1969 and DCRT for 1969-1970, when these programs were separately budgeted, are shown in totals onlY.

concludes GRS programs for 1974-1980, formerly spread among l/RDs (but 1973 funds released in 1974 are spread)

SOURCE National lnsOtutes of Health, f%SIC~afa~P!dfi~g fothe Nationa//nstifufes of HeaMr. 1981, May 1981.
16

ORGANIZATION OF NIH*

NIH is an agency of PHS in the Department of

Health and Human Services (DHHS). Its mandate, stated broadly, is to improve human

health by increasing understanding of the processes underlying health and acquiring new

knowledge to prevent, detect, diagnose, and

treat disease and disability.** This mission is

pursued via an array of intramural programs

conducted at NIH and through an extensive network of extramural grants and contracts to private and public institutions in the United States

and other countries. The bulk of the actual research is done extramurally; in 1980, 16.4 percent of NIH’s $3.4 billion in obligations were for

direct activities including intramural research,

while the remaining 83.6 percent were for extramural grants and contracts (49).

NH-I is organized into 11 institutes (two of

which have bureau status), the National Library

of Medicine (NLM, which is also a bureau), and

six research and support divisions. Figure 1

j

*This discussion is drawn primarily from The Implications of

Cost- Effecti~~eness Analysis of Medical Technology (89) and 1rzuesti,gatiotl of tllf National Institutes of Health (114).

**The mission will be discussed more fully in ch. 5.

I

1

Aging

I

shows the NIH components. The organization

has been characterized as loosely categorical,

meaning that the various research institutes

focus, in a general sense, on particular classes

(categories) of diseases or subject matter (7). The

scientific content of two of the institutes, the National Institute of Aging and the National Institute of Child Health and Human Development, is organized around biologic processes,

and thus tends to cut across the programs of the

more traditional institutes. Their organization

has been said to solve some, but create other,

coordination problems. Overall, the categorical

structure has been both praised and criticized

(114).

The institutes differ in their statutory bases.

Two institutes, NCI and the National Health,

Lung, and Blood Institute (NHLBI), have renewable authorizations with monetary ceilings.

Other institutes have authorizing statutes with

no time or money limitations, One institute, the

National Institute of Environmental Health Sciences, has no specific authorizing statute, but

depends o,~ section 301 of the Public Health

Service Act. The institutes also differ in their reFigure 1 .—The Organization of the National Institutes of Health

DHHS

Public Health Service

SOURCE: National Institutes of Health, L?asIc L3ata Re/atlng to the National k?stitutes of Health: 1981, May 1981.
17

lationship to PHS. Two institutes–NCI and

NHLBI—as well as NLM, are bureaus in PHS.

The remaining institutes and support divisions

are division level organizations in PHS. Although the bureaus are an echelon above the divisions, the difference in these designations is

largely cosmetic (107) in terms of operations.

Additional differences exist among the institutes

in the way that they carry out their business, in

the philosophy of the staff, and in the mechanisms used to conduct research. Part of these differences are defined in statutes, and part are a

result of individual institute determination.

These various semiautonomous organizations

are coordinated through the Office of the Director of NIH. The Office of the Director is organized along managerial, rather than substantive,

lines and reflects the principle of centralizing

supporting services wherever feasible, but placing essentially all program operations within the

bureau and division levels. It also reflects the

role of the Director, which is primarily to coordinate program and policy development and to

integrate resource procurement and execution

among the institutes and divisions. There have

been longstanding proposals by NIH and others

to strengthen the Director’s hand, such as additional staff for the Director’s Office and limited

authority for the transfer of funds from one appropriation to another. They continue to be rejected (107).

Extramural Research Programs

As noted, the extramural research programs

comprise the bulk of NIH’s budget. And, as

shown in table 7, research grants are the primary

funding mechanism, budgeted at nearly $2.4

billion out of a total of over $3.6 billion for all

progams and operations in fiscal year 1982. Out

of the research grants, research project grants

receive the bulk of the funds. Program project

grants and center grants are two additional important categories of research grants. Most of

the remaining extramural dollars go to R&D

contracts and to individual and institutional

training awards. Technology transfer activities

are funded by grant and by contract; these two

mechanisms will be described in greater depth.

A relatively new funding mechanism, the cooperative agreement, is being used more frequently (as mandated by the Federal Grant and

Cooperative Agreement Act of 1977). Some existing grants and contracts are being converted

to this mechanism. However, since there are few

cooperative agreements in place, they will not be

discussed further in this chapter. *

Intramural Research

The conduct of biomedical research within the

walls of NIH is the oldest of NIH’s missions. Ten

of the eleven institutes have intramural programs, with the National Institute of General

Medical Sciences as the only exception. The role

of the intramural programs in relation to the extramural programs tends to vary from institute

to institute. Some activities are similar, except

for their precise subject matter, to extramural

activities. Others are complementary to the outside world in the sense that they are too expensive, too risky, too uncertain, or have too long a

time frame. In addition, there are intramural research activities underway in areas where there

is a definite national lack of research resources.

*NCI expects to fund all of its clinical trials by the cooperative

agreement mechanism by 1983 (66). An NCI publication notes,

“When the purpose of the relationship is the same as that of grants,

but the Federal Government anticipates substantial involvement

with the recipient during the course of the activity, a cooperative

agreement is the funding instrument to be used. ” (66) The cooperative agreements will be funded using a process similar to the process now used for grants, rather than the one used for contracts.
18

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In
Chapter 3

The Process of

Technology Transfer

.
Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Factors Affecting Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Characteristics of the Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Characteristics of the Technology Developer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Characteristics of IndividuaIs Using the Technology . . . . . . . . . . . . . . . . . . . . . . . . ,

Characteristics of Organizations Using the Technology . . . . . . . . . . . . . . . . . . . . . .

Attitudes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Research Policies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Regulation and Reimbursement Policies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methods for Measuring and Evaluating Technology Transfer . . . . . . . . . . . . . . . . . . .

List of Figures

21

23

23

23

24

24

24

24

25

26

Figure Page

2. The Process of Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
.

Chapter 3

The Process of Technology Transfer

INTRODUCTION

Technology transfer, as an explicit concept,

has been used in the health field only in the last

decade. Its increasing use has paralleled the increasing development of policies related to medical technology. Definitions are numerous, ranging from the narrow and more specific to the

broad and general, The common thread among

them, however, is that technology transfer

represents a process that includes a series of

events. It cannot be described as one activity or

one point in time, although discrete activities

can certainly be the focus of the process.

The first type of definition is exemplified by

Brown, et al. (10), who define technology transfer as “instances where the given technology

moves from one situation to another, which

may require changes in the technology, the context to which it is moved, or both . . . . [It]

diverts the movement of the technology toward

increasing specificity [which occurs in the innovation process] by either changing the technology to fit a new application or, conversely,

by changing the specificity of an application to

fit the technology.” The second type, the broad

definition, is represented by Dans (18), who

defines the term “technology transfer” as “shorthand for the diffusion of technology from its discovery to its appropriate application. ”

The National Institutes of Health (NIH) stated

definition (57) falls into the broad category:

“Technology transfer involves the transfer of research findings to the health care delivery systern. ” Yet this definition has been made narrow

in its operation by a focus on only two activities—the development of technical consensus

on new interventions and the demonstration of

these new technologies in the health care system.

As with its definition of medical technology, ’

OTA defines technology transfer broadly. Medical technology transfer is the process of

medical technologies from their creation

moving

to their

*See ch.2.

application in clinical practice.** It is the means

by which medical technologies move through

their lifecycle, beginning at the stage where new

knowledge is translated into new technology

through applied research and ending at the stage

where it is applied to the population. Figure 2

depicts the technology transfer process. Though

represented in a linear fashion for the purpose of

discussion, the process is rarely, if ever, linear.

Technology transfer is related to the innovation

process* * * and can be viewed as the subset of

that process that is concerned with innovations

that are technologies.

Technology transfer occurs either informally

or formally. Informal technology transfer refers

to transfer that happens without directed efforts

toward putting a technology into clinical use. It

usually occurs prior to evaluation of the technology, through activities such as personal experience, peer interaction, and publications. Formal

technology transfer is a directed series of activities designed to facilitate appropriate application of the technology. These activities are the

components of the ideal model of the lifecycle of

medical technology development and use, including evaluation activities, demonstration and

control programs, and directed education of the

professional and lay communities in the use of

the new technology. All types of evaluation,

then, including technology assessment, are an

important part of the formal technology transfer

process. Information dissemination activities

assist both informal and formal technology

transfer.

In general, the overall objective of studying

technology transfer is to develop (and refine)

methods and activities to affect the process

* *In the context of this report, the term “technology transfer”

actually refers to “medical technology transfer. ” “Medical

technology transfer” could also be called “health-related

technology transfer;” the important point is that the process occurs

in the health care system.

● ● *For a discussion of the innovation process, see Stratcgit’s ft)r

Medic~~/ TQr/7t10/cJg.v A55c5s)tIctIt (92.

21
22

.

Figure 2.—The Process of Technology Transfer

Stages in

the Iifecycle

of medical

technology

● 9

Basic Applied Development Application

research * research *

of * Evaluation * Demonstration * Adoption * in medical * Obsolescence technology practice *

Nonuse

SOURCE: Office of Technology Assessment,

—either to accelerate its pace, to slow it down,

to modify it, or to stop it entirely. For technologies showing promise early in their lifecycle or

for those evaluated to be useful in certain clinical

applications, it is desirable to hasten the process.

On the other hand, for technologies not yet evaluated or for those with early indications of being

inefficacious or even harmful, it is desirable to

slow or, in extreme cases, stop the process.

The specific objective of looking at technology transfer for any particular technology will

vary according to that technology’s state of

development—emerging, new, existing, or new

application of existing technology. * In any of

these cases, however, there is a need to identify

——— —

‘Existing technologies are those that have already been “transferred. ” However, they may, as in the case of radical mastectomy,

be candidates for transfer activities that “should have been” conducted prior to their adoption. Once evaluated (or reevaluated),

transfer activities can be used to influence adoption under the very

specific circumstances.

the technologies whose movement through the

transfer process will be accelerated or slowed.

When evaluating the technology transfer process, mechanisms for identification of technologies (at any of the stages of development)

should be assessed. These mechanisms at NIH

are presented in this report.

The technology process will also vary according to its “clients’’ -those who learn about the

technology and actually put it to use. Clients of

the process include: other scientists, who

develop the technologies further or discover new

applications; industries, who produce, test, and

market hard technologies (e. g., drugs and devices); physicians and other health personnel,

who apply the technologies; patients, who receive the benefits (and risks); policy makers, who

use the information to make decisions affecting

future technology transfer; and the general

public, who may fall into the other categories at

any time.
23

.

FACTORS AFFECTING TECHNOLOGY TRANSFER

There is a large body of literature concerned

with the diffusion of innovations; by definition,

then, it is also concerned with medical technology transfer. It can be divided into three

sources:

1. sociological research on the diffusion of innovations in social systems;

2. the effects of communication variables on

attitudes and behavior; and

3. the scattered, nontheoretical literature in

medicine, consisting of descriptive studies

of dissemination and adoption of different

medical innovation (92).

Factors affecting technology transfer can be

placed into categories, including characteristics

of the technology, characteristics of the technology developer, characteristics of individuals

using the technology, characteristics of organizations (and their members) using the technology, attitudes, research policies, and regulation

and reimbursement policies. As is usually the

case with categorization in this area, these categories are created more to facilitate discussion

than to convey a sense of discrete sets. In fact,

there is a great deal of overlap and interrelationships among them. For example, factors in

the last three groups (which are mostly “external” factors) often influence factors in the first

four groups (“internal” factors). And although

there have been many studies about these factors, the only consensus is that there is much

more to learn.

The primary reason for understanding factors

which affect technology transfer is to use the

knowledge to improve transfer activities. However, understanding these factors and their interrelationships heIps to explain why the best efforts by public and private organizations to affect technology transfer do not always work. In

the remainder of this section, the factors will be

described. The purpose is to place NIH activities, described in chapters 5 through 7, in

perspective; thus, the description is not complete.

Characteristics of the Technology

The nature of the technology itself will affect

the technology transfer process. Previously

mentioned characteristics include the stage of its

development (emerging, new, existing, new applications of existing technology) and its medical

purpose (preventive, diagnostic, therapeutic,

etc. ) Other characteristics include its complexity

and perceived effectiveness (18), its initial success or failure when tested, and its potential for

marketability (where an actual product is the

objective) (99).

Characteristics of the

Technology Developer

If the new technology developer is an individual, his or her characteristics may influence

technology transfer. They include personality,

degree of fame, access to other scientists, and

ability to appreciate the importance of the

discovery (99). For example, an unknown physician named Hammer diagnosed coronary artery

occlusion in one of his patients. His published

report in 1878 received no attention, and it was

34 years until another scientist named Herrick

made the same discovery. Access to resources is

another factor important for individual and

organizational technology developers. For

organizations, particularly companies, their size

may influence their ability to develop new

technology. It has been found that small companies contribute most to innovation in the early

stages of a technological field, but large companies dominate by the time the field matures (92).
—

24

Characteristics of Individuals Using

the Technology

The effects that characteristics of individual

users have on technology transfer have been

widely studied, particularly for physicians. Factors influencing transfer include amount of and

access to information on the technology; degree

to which the individual can be described as

cosmopolitan or local; amount of education;

preference for the goal of quality health care

rather than economic efficiency (10); and the

degree of openness to trying new ideas (99).

A crucial distinction has been made between

communication that informs physicians about

novel technologies and that which influences

physicians to act. Clearly, both types are part of

the technology transfer process. The most important source of new knowledge about improvements in medical technologies is professional literature. However, physicians cite professional colleagues more often as sources they

turn to when actual implementation of new procedures is contemplated. Physicians of greater

prestige tend to hear about innovations sooner;

they are mentioned by their fellow professionals

as influential sources on the medical practice of

others (92).

Characteristics of Organizations (and

Their Members) Using the Technology

If the technology user is an organization, its

organizational structure as well as characteristics

of individuals within it will affect technology

transfer. There has been a great deal of sociological research in this area, and there are nearly

as many theories as there are studies. Not surprisingly, the results have been conflicting. No

attempt will be made here to resolve the conflicts, although it should be noted that characteristics of the technology being adopted may affect

the effects of the organization.

Greer (29) summarized some of the work on

organizational structure variables. Size and

resource base are important variables, In general, the larger the organization and the greater its

resource base, the more likely it is to adopt innovations. Yet the effects of these variables are

often overriden by others—organizational complexity, centralization of decisionmaking, and

formalization of rules and behavior.

Attitudes

Attitudes is a class of factors influencing the

technology transfer process at all stages.

Favorable attitudes can speed up the process,

while negative attitudes can slow it down. Attitudes of the individuals potentially adopting or

developing a new technology will interact with

the attitudes of the society around those individuals in affecting the decision to develop or

adopt. For example, if the general attitude of

society regarding technological intervention in

the birth process had been negative, it is possible

that the widespread use of electronic fetal monitoring prior to demonstration of its efficacy

would not have occurred. Similarly, that technology has been a relatively recent focus of interest and concern (4), in part because of current

increasingly numbers negative attitudes toward

such intervention. A final point to be made here

is that it is unlikely, if not impossible, that contribution of attitudes to technology transfer will

ever be quantified. However, their importance

must be recognized.

Research Policies

While it is true that

are actually part of the

ess, it is also true that

various types of research

technology transfer procseveral types of research

policies affect the process. First, the way total research funds are distributed among the stages of

the transfer process will affect the transfer which

occurs. While basic research is not actually part

of technology transfer, it provides the knowledge base for technology development (several

examples are provided in ch. 2). Thus, the relative amount of funds devoted to basic research

will affect the amount of knowledge ready to be

applied, the amount of funds devoted to applied

research will affect the amount of technologies

to be developed and transferred, and so forth.

The amount of funds available for evaluation

and demonstration will not necessarily affect the

amount of technologies transferred, but it will

affect the amount of technologies that are
25

transferred appropriately (i. e., those that are

transferred after being shown to be efficacious,

safe, cost effective, etc. ).

Second, the criteria used for setting research

priorities, both overall for an organization and

within any program for specific projects, will affect the types of technologies transferred. Within

an organization, research programs could place

priority on filling gaps in knowledge in areas

that:

1.

2.

3.

4.

5.

6.

7.

Americans fear most (such as cancer);

are associated with a greater loss of “quality adjusted life years;”

have the greatest cost impact on individuals

or society but do not necessarily affect the

greatest number of people (such as renal

dialysis);

have the greatest cost impact as a result of

affecting the greatest number of people;

have the greatest opportunity for study;

happen to be in vogue scientifically or

politically; or

have the greatest impact as a result of a

combination of high cost, high morbidity,

and high mortality (18).

Within programs of an organization, projects

can be selected according to scientific merit,

potential usefulness in clinical applications,

political popularity, total cost, and past contributions of the principal investigator, among

others.

Finally, the places where research is conducted will affect technology transfer with

respect to the degree to which the research

organization is plugged into the professional

literature or into clinical practice. For example, a

top medical school associated with a top teaching hospital is more likely to have a new procedure move into widespread application than a

relatively unknown clinic.

Regulation and Reimbursement

Policies*

Regulatory actions and more informed reimbursement decisions help to insure that emerging

.———.—

● Thi\ d[;cussic~n I\ adapted from St~,~t(14yICS f[)t Ll,[ii, [~1 TLIclI-

~ 1, ~ ~[ 1 Q u ,~~ . \LT\ +) )~t,} ~ t ( Q2 )

technologies are efficacious, have acceptable

risks, and are used appropriately (e. g., are used

cost effectively). Private industry determines

which drugs and devices it will develop primarily through market-based criteria. To address

perceived deficiencies of the market approach,

governmental actions infuse additional criteria

based on social and political concerns. These

governmental actions have generally been regulatory in nature, concentrating on the costs to

our health, safety, and environment. Because

these costs are diffuse, they can be addressed

through collective, governmental actions but

not as effectively by individuals. Government’s

role as a purchaser of technologies, of great significance in health care because of government’s

role as insurer, has also led to a need to minimize

reimbursing for the use of ineffective technologies. This role has also created a need for ways

to help decide which among the array of technologies are the most appropriate. In the regulatory process, diffusion into the marketplace is

unquestionably slowed, and some technologies

are filtered out. Reimbursement policies can also

slow (or speed up) diffusion. Slowing the diffusion of new technologies may allow for more

informed and timely decisions before widespread use.

The effect on innovation (or technology transfer) from regulatory and reimbursement policies

is not simply one of whether the process is inhibited but also whether the alterations in it are

unintended or undesirable. Government support

of R&D has long sought to alter the process,

most notably to accelerate its pace and push it in

certain directions. Regulation, particularly when

it alters the competitive market, can alter the

direction that innovations take. Reimbursement

policies probably have more effect on the pace

of the process. There is general agreement that

competition among medical care providers is

typically not based on price. Under current

reimbursement policies, there are incentives to

adopt all available diagnostic tools and to pursue any therapy anticipated to have any value,

especially in hospitals. Third-party coverage

currently accounts for about 90 percent of expenditures for hospital care. As the price of

technology has little effect on providers and patients under existing health insurance ar-
26

rangements, a greater adoption of technology

can be expected to occur (and has actually occurred in many cases) than under more price

competitive reimbursement arrangements.

At a simple level of comparison, recent

changes in current regulatory and third-party

reimbursement policies can be thought of as approaching some middle ground from opposite

ends of the spectrum. Regulation purposefully

slows down the innovation process, particularly

at the diffusion stage, and modifications are now

being sought (e.g., in premarket approval requirements for drugs) to insure that this slowing

of the innovation process is no more than

necessary to achieve the regulatory program’s

objectives. Current reimbursement policies, on

the other hand, are seen as boosting the diffusion of new medical technologies beyond what

would take place under more price competitive

systems, and reforms are being aimed at constraining the adoption process.

Because regulation’s purpose is to infuse social

criteria into judgments of a new technology’s

worth, conclusions based on the economic impact of regulatory requirements must be reached

with caution. Regulation is expected to change

the innovation process. The issues are whether

the specific changes were intended and whether

the benefits of regulations are worth the price

paid in resulting alterations of the innovation

process.

In reimbursement policy, a need is to infuse

more price sensitivity into the dissemination and

use of new medical technologies. Taken together

with the regulatory approach, these changes

would theoretically: 1) allow into the marketplace innovations which have met social criteria

of worthiness, and 2) make it possible for those

new technologies which have passed the regulatory test to then compete with each other on a

price basis. Curtailing excessive demand by a

more price-sensitive approach, however, means

changing the conditions of the current medical

technology innovation process. Again, the question here is whether such major changes in the

demand for new medical technologies will affect

the innovation process in unintended and undesirable ways.

METHODS FOR MEASURING AND EVALUATING

TECHNOLOGY TRANSFER

Methods for measuring and evaluating medical technology tranfer as a coherent process are

not nearly as well developed as methods for

measuring the effects of any one part of the

process. There are methods available to measure

the way physicians adopt a new technology, to

evaluate the efficacy of a procedure, or to determine if a demonstration program met its stated

goals. Yet there are no well-developed and

highly structured research methods that can be

used to answer questions about the translation

of science to health care (99).

The most promising approaches are refinements of case study methods like those used to

trace the scientific lineage of major technological

breakthroughs. The most prominent examples

of past work are the studies (and their followups) by Comroe and Battelle-Columbus Laboratories for the President’s Biomedical Research

Panel (99). These past studies, though, do not

usually extend beyond the development stage of

the process to implementation in medical practice.

An alternative to the case study approach is

the assessment of activities which occur as part

of the technology transfer process. In this approach, the focus is on the environment in which

the technology is transferred rather than on the

technology itself. The major weakness of this

approach is that it does not look at the entire

process at once; however, by examining all activities in one study, the effects of this weakness

are lessened. In addition, the connection between the activities and the actual transfer must

be assumed, although the influence of other factors is well known. The major strength of the

method is the potential for examining any activity in depth, including its relationship to other

methods. It is also most useful when the focus of

study is one particular organization.
—

Chapter 4

Evaluation of

Medical Technologies
Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methods of Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Preclinical . . 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Informal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epidemiological and Statistical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Controlled Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Formal Consensus Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cost-Effectiveness Analysis/Comprehensive Technology Assessment

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

29

31

31

31

32

32

33

34
Chapter 4

Evaluation of Medical Technologies

INTRODUCTION

The process of biomedical research and development (R&D), from basic through applied to

development research, produces new medical

technologies. As noted in chapter 2, the pace of

this process has been accelerating. Frequently,

the benefits of new technologies have been clear

and convincing. There are numerous examples

of new equipment, drugs, and procedures which

have significantly advanced the practice of

medicine. Some diseases can now be effectively

prevented, and medical innovations such as

antibiotics have provided effective therapies for

a number of other diseases. New diagnostic techniques have often made it possible to detect disease in time to apply an appropriate therapy.

Even in cases of diseases for which no effective

preventive or therapeutic measures are available, technologies have aided in relief of pain,

amelioration of symptoms, and rehabilitation of

individuals affected by chronic conditions (88).

Finally, some new technology has increased access to health care, some has reduced the cost of

care, and some has improved the outcome of

care (45).

Yet advances in medical technology development have not occurred without concerns, particularly recently. They may be outlined as

follows:

● A number of advances invoIve significant

risks, some intrinsic and some which vary

according to the setting in which and the

skill with which they are applied. All invasive procedures, including the administration of drugs, surgery and the use of equipment, involve some finite risk to the patient. However, determination of the safety

of new technologies is crucial, because some

level of the risks that may be encountered

must be judged acceptable in relation to the

potential benefits.

●

●

●

●

Many technologies have been widely diffused before their efficacy has been established. Concerns about efficacy are raised

when a new technology is introduced without proof of its efficacy (e. g., electronic

fetal monitoring (3)), when a widely used

technology is later shown to be inefficacious (e. g., oral anticoagulants in the treatment of myocardial infarction), or when the

relative efficacy of alternative therapies is

compared (e. g., the radical mastectomy)

(88).

Health care costs are escalating rapidly. The

expanded use of medical technologies is an

important factor in the rising costs, imposing economic burdens which cause problems for patients, for their families, and for

society. Medical technologies contribute to

medical care costs in various ways: Some

have large capital investments, some require the use of costly supportive services,

some present the possibility or requirement

of costly followup care, some establish the

need for continued use, some are overused

after initial proof of reliability of efficacy

(particularly diagnostic technologies), and

some are used for inappropriate purposes.

An increasing number of technologies raise

ethical issues. The concerns may center on

the use of the technology (e.g., as amniocentesis or renal dialysis), or on the use of

human subjects during research on the technologies (e. g., as many cancer drugs).

Medical technologies also raise other social

issues. For example, with the advent of lifeextending technologies such as artificial

● Efficacy refers to the probability of benefit to individuals in a

defined population from a medical technology applied for a given

medical problem under ideal conditions of use, Effectiveness, a

term used interchangeably with efficacy by some, refers to the

benefit of a technology under average conditions of use (85/.

29
30

hearts and kidneys, modern technology has

challenged society’s traditional view of

death and dying (88). Critics of the increased use of technologies charge that

medicine is being dehumanized by the use

of machines and scientific methods (85).

Legal issues may arise in several areas, including allocation of resources, liability,

and informed consent.

These concerns cover both technical and social

issues. Although these sets of issues and the

categories within them are often separated for

discussion purposes, in fact they are inextricably

linked. For example, ethical considerations,

seemingly remote from technical matters, can

hamper the determination of medical efficacy of

some technologies. Although different methods

are used to assess the technical and social impacts of new technologies, it must be recognized

that problems (and their solutions) cannot truly

be separated (88).

Because of these concerns, increasing attention is being focused on the process of medical

technology development and use. * In principle,

new technology should be introduced into the

practice of health care when its benefits to society or individuals outweigh its costs. In practice,

however, knowledge of either benefits or costs is

often very limited at the time decisions (either

formal or informal) regarding the dissemination

of a new technology are made (45). Evaluation

of technologies is the process in which the

knowledge of benefits and costs is gathered and

synthesized. It occurs, or should occur, after

development and before diffusion and use.

Thus, it is a vital component of formal technology transfer.

Like R&D, evaluation covers a broad spectrum of activities. These activities vary according to the nature of the technology being evaluated and according to the criteria being used.

The historically most common, and perhaps

most important, criteria used in the initial stages

of evaluation of health-related technologies are

safety, efficacy, technical feasibility, and tech-

—-

● Ch. 2 describes this process.

nical performance. For commercial products (or

potentially commercial products, even if developed with public or nonprofit funds), another

basic criterion is potential profitability. Other

evaluation criteria will then follow, including:

effectiveness, reliability, suitability for the goals

of its use, cost, cost effectiveness, affordability,

potential or actual reimbursement status, repairability, convenience, esthetics, consumer satisfaction, social implications, legal impacts, patent protection, ethical concerns, and so on (93).

Clearly, some evaluation criteria pertain only

to “product” technologies, such as devices or

drugs. Other evaluation criteria pertain to the

medical purpose for which the technology is

used. Efficacy and safety, however, are the basic

starting points in evaluating the overall utility of

a technology. Other criteria, such as legal concerns, are rarely needed if the technology is

shown to be inefficacious or unsafe. And, efficacy and safety information is often needed for

evaluations of cost effectiveness or potential for

reimbursement, for example (85).

The specific objectives of any evaluation depend on the specific criteria being used. In general, the purposes of evaluating medical technologies are:

●

●

●

To ensure that technologies demonstrated

to have potential benefits with acceptable

risks are made available rapidly in the private and public sectors. Administrators of

public regulatory and financing programs

could make sounder and faster decisions

regarding the use of the technologies with

such information.

To constrain the diffusion and use of technologies which either lack efficacy or cause

excessive harm or whose total societal costs

are judged greater than total societal benefits.

To guide appropriate use of all technologies, because technologies are rarely completely inefficacious, unsafe, or undesirable

to society.

Thus, the overall goal of evaluation is the production of information that can be used to affect

the technology transfer process.
31

METHODS OF EVALUATION*

There are numerous methods available for

evaluating medical technologies. The method

used varies according to the criteria for evaluation (i. e., efficacy, safety, effectiveness, etc. )

and according to the nature of the technology

being evaluated (i.e., drug, device, procedure,

etc). No technique is universally applicable for

every technology. In many instances, less complex methods may be more appropriate than the

sophisticated approaches. Frequently, combinations of techniques are used (85). And some

methods, particularly those used for evaluating

social impacts, are actually combinations of

other methods.

This section describes six groups of methods:

preclinical, informal, epidemiological and statistical, controlled clinical trials, formal consensus

development, and cost-effectiveness analysis/

comprehensive technology assessment. Generally, the first five groups* * are used in evaluation concerned with technical issues relating to

health effects (such as efficacy and safety), while

the last two are used in evaluations concerned

with social issues. It must be clearly stated that

the categories are created to facilitate description; there are overlaps and combinations of

methods in the categories used. In particular, the

methods used for evaluating social impacts utilize some of the methods in the previous categories. Traditionally, clinical experience, based

on informal estimation techniques, has been the

most important. Other techniques, such as epidemiological studies, randomized controlled

clinical trials, and formal consensus development are being used increasingly.

Preclinical

Many medical technologies are evaluated in

biochemical and animal tests prior to human experimentation. There are two purposes for these

tests: 1) to gather preliminary evidence to gain

‘This section is based largely on OTA’S previous report, Assess-

~~~g the Efficacy ant? Safety of Medical Tech/zologies (85). The section “Cost-Effectiveness Analysis’Comprehensive Technology

Assessment” is derived from the 1980 and 1976 OTA reports

(89,114).

‘ *Formal consensus development belongs in both categories.

the right to test with humans, and 2) to develop

performance standard compliance to establish

marketability. Biochemical tests include chemical analyses for purity, quantity, and quality of

the active agents; analyses for potential pharmacological activity of filler and stabilizing

substances; determinations of biocompatibility;

and tests for long-term dissolution of body fluids

and the possible presence of toxic residues in the

production of plastic materials. Animal testing

provides a guide to capacity to induce toxicity as

well as potential therapeutic activity. Determining the degree of toxicity, or safety, is the major

function of animal tests.

A controversial issue is the accuracy of animal

models in determining the probable effects of

drugs on people. Questions that arise include

short-term high dose v. long-term low dose,

animal species selection, population size, and

controls. These questions are particularly pertinent with respect to carcinogenic agent evaluation. However, despite the inherent problems,

an earlier OTA report concluded that animal

tests are acceptable models for cancer studies

and should probably be regarded as reasonable

precursors to clinical studies (87).

Informal

The increasing need to formally evaluate medical technologies, particularly for efficacy and

safety, has been described. However, the majority of such evaluations are still based on informal approaches. They may take place during

medical school and specialty training and

through personal or peer experience. Physicians

and other health personnel are constantly exposed to medical technologies throughout medical school, residency, and special courses. Usually, students assume that these technologies are

efficacious and safe. Some of them have undergone formal assessments, but most are recommended based on previous experiences or training received by the instructor. Personal experience, the actual use of technologies, is a cummon qualitative method used to assess both efficacy and safety (and other evaluation criteria).

Although it has limited statistical value and
32

lacks control over scientific quality, it may be

advantageous in some cases. Personal knowledge of a patient, for example, may promote

beneficial adjustments to the type and level of

treatment. Peer experience is more explicit than

personal experience; information may be exchanged by items such as journal articles, pamphlets, and personal communication.

Informal techniques are based on the clinical

approach of qualitative, artful decisions as compared to the scientific approach of quantitative,

mathematical decisions. In any comprehensive

system of evaluation, there is a place for both

approaches, since each extreme may be appropriate in certain situations. In addition, many

assessments require combinations of techniques.

Furthermore, cooperation between clinicians

and statisticians must exist to attain appropriate

decisions when the more rigorous techniques are

used.

Epidemiological and Statistical

Epidemiology is the study of the determinants

and the distribution of diseases and injuries in

human populations. It also incorporates the

study of the impact of medical interventions on

diseases and injuries. There are a number of

epidemiological methods useful in evaluating the

effects of medical technologies. Each of these

methods involves the collection of data, for at

least two groups, on disease manifestations, on

changes after the medical intervention (or lack

of it), and on certain factors which may be associated with the determinants or distribution of

the disease or injury under study. Once the data

are collected, statistical analyses are performed

to compare the two groups.

The methods differ in the types of data collected, the way the groups for study are selected,

and the time frame studied. Retrospective studies compare groups of people who have a disease

with those that do not. These studies are designed to determine whether the two populations differ in terms of percentage exposed to

certain critical factors. The relationship between

oral contraceptives and thromboembolism was

established this way. Most information used in

retrospective studies is derived directly from the

patients, their relatives and friends, and their

medical and other records. Thus, there may be

doubt about the uniformity, accuracy, and completeness of information (especially on death

certificates). In addition to incomplete or biased

data, the selection of appropriate comparison

groups presents a major problem with this method. There are advantages with the method, however, especially utility, low cost, and quick results.

Prospective studies follow the histories of persons both exposed and unexposed to a critical

factor under study. The incidence of deleterious

effect (or improvement) resulting from such exposure is then determined for persons in the two

groups. A major advantage of prospective studies is the relatively clear designation and selection of both the study and the comparison

groups by means of matching characteristics with

minimum bias before the disease develops. Disadvantages of these studies include their high

cost and long latent periods before results are

obtained, the possible occurrence of changes in

patients and methods over the duration of the

test.

Computer modeling and simulation are methods used most effectively in evaluation when

mechanisms of a technology are understood. By

simulating physiologic conditions on the computer, the evaluator can apply the technology

and obtain information about its effects in different clinical situations without ever involving

patients. A major drawback to these methods is

that the means of applying them is not yet adequately developed. In addition, they require a

fair amount of knowledge about the effects of

the technology in order to apply them. They

may be particularly useful in evaluating effectiveness of certain technologies, however, and

provide information at an accelerated rate at less

risk to patients (45).

Controlled Clinical Trials

Controlled clinical trials are a powerful tool in

evaluating the impact of technologies on individuals, because they involve the actual controlled application of the technology and objective observation of the results. Perhaps the most
33

important type of controlled clinical trial is the

randomized clinical trial (RCT). * In an RCT, patients who agree to participate are randomly

assigned to one of two (or more) groups: one

which is exposed to the experimental treatment,

and one which is exposed to the standard treatment which may be no therapy such as a placebo

(for comparison with a new treatment) or a variation (e. g., a different dosage) of the experimental treatment. Clinical tests and examination

of the members of each group are used for evaluations of the relative benefits and risks of the

technology.

The principal advantage of RCTS is that they

have high internal validity, i.e., they permit relatively unambiguous conclusions as to whether

the observed effects of a treatment are due to the

technology or some other factor(s). RCTs are

the most useful when: 1) the benefit of a new

technology is uncertain, or 2) the relative benefits of existing therapies are disputed. There is

much statistical theory that supports the scientific utility of the randomization procedures in

these trials. And, if a large sample of patients

and conditions are tested, external validity (the

generalizability of the observed effects to other

patient populations, settings, or conditions) may

be high.

Yet RCTs have a number of problems. The

most controversial problems are ethical; they

are based on a concern for both patient and

physician rights and responsibilities. Critics of

randomization point out that: physicians must

make clinical judgments and act according to

their consciences (which is precluded by acting

according to a protocol); personal physicians

must influence whether their patients enter a

trial and what treatment is administered; patients must be given the best possible information in consent forms; and patients should be

able to choose which treatment is delivered.

Other criticisms do not focus on randomization,

but instead on the processes used in the trials.

Questions about the rights of patients are raised,

particularly for children. For example, when can

informed consent be given by a child? at what

*Controlled clinical trials which do not involve randomization

are also ]mportant, particularl y it the treatment may have the

potential of curing the disease but killing the patient,

age? with what medical conditions or illnesses?

And, who, if not the child, will guard those

rights? The long-term effects of treatments or

other medical technology interventions can be

serious and long in evidencing themselves, particularly in children.

There are those who defend the ethics of using

controlled clinical trials. One reason is that

physicians can not do just what they “believe”

best, since their practice should be based upon

sound scientific evidence. Further, if each patient is so unique as to be ineligible for statistical

randomization, how can the individual physicians use clinical judgments based on past experience as the optimal guideline for determining

the treatment of the next patient? Another defense of RCTS states that the rights of patients

are protected in their ability to refuse participation in the trial.

There are also more practicaI problems involved in the use of RCTs. One is that many

trials require a long period of time and large

commitments of money, resources, and subjects.

In addition, they can be difficult to conduct in

settings such as hospital clinics and physicians’

office. RCTs can also be especially difficult to

conduct for technologies that are already widely

diffused. In these situations, administrators and

clinicians may be reluctant to make the changes

in policies and procedures necessary to conduct

the trials. Finally, a priori conclusions on the

treatment being evaluated are a major obstacle

to conducting RCTs, since such conclusions may

subvert the randomization process.

Overall, there are no unequivocal answers to

the concerns raised. In general, many articles

note the problems, but recommend cautious use

of the technique.

Formal Consensus Development

Formal consensus development is an evaluation method which synthesizes evaluation results from earlier, more specific studies. It is generall y employed when evidence from previous

studies does not lead to an unequivocal decision

on the effectiveness, safety, etc. of the

technology under consideration. A consensus

group is a panel of experts formed both to
34

evaluate all pertinent available information,

which may range from informal to detailed

statistical studies, and to recommend its findings

to the medical community.

There are two types of consensus groups relevant here. One type of group evaluates the current state of efficacy and safety knowledge regarding either a particular medical technology or

technologies that relate to a specific medical condition. This type of group is found at NIH and

will be discussed in depth in chapter 5. A second

type of group both analyzes a medical technology, particularly devices, and recommends possible standards to be used in the conduct of

future assessments.

Cost= Effectiveness Analysis/

Comprehensive Technology

Assessment

This category of methods represents evaluation techniques whose primary feature is that

they are actually formal processes. As such, they

incorporate other methods of evaluation. Both

require basic information on the technical impacts of the technology being assessed and are

used when the evaluation criteria are “social” in

nature. Another characteristic of these methods

is that they are intended to be decision-assisting

ones.

Cost-effectiveness analysis (CEA) can be

thought of as a synthesis of both the health effects and the economic effects of a technology.

In an earlier OTA study, The implications of

Cost-Effectiveness Analysis of Medical Technology (89), this method was studied in depth.

OTA found that the value of CEA lies more in

the process of performing the analysis than in

any numerical results which are derived from it.

In addition, there is no one “correct” way to do

an analysis. The most appropriate approach to

CEA and similar methods is to perform it in an

open forum such that assumptions and underlying values can be challenged; to identify,

measure, and, to the extent possible, value all

relevant benefits and costs; and to present the

results of the analysis in an “array” of effects

rather than forcing them into some aggregate

single measure.

Comprehensive technology assessment is a

form of policy research that evaluates the shortand long-term social consequences (e. g., societal, economic, political, ethical, legal) of the

application or use of technology. Like CEA,

comprehensive technology assessment was the

focus of an earlier OTA report, Development of

Medical Technology (88). The principles that

apply to CEA also apply here; the major difference is that comprehensive technology assessment covers a broader range of factors, especially those of a social nature.
—

Chapter 5

Technology Transfer at the

National Institutes of Health
Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

General Overview: A Changing Role . . . . . . . . . . . . . . . . . . . . . .

R&D and Technology Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . .

Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Office for Medical Applications of Research . . . . . . . . . . . . . . . .

Demonstration and Control Programs.

Information Dissemination . . . . . . . . . . -** . -. Technology

Training . . . .

List of Tables

Table No.

8.

9.

10.

11.

12.

13.

transfer to lndustry . . . . .

. . . . . . . . . . . . . . . . . . . . . .

NIHR&DActivities, 1982. . . . . . . . . .

Amount of NIH Support for Clinical

by Institute for Type of Support . . . . .

Number of Clinical Trials Supported

by Institute for Type of Support. . . . .

Number and Amount of Support for

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

,,..... . . . . . . . . . . . . .

“Trials Active-in” Fiscal

. . . . . . . . . . . . . . . . . . . .

by NIH in Fiscal Year

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

.,..,, . . . . . . . ,,,

. . . . . . . . . . . . . . . .

...,,. . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . .

. . . . . . . . . . . . . .

“Year 1979,””””

1979,” ”’””””””

. . . . . . . . . . . . . .

NIH Supported Clinical Trials Active

Fiscal Year 1979, by Institute for Type of Intervention . . . . . . . . . . . . . . . . . . . .

. .

. .

37

37

37

39

40

43

48

49

51

52

. .

. .

. .

in

. .

39

41

41

42

NIH Consensus Development Meetings, September 1977ThroughNovember 1982,

Office for Medical Applications of Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Training Grant Appropriations by Funding ComponenL Fiscal Years 1950-80. . 53
Chapter 5

Technology Transfer at the

National Institutes of Health

INTRODUCTION

Obviously, the involvement of the National

Institutes of Health (NIH) in technology transfer

goes beyond research and development (R&D),

as evidenced by its support for activities such as

evaluation, demonstration and control programs, information dissemination, and consensus development conferences. What is not obvious, though, is the extent to which NIH should

be involved in technology transfer or what its

role should be in relation to other public and private organizations. These are questions that

need to be addressed by policy makers. Yet they

cannot be answered unless the actual extent to

which NIH contributes to technology transfer,

both formally and informally, is known.

The purpose of this chapter is to provide an

overview of technology transfer at NIH. OTA

finds that a broad spectrum of activities is actually part of the transfer process, although not

ACTIVITIES

General Overview: A Changing Role

The rapid growth of NIH between its beginning as a multiinstitute organization in 1944 and

the mid-1960’s was in contrast to the limited

Federal involvement in other activities in the

health field at that time. Faced with its broad

mission on one hand and the tradition of limited

Federal involvement on the other, NIH made at

least three key policy decisions during that

period affecting its current and future role in

technology transfer (111).

First, the decision was made to foster the development of biomedical research programs in

medical schools and their affiliated hospitals. An

effect of this decision was to expose medical students to research in the basic medicaI and clinical sciences and give them sufficient understandnecessarily formally recognized as such. First, a

general overview, including a brief history, of

NIH’s authority and mission in the area is presented. Next, current activities relating to technology transfer—R&D, clinical trials, consensus

development conferences, demonstration and

control programs, information dissemination,

relationship with industry, and training—are described.

It is beyond the scope of this report to cover

all activities at all institutes. Thus, this chapter

will present the overview, and the next two

chapters will discuss the National Cancer Institute (NCI) and the National Heart, Lung, and

Blood Institute (NHLBI), the two largest, in

depth. At the actual level of operation, the differences among the semiautonomous institutes

often exceed the similarities.

ing, tools, and motivation to master and use

new knowledge as it was developed. Second, the

decision to adopt training grants as the main

mechanism to foster the training of clinical investigators was made. As a result, clinical departments of medical schools were strengthened,

and the link between research and practice was

developed. The third major decision was to concentrate on building the research program, while

minimizing service-oriented activities, such as

disease control programs. At the time, NIH was

concerned only indirectly with the diffusion and

adoption of new technologies.

Until 1965, NIH was oriented as a supporter

of basic bioscience research organized around

categories of diseases. This organization satisfied

those who were results oriented (7). However, in

37
38

1965, Congress authorized the Regional Medical

Program to be administered by NIH. This program was designed specifically to facilitate the

application of medical advances by using regional medical centers as a focus of technology

diffusion and information dissemination (7). According to Tilsonf et al. (111), this legislation

“epitomizes the emerging congressional interests

in making the NIH responsible for the practical

application of new knowledge as well as its development .“

While not generally considered successful, the

Regional Medical Program signaled the start of

new trends in congressional interest and action

for NIH. The National Cancer Act of 1971 and

the National Heart, Blood Vessel, Lung, and

Blood Act of 1972 mandated demonstration and

control programs in the two institutes. The 1974

cancer amendments mandated a President’s Biomedical Research Panel, which, in its study of

biomedical and behavioral research at NIH and

the Alcohol, Drug Abuse, and Mental Health

Administration, covered service-oriented and

applied activities. The President’s Panel research

and report began to focus attention on the overall appropriate role and effectiveness of NIH as a

“transfer agent” in the continuum from fundamental research to accepted medical practice

(107). Congressional hearings on NIH requested

testimony on the subject several years in a row

(116,117). And throughout this period, Congress provided special funding for selected

elements of knowledge application and dissemination in several of the institutes (97).

Simultaneous with increasing interest in technology transfer activities by Congress was increasing interest by leaders at NIH. In 1975, the

mission of NIH was stated as a broad continuing

one:

. . . to advance the health and well being of

man through (I) enlarging knowledge and understanding of the normal and pathological

processes of the human body, and (2) developing ways in which the providers of medical care

can safely and effectively intervene to prevent,

treat, or cure diseases and disabilities. NIH pursues this mission through supporting:

● biomedical research and development, including in some instances, demonstration

and control;

● research training;

● development of research resources; and

● communication of findings and results of

research (56).

The mission essentially implies knowledge development without a similar commitment to

knowledge applications. As a result, there have

been several unsuccessful attempts to broaden

the statement (114).

In written form, the mission appears to remain the same; there is no corresponding statement in the 1981 Research Plan (58). However,

even when the preceding statement was written,

and certainly continuing today, there has been

considerable attention by NIH to increasing its

technology transfer activities. One of the most

important results has been the establishment of

the Office for Medical Applications of Research

in October of 1978. This office will be described

further separately.

Another result has been an increasing written

focus on transfer activities, including evaluation, consensus development, demonstration

and control programs, etc. In 1979 and 1980, the

Director of NIH focused attention on technology transfer issues by circulating a document

that conceptualizes NIH-sponsored research as a

flow of basic science research to its transfer in

the field. There are four steps in the process:

1) conducting of basic science research (science

base), 2) development of technologies for solving specific problems and testing their application in the field (application), 3) building of a

consensus among the scientific community regarding a solution’s feasibility followed by its

transfer to the field for demonstration (transfer),

and 4) training of researchers to ensure the development of basic science research (training)

(17). In 1980, the percent of total NIH resources

allocated to each respective area was 77, 12, 5,

and 5 (57).

An additional example of focus on technology

transfer is a compilation of the statutory authority for all of the institutes in the areas of technology assessment and transfer (60). This document

demonstrates there is ample authority for transfer activities (as defined in this report) in all institutes. However, the extent of the activities writ-
39

ten in the laws, and therefore specially funded

varies widely from institute to institute. For example, the sections covering the National Institute of Arthritis, Diabetes, and Digestive and

Kidney Diseases (NIADDK) mandates such programs as diabetes research and training centers,

arthritis demonstration projects, and an information and education center for digestive diseases. The National Eye Institute (NEI) has no

similar legislated directive.

R&D and Technology Transfer

R&D activities are not generally considered to

be part of technology transfer. However, these

activities are very much a part of the technology

transfer process—basic research provides the

knowledge base, and applied research and development use the knowledge to solve specific

problems. In many cases, the solution to the

problem is a technology. As noted throughout

this report, technologies in the medical area are

drugs, devices, medical and surgical procedures

used in medical care, and the organizations and

support systems within which such care is provided.

Thus, the relative amount of resources devoted to each of the “categories” of R&D—basic

research, applied research, and development—affects technology transfer. In addition,

the grant awarding process at NIH affects technology transfer. These areas will be discussed

below.

Resources for R&D

Table 8 illustrates the amount of resources in

1982 targeted to basic research, applied research,

and development activities. In total, R&D activities comprise 94.2 percent of the entire NIH

budget. Of the R&D activities, 53.7 percent is

for basic research, 35.2 percent is for applied

research, and 11.1 percent is for development.

Among the individual institutes and divisions,

these figures vary widely. For instance, the National Institute of General Medical Sciences

(NIGMS) will spend 86.5 percent of its research

dollars on basic research, 12.3 percent on applied research, and only 1.2 percent on development. In contrast, NCI will target 34.2 percent

to basic research, 43.3 percent (the bulk) to applied research, and 22.5 percent to development.

And, NHLBI’s distribution mirrors the total NIH

distribution. The variances among the institutes

are not surprising, if the missions of the individual institutes are considered. NIGMS exists

to support research and research training in the

sciences basic to medicine. However, NCI has a

number of broader goals in addition to its cancer

research, including cancer control programs,

and collecting and making available information

on cancer (48).

Table 8.—NIH R&D Activities, 1982 (dollars in millions)

Basic Applied R&D

research research Development Subtotal Training facilities Total

NCI . . . . . . . . . . . . . . . . $ 327.9 $

NHLBI . . . . . . . . . . . . . . 302.4

NIDR . . . . . . . . . . . . . . . 32.1

NIADDK . . . . . . . . . . . . 219.7

NINCDS . . . . . . . . . . . . 167.0

NIAID . . . . . . . . . . . . . . 143.8

NIGMS . . . . . . . . . . . . . 252.9

NICHD . . . . . . . . . . . . . 111.2

NEI . . . . . . . . . . . . . . . . 64.4

NIEHS . . . . . . . . . . . . . . 53.7

NIA . . . . . . . . . . . . . . . . 46.8

DRR . . . . . . . . . . . . . . . . 96.7

FIC . . . . . . . . . . . . . . . . 8.5

NLM . . . . . . . . . . . . . . . 3.1

OD . . . . . . . . . . . . . . . . . 9.2

B&F . . . . . . . . . . . . . . . . –

414.5

166.3

34.6

109.0

77.8

61.5

36.0

91.5

52.3

42.1

29.3

76.2

0.6

5.7

9.0—

$215.4

61.1

0.8

20.9

12.5

22.0

3.5

14.7

7.2

3.9

3.4

10.6

0.1

: : : —

$ 957.8

529.8

67.5

349.6

257.3

227.3

292.4

217.4

123.9

99.7

79.5

183.5

9.2

11.7

20.8—

$ 23.4

29.8

4.5

18.6

8.6

8.6

47.4

8.9

3.5

6.6

2.4

0.7

—

32.7

1.8—

$ 5.4—

—

—

—

—

—

—

—

—

—

—

—

—

—

9.9

$ 986.6

559.6

72.0

368.2

265.9

235.9

339.8

226.3

127.4

106.3

81.9

184.2

9.2

44.4

22.6

9.9

Total, NIH . . . . . . . . . $1,839.4 $1,206.4 $381.6 $3,427.4 $197.5 $15.3 $3,640.2

SOURCE: D!ws!on of F[nanclal Management, Office of the Director, National Institutes of Health
40

In theory, the resources expended on applied

R&D are part of technology transfer, albeit at

the beginning stages of the process. It could be

said, then, that NIH allocates 46 percent of its

research dollars to technology transfer, defined

broadly. There are several problems with this

figure, however. First, the figure does not provide a measure of the transfer process, that is,

how or whether the basic research results move

into applied research and so forth. Second, and

perhaps more important, essentially all of NIH’s

activities, including its more formal transfer activities (e. g., consensus development conferences, demonstration programs) are included in

the basic, applied, and development figures.

These other activities are actually part of the

later stages of the transfer process, and this fact

is not reflected. Finally, a related problem is that

definitions of basic research, applied research,

and development mean different things to different analysts, and the criteria used to classify

activities differ from program to program and

from year to year (118). An example of this is

the comparison between the breakdown in table

8 and the percentages reported for 1980 in the

previous section—77 percent of resources for the

“Science base,” 12 percent for “Applications,” 5

percent for “Transfer,” and 5 percent for” Training. ”

Grant Awarding Process

The “dual review system” grant awarding

process at NIH, described in appendix B, affects

technology transfer in at least three ways. First,

the initial review, or peer review, is a mechanism intended to assure that the work being supported is of excellent quality and is likely to produce results. For basic research, the form of the

results is uncertain. The important point,

though, is that new knowledge that can be transferred will be created. For applied research and

development, the results are often medical technologies to be transferred. There have been

numerous reviews of the peer review system,

and its critics have raised questions regarding

objectivity and practice in accord with contemporary standards of public agency behavior

(114) and the degree to which a different review

group would make the same recommendation

(12,13). Nevertheless, most reviewers believe

strongly that no better system assures such high

quality (12,97,114).

Second, the use of advisory councils or boards

to approve actual grant awards is intended to assure that the proposals funded are relevant to

the priorities of the awarding unit. Thus, when

technology transfer activities are a priority for a

particular institute, its advisory council can

affect whether these activities actually occur.

This is particularly true for NCI, NHLBI, and

NIADDK, who have a number of mandated formal transfer activities. Third, the members of

the initial review groups and advisory councils

are generally not government employees, but instead hold full-time positions elsewhere. In the

case of the initial review groups, the members

are well-known scientists. In the case of the advisory councils, the members are either experts

in fields related to the institutes’ missions or public members. In each case, the members affect

technology transfer by informally reporting on

NIH research activities to their “outside” worlds.

Clinical Trials

As one of the most impor

ating the efficacy and safety

ogies, clinical trials are a cr

ant tools for evaluof medical technoltical component of

the technology transfer process. A clinical trial,

as described more fully in chapter 4, is a scientific research activity undertaken to prospectively define the effect and value of prophylactic,

diagnostic, or therapeutic agents, devices, regimens, and procedures applied to human subjects

(114). These trials provide the basis for the testing and orderly application of fundamental research knowledge prior to its general introduction into the health care system. When utilized,

they are part of the ideal technology transfer

process, because they provide the evidence to

prevent the premature diffusion of technologies

into medical practice. Similarly, they may be

used to accelerate the transfer of new technologies. In an ideal transfer process, clinical trials

are done after development research but before

demonstration and control projects.

NIH is the single largest supporter of clinical

trials in the United States (92). Its involvement

in clinical trials in fiscal year 1979 was $136.1
41

million; this amount represents 4.3 percent of its

total obligations that year (49). Since most trials

last longer than a year, completion of the trials

underway is estimated to cost at least three times

the funds spent in 1979.

The early 1970’s was the biggest time of

growth in clinical trial activity. Between 1971

and 1974, four of the 11 institutes (NCI, NHLBI,

the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS),

and NEI) nearly tripled their obligations for major clinical trials (85). In 1975, support for

clinical trials at $110 million represented 5 percent of the total budget for that year. Thus,

although the increase in total funds between

1975 and 1979 was nearly 24 percent, the rate of

increase in clinical trials has decreased. In

response to this, NIH noted that such a statement does not take into account the increase in

efficiency with which clinical trials are conducted.

Tables 9, 10, and 11 illustrate NIH support for

clinical trials during fiscal year 1979. Table 9 delineates clinical trial investment by institute and

by type of support. Table 10 shows the number

of clinical trials conducted by institute and by

Table 9.—Amount of NIH Support for Clinical Trials Active in Fiscal Year 1979,

by Institute for Type of Support

Extramural support Total

Grant and Intramural amount of

Institute Grant Contract a

contract Total Supportb

Support

NIH . . . . . . . . . . . . . $47,304,588 C $75,738,766 $1,954,960 $124,998,316 $11,161,800 $136,160,1 16’

NEI . . . . . . . . . . . . .

NHLBI . . . . . . . . . .

NIAID . . . . . . . . . . .

NIAMDD. . . . . . . . .

NICHD . . . . . . . . . .

NIDR . . . . . . . . . . .

NINCDS . . . . . . . . .

NIGMS . . . . . . . . . .

NCI . . . . . . . . . . . . .

3,141,547

4,006,736

2,435,341

1,927,658

3,074,448

221,977

1,786,449

225,750

30,484,68F

5,378,262

50,933,477

3,827,597

5,226,975

556,296

557,672

439,000—

8,819,489

—

159,788

—

—

—

1,795,172

8,519,809

55,100,001

6,262,938

7,154,633

3,630,744

779,649

2,225,449

225,750

41,099,343

85,800

1,423,500

234,000

1,085,500

552,500

999,050

435,500

6,345,950

8,605,609

56,523,501

6,496,938

8,240,133

4,183,244

1,778,699

2,660,949

225,750

47,445,293 C

acontract includes interagency agreements without intramural SuPpOrt.

b]ntramural support includes intramural support In combination with interagency agreements

cone trial dld not report amount of suPPOd

SOURCE: National Institutes of Health, 1979 /rrverrtory ot C/m/ca/ Tr/a/s.

Table 10.–Number of Clinical Trials Supported by NIH in Fiscal Year 1979, by

Institute for Type of Support

Number of trials supported extramurally Number of trials Total

Grant and conducted- number

Institute Grant Contract a

contract Total intramurally of trials

NIH . . . . . . . . . . . . 592 212 11 815 171 986

NEI . . . . . . . . . . . . 20 3 . 23 3 26

NHLBI . . . . . . . . . 3 13 1 17 20

NIAID . . . . . . . . . . 80 34 — 114 : 120

NIAMDD . . . . . . . 30 22 — 52 15 67

NICHD . . . . . . . . . 24 6 — 30 2 32

NIDR . . . . . . . . . . 2 11 — 13 13 26

NINCDS . . . . . . . . 17 3 — 20 20 40

NIGMS . . . . . . . . . 1 — — — 1

NCI . . . . . . . . . . . . 415 120 10 54: 109 654

a contract Includes interagency agreements without Intramural support, Two trials were supported mostly by contract with

some intramural support.

b lntramural Suppofl includes intramural support in combination with interagency agreements. One trial was supported mostly by Intramural support with some contract support.

SOURCE: National Institutes of Health, 7979 Inventory of Clinical Trials

91-486 0 - 82 - 4
—

42

Table 1 I.–Number and Amount of Support for NIH Supported Clinical Trials Active in Fiscal Year 1979, by

Institute for Type of Intervention

Total trials supported Type of Intervention

in fiscal year 1979a Therapeutic a Prophylactic a Diagnostic a

Institute Number b Amount b Number Amount Number Amount Number Amount

NIH . . . . . . . . . . . 666 $112,847,367 494 $50,540,964 118 $58,875,778 53 $3,170,625

NEI . . . . . . . . . . . .

NHLBI . . . . . . . . .

NIAID . . . . . . . . . .

NIAMDD . . . . . . .

NICHD . . . . . . . . .

NIDR . . . . . . . . . .

NINCDS . . . . . . . .

NIGMS . . . . . . . . .

NCI . . . . . . . . . . . .

26

20

120

67

32

26

40

1

334

8,605,609

56,523,501

6,496,938

8,240,133

4,183,244

1,778,699

2,660,949

225,750

24,132,544

22

10

57

60

16

7

35—

287

4,890,194

9,726,605

2,992,347

7,680,072

2,532,054

779,051

1,565,020—

20,375,621

2

10

39

4

15

17

2

1

28

3,415,997

46,796,896

2,697,064

246,798

1,629,175

776,871

959,429

225,750

2,127,798

2—

24

3

1

2

3—

18

299,418—

807,527

313,263

22,015

222,777

136,500—

1,369,125

a

Trials in cooperative groups not included.

bone trial did not report amount of support. One trial did not specify type of intervention.

SOURCE: National Institutes of Health, 1979 Inventory of Clinical Trials.

type of support. From these tables, it is clear that

the average expenditure per trial ranged widely,

from $2.8 million for NHLBI to $54,000 for the

National Institute of Allergy and Infectious

Diseases (NIAID). The NIH-wide average is

$138,000. The tables also indicate that the

mechanism of support varies from institute to

institute. Most clinical trials are conducted extramurally; the only exception is at the National

Institute of Dental Research (NIDR). Of the extramural types of support, the bulk of dollars

was spent on contracts. This was true for five of

the nine institutes supporting trials. However,

the greatest number of trials were conducted by

grant; only NHLBI and NEI had a greater number of contracts. It seems reasonable that the

largest trials be conducted by a mechanism

which allows greater control by the institute.

It is interesting that the two largest sponsors

of trials—NHLBI and NCI—use such different

mechanisms to fund them. Although the NCI trials are currently being converted to cooperative

agreements, there will still be great differences

between the mechanisms and processes. Chapters 6 and 7 discuss clinical trials at these institutes in depth.

Table 11 delineates expenditures for trials by

three functions of technology: therapeutic, prophylactic, and diagnostic. For the entire NIH,

the greatest amount of funds was spent evaluating prophylactic interventions. Therapeutic

technologies were close behind, and diagnostic

technologies followed at quite a distance. The

view of the total NIH picture is somewhat misleading, since most of the trials and most of the

dollars were spent on therapeutic technologies if

NHLBI figures are excluded.

An earlier OTA report, Assessing the Efficacy

and Safety of Medical Technologies (85), r e -

ported on the expenditures for clinical trials by

functions of technology in 1975. At that time,

clinical trials investigating therapeutic technologies were predominant. Furthermore, a majority of the trials were conducted to test drugs

either in isolation or in combination with another type of technology (with the bulk tested in

isolation). More than 300 of the trials tested cancer chemotherapies, while only 25 evaluated surgical procedures. Few trials examined the efficacy of screening or early diagnosis, or primary

prevention technologies. Except for the reversal

in the relative ranking of trials of prophylactic

technologies and of therapeutic ones (caused by

the large increase in NHLBI trials of prophylactic technologies), it appears that the findings of

the earlier OTA report are still accurate.

NIH’s interest in clinical trials does not end

with supporting them. Upon their completion,

major attention turns toward presentation of the

basic results in scientific and professional journals. The primary means of disseminating the

analysis of a trial to the research community is

publication of the results. Dissemination also occurs through workshops, conferences, and pro-
.

43

fessional societies (42). Other examples of interest in clinical trials can be found at the institute level. At NCI, the Board of Scientific

Counselors has a Clinical Trials Subcommittee

to make recommendations relating to all aspects

of the trials (66). If the results of the trials on a

particular technology do not lead to a clear decision about its application in clinical practice,

NIH has a mechanism to synthesize the evidence

for dissemination. This mechanism, the consensus development conference, will be discussed in

the next section.

There are several issues that pertain to the role

of clinical trials at NIH. One concerns the appropriate amount of investment in clinical trials.

This is a difficult issue to address. Clearly,

greater and greater amounts of resources are

being expended for clinical trials, although the

amount as a percent of the total budget has decreased in recent years. On the one hand, investment in clinical trials is extremely important and

potentially remunerative since it can prevent

new unproved procedures from finding their

way into medical practice (and into reimbursement by the Federal programs) (114). However,

trials are in many cases quite costly. And, the

demand for trials appropriately leads to more

trials. Yet resources devoted to trials must

necessarily be balanced with more fundamental

investigations of etiology and pathophysiology

of disease, the foundation of our ability to prevent and treat disease and the source of new

clinical hypotheses requiring testing (42).

Another important issue relates to the funding

mechanism used to support clinical trials—grant

v. contract v. cooperative agreement. Differences between these mechanisms include the

amount and type of review on the proposal, the

initiation of the idea for the study, the timing of

the application process, the amount of control

and monitoring which can be conducted by the

institutes, and types of end products required

(100). In addition, the mechanism may affect the

technologies selected to be tested. For grants, the

scientific merit of the proposal (rather than its

topic) determines award selection. Although

there are specific policies that attempt to define

the differences between the mechanisms, the

distinctions between them are becoming blurred.

As noted earlier, the various institutes utilize different mechanisms. Thus, particularly because

of the current drive to change grants to

cooperative agreements (at least at NCI), the effect of the different mechanisms on trial outcomes should be carefully evaluated.

A related issue is the impact of the budget constraints, in combination with a drive to stabilize

the number of competing grant awards, on the

ability to begin new clinical trials. While the

budget of NIH has not yet suffered the cuts that

many other Federal programs have felt and will

feel in fiscal years 1981, 1982, and 1983, the rate

of budget increase has certainly not kept up with

inflation. At the same time, there has been an effort to stabilize the number of competing grant

awards to be made each year to eliminate erratic

changes in likelihood of meritorious projects

being funded. This search for stability, while

potentially alleviating one serious problem, has

created certain tensions in other areas, notably

in the institutes’ ability to begin new clinical

trials. For instance, in the 1983-85 Research Plan

published in December 1981 (58), NHLBI states

that:

. . . the most severe impact [of stabilization]

will be felt in clinical trials and targeted research, funded under the contract mechanism,

where no new efforts can be implemented in

1980-1982. . . The contract mechanism is best

suited to fund clinical trials, and rapid advances

in research and developments in cardiovascular

and pulmonary treatment techniques necessitate

clinical evaluation at a time when no new contracts can be awarded.

Other institutes with smaller budgets and less efforts in the clinical trials areas, such as the National Institute of Child Health and Human Development (NICHD), NIAID, and NIDR, make

similar statements.

Office for Medical Applications

of Research

Background

In response to the congressional concern with

the systematic assessment and transfer of new

technologies, the Director of NIH conducted an

extensive study of the potential NIH role in this
44

area. The study resulted in a paper entitled,

“The Responsibility of NIH at the Health Research/Care Interface, ” dated February 28, 1977

(80). This paper defined the problem and the

role of the individual institutes and divisions in

technology transfer, and expressed the need for

a central office to coordinate the existing activities. It took the current status a step further

and indicated a need for a formal systematic approach for assessing health care technology and

disseminating clinically relevant research findings to the medical practice community and the

public.

On May 11, 1977, the Director of NIH initiated a request to the Department of Health,

Education, and Welfare (HEW) to establish the

Office for Medical Applications of Research

(OMAR). This request spelled out the need for

new procedures of transferring knowledge that

would promote effective community application. The primary mechanism proposed for this

task was the development of consensus along

with the consideration of the implications involved in the application of the technology.

OMAR was informally established in the Office

of the Director in September 1977, and was officially created by the Assistant Secretary for

Management and Budget of HEW on October 4,

1978 (59).

As published in the Federal Register, OMAR’S

functions are as follows (59):

1)

2)

3)

4)

5)

Advises the Director, NIH, and his senior

staff, and provides guidance to the bureaus,

institutes, and divisions on medical applications of research;

Coordinates, reviews, and facilitates the systematic identification and evaluation of clinically relevant NIH research program information;

Promotes the effective transfer of this information to the health care community and

through the [National Center for Health

Care Technology (NCHCT)] to those agencies requiring such information;

Provides a link between technology assessment activities of the bureaus, institutes, and

divisions of the NIH and the OHT (Office of

Health Technology of DHEW): and

Monitors the effectiveness and progress of

the assessment and transfer activities of the

NIH.

In June of 1980, the Director of NIH appointed a committee to review the activities and

mission of OMAR. The review also covered related areas, including technology assessment at

NIH, effective coordination of medical applications of research activities at NIH, and the value

of a central NIH focus and an apparatus for advice and oversight. A report was issued on

September 24, 1980 (59). The committee’s findings are generally applicable today, since

OMAR has changed little in structure since its

inception, although the processes of the office

have become more formal. Indeed, the major

change affecting the office has occurred outside

of NIH: NCHCT was not funded in fiscal year

1982, and thus, OMAR’S activities formerly conducted in coordination with NCHCT are either

conducted by OMAR alone or not conducted at

all. Thus, the sections of the committee’s report

concerned with the former NCHCT do not apply. At issue today is whether some of the

former NCHCT’S activities should now be acquired by OMAR. This issue will be discussed

further.

Structure and Role

OMAR is a relatively small office, with five

professional and four support staff members.

During its first 2 years, the program cost approximately $700,000 per year. In 1981, $1.2 million

was the approximate figure, exclusive of staff

costs and evaluation studies (83).

OMAR’S Advisory Committee, consisting of

representatives from the various bureaus, institutes, and divisions of NIH, assists OMAR in

achieving its goals. Its members and the OMAR

staff meet monthly to discuss, determine, and

plan consensus development activities and to exchange information relating to other NIH involvement in assessment of biomedical technologies (90). The committee has been in existence

since August 1977, even before the formal establishment of OMAR.

The report on OMAR noted that the lack of a

clearly defined role for OMAR (except in the development of the consensus conferences) and

preoccupation with the administrative details of

the meetings have contributed to decreased interest among Advisory Committee members and

a high turnover among institute (and division)
45

representatives. The committee and its subcommittees have been effective, however, in the development of issue papers. Topics covered in the

issued papers have included the activities and

mandates of NIH, the development of evaluation schema, methods for updating consensus

statements, and advice on the definition and reporting of emerging technologies. The committee has also served as a principal means for sharing information about technology transfer issues

within NIH (59).

Consensus Development

OMAR’S primary activity has been the administration of the consensus development program

at NIH and support of the actual consensus conferences. The consensus development conferences bring together scientists, practitioners,

consumers, and others in an effort to reach general agreement on the safety and efficacy of

medical technologies. The technologies of interest may be emerging or may be in general use.

Recent conferences have tended toward examining emerging technologies, while early conferences generally focused on existing—and sometimes controversial—technologies. The technologies studied may be drugs, devices or medical,

surgical, or dental procedures. Since the first

conference in September 1977, there have been

32 conferences held and four more are currently

scheduled. Table 12 lists the topics, dates, and

sponsors.

The first step in planning a consensus development conference is the selection of the technology to be assessed. Since this activity occurs at

the individual institute or division level, procedures vary widely. Before a conference topic is

finally selected and scheduled at OMAR, it will

have been discussed and reviewed for 2 to 1 5

months at the institute level. It will also have

been discussed by the OMAR Advisory Committee to generate suggestions and interest from

other institutes that may have escaped the original sponsors. Should the case arise (and it has

not to date) that there are more topics identified for conferences than OMAR has the resources to support, the OMAR Advisory Committee would be the body to recommend a priority order in which the conferences would be

held.

Once the conference topic has been identified,

the planning process begins. OMAR provides

the initiative and logistic support and offers

guidance based on the experiences with previous

consensus development exercises. The planning

period typically lasts 9 to 18 months (90). A

number of planning meetings, first involving

only NIH and OMAR staff, and later involving

outside experts, are usually held to delineate the

key issues. Also determined during the meetings

are the specific questions surrounding the technology under discussion and the approaches to

be used in reaching consensus. Individual experts may prepare papers prior to the meeting

summarizing the state of the science; alternatively, or in addition, task forces are asked to produce draft documents for consideration at the

conferences.

Consensus development panels are carefully

constituted to reflect the range of individuals

and organizations with expertise and interest in

the use of the technologies. They include researchers in relevant fields, members of the pertinent clinical specialties, health care consumers, and others. Without question, however, the

panel is overwhelmingly scientific, often reflecting the orientation of its sponsor. The conference is open to the public and audience participation is encouraged.

Most NIH consensus development conferences have used some variation of the following

general format. The conference begins with a

plenary session, during which individual experts

or representatives of task forces present information on the state of the science. Comments by

panelists may follow. Also, members of the audience may ask questions or provide comments.

In some cases, work groups or task forces then

meet to discuss specific aspects of the technology. In a closed session, the panel then convenes

in an attempt to reach a consensus on the relevant issues. At the final plenary session, the consensus statement is presented to the audience for

comment. At times, the audience comments are

incorporated. Panel members who disagree with

major conclusions may issue a minority report.

A minority report has only been issued once.

Consensus statements are not, and do not attempt to be, regulations on the “proper” practice
46

Table 12.—NIH Consensus Development Meetings, September 1977 Through

November 1982, Office for Medical Applications of Research

Sponsors Title Dates held

NC I

NCI

NIDR

NCI

NIA

NINCDS

NIAID

NCI

NIGMS

NIAMDD

Interagency Committee

on New Therapies for

Pain and Discomfort

(Organizer)

NICHD

NHLBI

NHLBI

NCI

NCI

NE I

NIA

NIAID

DRS

NIDR

NHLBI

NINCDS

NCI

NCI, NIA, NICHD,

NCHCT

NIAMDD

NICHD

NCI

NHLBI, NCHCT

NINCDS, NIAID,

NIAMDD, NICHD,

NIEHS, DRS

NINCDS, NCI

NIAID

NIADDK

c c

NIAID

DRS

Breast Cancer Screening

Educational Needs of Physicians and the

Public Regarding Asbestos Exposure

Dental Implants Benefit and Risk

Mass Screening for Colo-Rectal Cancer

Treatable Brain Diseases in the Elderly

Indications for Tonsillectomy and

Adenoidectomy: Phase I

Availability of Insect Sting Kits to Nonphysicians

Mass Screening for Lung Cancer

Supportive Therapy in Burn Care

Surgical Treatment of Morbid Obesity

Pain, Discomfort, and Humanitarian Care

Antenatal Diagnosis

Transfusion Therapy in Pregnant Sickle Cell

Disease Patients

Improving Clinical and Consumer Use of

Blood Pressure Measuring Devices

The Treatment of Primary Breast Cancer:

Management of Local Disease

Steroid Receptors in Breast Cancer

Intraocular Lens Implantation

Estrogen Use and Postmenopausal Women

Amantadine: Does It Have a Role in the

Prevention and Treatment of Influenza?

The Use of Microprocessor-Based

“intelligent” Machines in Patient Care

Removal of Third Molars

Thrombolytic Therapy in Thrombosis

Febrile Seizures

Adjuvant Chemotherapy of Breast Cancer

Cervical Cancer Screening: The Pap Smear

Endoscopy in Upper GI Bleeding

Childbirth by Cesarean Delivery

CEA and Immunodiagnoses

Coronary Bypass Surgery

Reye’s Syndrome Diagnosis and Treatment

CT Scanning of the Brain

The Effect of Diet on Hyperactivity

Hip Joint Replacement

Critical Care Medicine

Immunotherapy - Treatment of Insect

Sting Allergy

Validation of Biomaterials

Sept. 14-16, 1977

May 22, 1978

June 13-14, 1978

June 26-28, 1978

July 10-11, 1978

July 20, 1978

Sept. 14, 1978

Sept. 18-20, 1978

NOV. 10-11, 1978

Dec. 4-5, 1978

Feb. 16, 1979

Mar. 5-7, 1979

Apr. 23-24, 1979

Apr. 26-27, 1979

June 5, 1979

June 27-29, 1979

Sept. 10-11, 1979

Sept. 13-14, 1979

Oct. 15-16, 1979

Oct. 17-19, 1979

NOV. 28-30, 1979

Apr. 10-12, 1980

May 19-21, 1980

July 14-16, 1980

July 23-25, 1980

Aug. 20-22, 1980

Sept. 22-23, 1980

Sept. 29-

Oct. 1, 1980

Dec. 3-5, 1980

Mar. 2-4, 1981

NOV. 4-6, 1981

Jan. 13-15, 1982

Mar. 1-3, 1982

Summer 1982

Oct. 6-8, 1982

Nov. 1-3, 1982

SOURCE: Office for Medical Applications of Research, National Institutes of Health.
4?

of medicine. Rather they are attempts to represent the best current thinking by a group of scientific experts and others in a position to make

judgments on safety and efficacy. Consensus

conferences differ from standard state-of-the-art

meetings in that consensus panels must consider

and seek closure on specific sets of questions,

and the format of the conference has been predetermined.

Dissemination

Those conducting consensus development

conferences hope that by supplying practitioners

with critiques of complex medical technologies,

the consensus reports will contribute to an improvement in the quality of medical practice.

Dissemination of the consensus statements and

supporting materials is thus an essential part of

the program. Practicing physicians and others in

the health care system, the biomedical research

community, and the public are the groups targeted to receive the statements. OMAR assists in

the actual dissemination and in the monitoring

of the following dissemination activities. Consensus materials and information have been

published in the three American medical journals with the largest circulation—the Journal of

the American Medical Association, the N e w

England ]ournal of Medicine, and the Annals of

Internal Medicicine. Distribution through State

medical journals, other scientific publications,

mainstream periodicals, and the general press is

encouraged, though such distribution is not directly initiated by OMAR (90). A brief review of

the literature by OMAR found that most of the

consensus reports were published in at least two

journals (80). OMAR actually publishes summaries of the conferences in a periodic publication, NIH Consensus Development Conference

Summaries (81), and distributes it to requesters

on its mailing list of over 21,000 names. In addition, the conference reports have been indexed

in the National Library of Medicine’s Index

Medicus since the winter of 1980, making their

existence even more widely known.

OMAR’S information dissemination activities

are focused solely on consensus conferences.

These activities are not formally coordinated

with NIH’s other numerous information dissemination activities, although coordination of information offices is accomplished to a degree

through periodic meetings with the Associate

Director for Communications. According to the

report of the Oversight Committee for OMAR

(59), the liaison between the Office of Communications and OMAR is satisfactory. However, work on use of nonpublished media and

interpersonal networks discussed by a Task

Force on Communications (established in 1975

and abolished in 1978) is not receiving adequate

effort. In 1981, a subcommittee on communications of the OMAR Advisory Committee prepared an OMAR dissemination plan. This plan

is awaiting implementation.

Other Activities

Since its creation, OMAR has provided a conduit for requests from other agencies for technical advice, generally in the areas of reimbursement and specific technologies. OMAR’S function has been to receive the requests, channel

them to the appropriate institutes for action, and

return the completed response to the requesting

agency. For reimbursement advice, NIH provides only technical material on the acceptability of a procedure in medical practice; it does not

actually develop reimbursement recommendations. These recommendations are currently developed for the Health Care Financing Administration (HCFA) by an office of the Assistant

Secretary for Health, DHHS. Formerly,

NCHCT developed the recommendations. In

1979 and 1980, NIH answered 63 such requests

(59). For specific technologies, OMAR had

channeled requests from NCHCT to the various

institutes to identify experts to prepare overview

papers. This activity does not currently occur,

although the mechanism is still in place.

Discussion

In the following ways, OMAR and its activities, particularly the consensus development

program, have successfully contributed to appropriate technology transfer. The consensus

statements and supporting materials provide a

resource to assist members of the health care

community and the public in making sound decisions regarding the use of medical and surgical

procedures, drugs, and devices. The program

has also helped scientists and policy makers to
48

identify gaps in current knowledge and opportunities for further research (95). And in contrast

to some original concern that consensus development would be thought to stifle innovation,

there have been reports that the inclusion of

recommendations for further research in the

statements actually fosters innovation (95),

The program has several weaknesses, however. One limitation of the program is in the

process itself. For instance, the use of adversary

groups and task forces has been almost entirely

abandoned recently, and the questions posed

have been strictly on issues on which there is

enough factual evidence to reach agreement. For

the purpose of synthesizing available knowledge, this approach may be adequate (assuming

that the available knowledge is all included and

understood). Some critics still believe that for

the purposes of identifying gaps in knowledge

and needs for future research this approach is

weak (92). NIH does not agree with this judgment, however, arguing that in instances where

consensus cannot be reached, the panels identify

areas of needed research. Even when the clearly

controversial issues are tackled, critics have

voiced concern that the fact that consensus has

been reached means that the statements are only

bland generalities that represent the lowest common denominator of the debate, and as such are

far from the cutting edge of progress (103).

As the office responsible for monitoring the

progress and effectiveness of the consensus development program, OMAR has launched two

major evaluative efforts. One study will compare alternative strategies for conducting NIH

consensus development activities (a look at the

process), and another will assess the impact of

the conferences.

Apart from questions over the method and

process of consensus development, an issue remaining to be resolved is whether the role of

OMAR should be expanded, since NCHCT has

been disbanded. Although NCHCT’S specific coordination activities are no longer being performed, OMAR is basically functioning the

same way today as it did before NCHCT’s demise. That is, it utilizes the same intra-NIH procedures for selecting consensus development

conference topics, planning the conferences, and

disseminating information on them as it did before; and it assists HCFA with technical advice

related to reimbursement as it always did. The

difference is that reimbursement requests come

from a temporary office in the Assistant Secretary for Health’s office instead of from NCHCT.

The assessments done with OMAR’S assistance

focus on safety and efficacy rather than ethical,

legal, economic, and political issues. However,

OMAR does not have the mandate to conduct

such broad-based studies. Additionally, there is

no NIH-wide mandate to systematically identify

emerging and existing technologies in need of review, as there had been in NCHCT’s day. Several institutes do perform this activity —NHLBI’s

program, though,

ized.

Demonstration

Demonstration

is certainly the most formaland Control Programs

and control programs, like

consensus development conferences, are formal

technology transfer activities. They are undertaken specifically to assure that new technologies that have been shown to be safe and efficacious are applied in clinical practice in the

most effective ways. In 1975, the Director of

NIH defined the terms as follows:

Demonstration means either showing that

something works, such as patient education, or

showing that something that works in an ideaI

setting works in a practical field setting. Control

has as its goal the reduction of disease, preferably by prevention, and is the ultimate objective of biomedical research. However, its meaning has changed to refer to the extension or diffusion throughout the health care system of an

intervention, technology or some other change

in the substance of medical practice (114).

Demonstration and control programs are generally discussed together as a category of activities (56,60,114). Technically, they are overlapping activities. Demonstration projects are not

always concerned with the control of disease in

the prevention sense, although demonstration of

the application of any medical technology is intended to affect some aspect of eventual disease

reduction. Control programs, however, usually

comprise a broad range of activities, of which
49

the most important are demonstration projects.

In a discussion of control programs at NHLBI, a

study panel concluded that “well-conceived

demonstration projects will conserve limited

resources, save money, and reduce the frustration that inevitably results from premature and

ill-conceived projects. They will ensure that new

programs are well-tested before they are committed to general use” (56).

Demonstration and control programs are not

a new NIH activity, but actually started with the

National Cancer Institute Act of 1937. In 1946,

the Cancer Control Branch was established

within NCI to provide grants to State health

agencies for cancer control activities. As new

categorical institutes were established at NIH,

additional disease control activities were added.

Some, such as the Heart Disease Control Program, were identified as discrete and visible programs, while others were not separately categorized and funded as control programs per se. In

the early 1960’s, the control programs of NIH

were transferred to the Public Health Service

Bureau of State Services. Then, in 1968, the control programs as they existed were phased out,

and some components were transferred to the

Regional Medical Programs. Demonstration and

control activities returned to NIH with the enactment of the National Cancer Act of 1971 and

the Heart, Blood Vessel, Lung, and Blood Act of

1972. These activities were expanded to other

disease areas with the passage of the National

Diabetes MelIitus Research and Education Act of

1974 and the National Arthritis Act of 1974.

The amount of demonstration and control

activity varies widely among the institutes.

The largest effort, by far, is the Cancer Control

Program at NCI; it is the only control program

with a line item in the budget, This line started

at $5 million in 1973, reached a high of $70 million in 1979, and is set at $55 million for 1982.

Corresponding figures for other institutes are

not available, but if they were, most would be

less than half the NCI amount. The National Research and Demonstration Centers Program of

NHLBI is the second largest demonstration and

control program at NIH. Programs at NCI and

NHLBI are discussed in depth in chapters 6

and 7.

An examination of the statutory authorities

for the institutes reveals that demonstration and

control are mentioned for only six of the 11

institutes—NCI, NHLBI, NIADDK, NIGMS,

NIDR, and the National Institute on Aging

(NIA). Of these, only four (NCI, NIADDK, and

NIGMS) have specific programs authorized.

While there are currently examples of such programs at eight of the institutes, it is clear that the

efforts are greater when Congress has specifically mandated the activities,

Some examples of demonstration and control

programs are as follows (58):

1.

2.

3.

4.

5.

6.

7.

8.

NIAID—accelerated vaccine development.

NIADDK—demonstration of prolonged

cadaver graft survival with multiple pretransplantation blood transfusions.

NCI—numerous activities coordinated by a

new Division of Resources, Centers, and

Community Activities.

NICHD—new methods for managing the

diabetic condition early in pregnancy will

be tested for effectiveness in reducing the

risk of congenital defects among offspring.

NIDR—demonstration of fluoride-containing agents under the National Caries Program.

NIGMS—development of artificial skin for

burn victims.

NHLBI—program of National Research

and Demonstration Centers.

NINCDS—Comprehensive Stroke Centers.

The general orientation of NIH is that demonstration and control programs should involve

the establishment of innovative disease control

technology through controlled, time-limited

projects conducted in limited populations (114).

Thus, most of the institutes have some interest in

demonstration and control activities.

Information Dissemination

Information dissemination is essential for

technology transfer to occur. It is the means by

which results travel from one stage in a technology’s Iifecycle to another. All information dissemination activities, therefore, affect technology transfer. The activities associated with the

more formal technology transfer programs, such
50

as the consensus development program and

demonstration and control programs, are designed to disseminate information about the appropriate clinical use of medical technologies.

On the other hand, the dissemination activities

associated with programs in the earlier stage in

the technology’s life (such as R&D or evaluation) are designed to assure that basic knowledge

can be translated into solutions potentially applicable to improving health.

Along with its responsibility to develop and

evaluate new biomedical knowledge, NIH has

had, since its early days, an implicit responsibility to disseminate information about research results to the research community, the health professional community, and the public in an effective and timely manner. However, this responsibility has been made more explicit by Congress

over the past decade, reflecting both a feeling

that dissemination activities are important and a

criticism of NIH’s less-than-vigorous efforts in

the past (114).

Of the 11 institutes, only four do not have

specific mandates to disseminate research results

(NIGMS, NEI, NIAID, and NINCDS). The statutory authorities for the seven remaining institutes vary according to the specificity of their

dissemination programs. The most specific law

concerns NIADDK. It mandates several programs of which information dissemination is a

major component, including: the Diabetes Data

Group and Clearinghouse, Diabetes Research

and Training Centers, arthritis demonstration

projects, the Arthritis Data System, multipurpose arthritis centers, and the National Digestive

Diseases Education and Information Clearinghouse. NCI and NHLBI also have several

designated programs in their statutes, while

NIDR, NIA, NICHD, and the National Institute

of Environmental Health Sciences (NIEHS) have

less specific directives.

Clearly, where Congress has created special

provisions for other technology transfer activities, it has also stressed information dissemination. This is evidenced in the original and

amended versions of the National Cancer Act of

1971, the National Arthritis Act of 1974, the

National Diabetes Mellitus Research and Education Act of 1974. The trend which started with

the National Cancer Act has continued and

strengthened—the latest amendments to the NIH

authority focused on NIADDK, and it is

NIADDK that has the most specific dissemination programs.

In 1974, the Director of NIH established a

Committee on Dissemination of Research Results to review NIH-wide dissemination activities and develop specific recommendations.

This committee produced yearly reports through

August 1977, when the fourth and final report

was written (53). When OMAR was created, the

committee ceased to function. The committee

divided the task of information dissemination

into programs for three target audiences:

research scientists, practicing physicians and

other health professionals, and the general public. Although formal yearly progress reports are

no longer written, the target groups remain the

same.

Dissemination to Scientists

In the area of scientist-to-scientist communication, the primary mechanism is through

publication in the more than 2,2oo scholarly and

scientific journals. This mechanism, which includes critical review of the results as a condition

of publication, safeguards the scientific community against widespread diffusion of incorrect

information.

It is generally agreed that this mechanism is effective (114). That NIH ranks fairly high in the

scientific literature is evidenced by a recent survey of 1,000 scientist-authors whose published

works from 1965 to 1978 were considered the

most cited in scientific literature (55). There

were 84 NIH intramural scientists among the

1,000, or 10.5 percent of the estimated 8 0 0

authors who published in fields relevant to the

NIH mission.

The National Library of Medicine (NLM) is

NIH’s largest activity in the area of scientific information acquisition and storage for easy

retrieval. * A major role of NLM is to provide

mechanisms for dissemination of information,

including 20 online data bases directly accessible

● NLM was the topic of study in an OTA staff paper in 1981 (91)

and in a technical memorandum to be completed in April 1982.
51

at more than 1,530 institutions (91), the

Regional Medical Library Program and the National Medical Audiovisual Center. Although

there are unresolved issues concerning NLM’s

future growth and directions, it is regarded as an

excellent program.

Dissemination to Health Professionals

In the area of communication of research findings to health professionals, it is not sufficient

simply to provide volumes of study results no

matter how worthy they may be. A busy practitioner would be inundated by the sheer volume

of information if he or she received the full output of published results. For this reason, it is

essential that there be a sorting-out process and

that communication efforts be concentrated on

the portion of research output that is ready for

use in clinical settings (114). Thus, NIH conducts

a number of activities in addition to NLM activities noted in the previous section. The consensus development conferences and subsequent

dissemination of their proceedings, sponsored

by OMAR, is the program most directly related

to the targeted transfer of technologies. It has

already been discussed. In addition, the various

institutes sponsor over 100 meetings annually

for practicing physicians (53). The Office of

Communications, in its annual list of publications (54), targets publications of particular interest to health professionals. And the Lister-Hill

National Center for Biomedical Communications (a division of NLM) conducts and supports

a continuing research program on the effectiveness and efficiency of biomedical communications.

Dissemination to the Public

In 1977, it was reported that the constituent

units of NIH received about 1,500 public inquiries each working day. About 80 percent of

those requests came from members of the general public and concerned specific disease problems (54). The volume of requests is even larger

today. In response to public as well as congressional pressure, NIH continues to increase its

dissemination to the public. The activities are

numerous; they include targeting publications in

the annual publications list to the general public,

supplying audiovisual materials to over 2,000

radio stations and over 700 television stations,

preparing instructional films, releasing news

briefs, and sponsoring disease-specific public information centers such as the National Digestive

Diseases Education and Information Center.

Technology Transfer to Industry

For medical technologies that are physical objects—drugs and devices—the technology transfer process involves industry. It is industry that

actually produces and markets the technologies,

thereby influencing their application in clinical

practice. In many cases, the bulk of the transfer

process occurs within the drug and medical device companies, from applied research to technology creation and development, through evaluation, to production and distribution. In these

cases, the basic knowledge utilized in the company’s applied research is often transferred from

an NIH-sponsored program. The transfer mechanism is usually scientist-to-scientist communication through the professional literature or at

professional meetings.

In other instances, however, the technology is

developed and perhaps evaluated under NIH

auspices. It is transferred to industry, then,

much later in its lifecycle. Recently, there has

been considerable interest within NIH and within Congress on this aspect of technology transfer

(58).

Collaborative programs with industry have

long been viewed by other agencies as a mechanism to facilitate the transfer process. Indeed,

the National Aeronautics and Space Administration recognized early on that involving industry

early in the technology development process

would increase the likelihood that the technology would be produced. And in the field of technologies for disabled people, the National Institute for Handicapped Research has begun similar relationships with industry.

NIH, with its more recent commitment to

knowledge application in addition to knowledge

development, is relatively new in its agencywide

interest in relationships with industry. For some

time, Congress and others have been concerned

about the commercial application of useful biomedical research findings. More recently, rela-
52

tionships with industry are expanding because of

budget constraints. There are those, mostly

within the government, that hope that the drug

and device industries can pick up forthcoming

cuts in biomedical research budgets. Pharmaceutical industry representatives, however, have

stated that, although they can continue to fund

“some areas” of biomedical research, they “can’t

pick up the massive slack” in available funds

(21). Furthermore, relationships with industry

are growing due to the clear commercial value in

applications from basic science fields where

there has been no precedent for profit (e. g.,

genetic engineering).

Industry patents and licenses are very important aspects of the transfer process. NIH is quite

active in this regard, with approximately 370

patents licensed to industry.

The Advisory Committee to the Director of

NIH has had as a priority for 1981 the relationship between NIH and industry. This priority

continues today. Issues of concern include the

following:

●

●

●

●

●

●

how patent rights are allocated;

how patent royalties are allocated—among

scientists and their university, among universities and industry-and whether the

government can recoup some of its investment in research;

whether a longer period of patent protection and licensing is needed;

how and when the government should invoke its march-in rights, the right to revoke

a university’s patent license if the license is

not properly handled;

what the best model for patent administration at universities is; and,

what the impacts of patenting on the nowopen system of communications in biomedical sciences will be.

Training

Since the objective of training programs at

NIH is to produce more and better biomedical

researchers, these activities do not have a direct

impact on the technology transfer process. In

several ways, however, they do affect the process indirectly. First, training funds develop the

personnel resources to develop and evaluate

technologies. This effect is most important to

targeted technology transfer when the researchers

are trained in conducting evaluative studies to

prevent the premature diffusion of untested

technologies into clinical practice.

Second, when training is conducted at the specialized centers funded by NIH, such as the Diabetes Research and Training Centers, there is a

formal combination of the training and technology transfer functions. The combination assists

in current transfer and orients the trainees to

develop similar programs of their own in the future. Finally, since much of the training occurs

in institutions associated with clinical practice,

interaction between the researcher trainees and

the health professionals can allow for informal

technology transfer.

Table 13 shows training grant appropriations

by funding component from 1950 to 1980. From

1950 to 1967, the increases in funds were large,

and the next period, until 1976, was one of fluctuation. Regulations issued under the National

Research Service Award Act of 1974 in 1975

directed that awards could be made only in

fields determined to be in need of research personnel; these regulations were partially responsible for the drop in 1976. Since that time, increases have been steady, particularly for the

larger institutes. Thus, the problem of instability

cited in 1976 by a congressional investigation of

NIH (114) and the President’s Biomedical Research Panel (97) was somewhat alleviated. Recent budget cuts are likely to affect stability.
Table 13.—Training Grant Appropriations by Funding Component, Fiscal Years 1950-80 (amounts in thousands of dollars)

NCI

2,625

2,415

2,415

2,725

2,855

2,725

2,725

4,675

4,725

6,050

7.205

7,055

9,055

13,470

12,482

9,000

10,900

11,068

11,350

11,641

11,941

10,774

4

16,474

16,750

13,742

17,097

12,888

15,541

15,191

17,110

22,901

NIMH

.—

2,956

3,349

4,000

3,750

4,176

4,310

5,885

12,000

14,000

18,213

26,208

39,470

34,858

49,373

65,188

73,213

86,231

94,448

(’)

. . .

NHLBI NIDR

834

888

891 .“.”

1,623

3,02 8

2,762

3,142

4,400 500

5,135 500

7,152 450

8,679 1,100

11,970 2,985

13,104 4,791

16,000 5,853

14,801 4,759

14,984 4,708

17,228 5,203

~7.525 5,248

17,698 5,469

16,150 5,609

19,008 5,495

17,643 5,208

18,701 5,582

19,343 5,270

16,089 5,515

14,515 3,692

11,839 3.235

17,733 3,309

19,321 3,219

19,098 2,780

27,622 3,487

NIAMDD NIAID

250

2 5 0

9 5 0

1,850

2,450 650

4,435 1,787

6,298 3,621

8,300 4,790

10,300 5,400

13,034 7,200

13,220 7,988

13,690 8.239

14,208 9,059

14,857 9,103

15,706 9,251

16,109 9,468

17,454 8.972

15,072 8,972

15,976 9,457

15,072 6,982

12,312 7,933

10,078 5,351

1,247 4,537

7,234 5,766

12,587 5,556

12,863 5,875

18,123 7,097

NINCDS NICHD NIGMS NIEHS NIAS NEI s ~~ 3

—

504 “.

1,004

1,600

4,150 ...” ““ : : :“

4,972

5,775 “.” ““

8,888 ““” . . . . . . :““ .“

8,450

10,OOO : .......: ””. ‘:. . . . .

13,767 . . . ....:.:... .“:” ::””

14,382 t 4,142 . . . . . . .

14,751 5,544 . . . . . . . . . . . . . . . .: ““ .

17,757 7,937 41,375 . . . . . . . . . . . . . . . . .

18,633 9,619 43.735 . . . . . . . . . . . . . . . . . . . . .

18,780 9,762 45,729 4,745 .

19,262 10,012 46,901 3,892 ..:::::” :.. ...::.:::”. :........ . ....::::::

17,950 9,892 48,477 3,617 . . . . . . . . . . . . . 3,31 3

14,300 10,142 43,746 3,11 7 2,998 352

15,158 10,751 46,371 3,304 . . . . . 3,178 373

16,324 11,598 47,511 4,13 1 3,398 416

16,516 6,552 39,247 2,900 .....::. 3,056 391

10,310 6.680 44,940 2,915 1,156 3,194 388

4,006 6,644 37,599 1,453 1,133 3,194 160

2,450 5,877 40,988 3,108 1,629 2,387 411

3,059 6,097 41,580 4,036 1,856 1,990 412

3,584 8,370 42,371 4,293 1,854 3,452 469

3,854 8,342 42.092 6,121 2,170 3,530 597

‘ Derived by transfers from other NIH appropnatmns as authorized by Congress ‘No appropruslm bdl aqned m !973 Fqures are baaed on the cordmumg resoluhon

z Transferred 10 HSMtiA July 1, 1967 ‘ Reserve Iegslaled by P L 93-192 not reflected

I GR & S discontinued Research Resources epprofmahon esrabhshed ‘Formerly a part of NICt+D

“ Includes port!ons Of $100.00Q0OO Cancer Conquest Program and S40.000,O@l S Authcmzed by P L 95.482 (Contmumg Rewlutmn)

supplemental 10No e“a~ted appmpmbons, .SUhnZd Ud3f Contlnulw ‘emiutmn

$ Formerly a part of the Neurology Institute

SOURCE National Institutes of Health

Total

6,415

6,652

7,392

6,184

10,813

11,051

14,502

28,075

32,932

49,902

75,037

110,000

118,506

154,139

172,602

181,311

209,898

224,486

138,806

141,390

148,469

132,322

145,325

148,795

126,253

120,274

87,915

108,551

114,904

121,919

145,936
—

Chapter 6

The National Cancer Institute
Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Cancer Mortality and Incidence . . . . . . . . . . . 58

Reducing Cancer’s Impact . . . . . . . . . . . . . . . . 60

Yardsticks for Measuring the Successor

Cancer Research . . . . . . . . . . . . . . . . . . . . 61

Increases in Knowledge . . . . . . . . . . . . . . . . 61

Reduced Mortality From Some Cancers . . 62

Changes in Cancer Incidence . . . . . . . . . . . . 63

Changes in Survival . . . . . . . . . . . . . . . . . . . 64

Technology Transfer Activities. . . . . . . . . . . . 68

Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . 68

Centers Program . . . . . . . . . . . . . . . . . . . . . . 71

The Cancer Control Program . . . . . . . . . . . 73

Goals of the NCI Cancer Control Program 76

Community Outreach and

Rehabilitation Branch Activities . . . . . . . 76

Prevention Programs . . . . . . . . . . . . . . . . . . . . 79

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Addendum A: Growth of the National

Cancer Institute After Passage of

the National Cancer Act . . . . . . . . . . . . . 82

Research Support From NCI Since

Passage of the National Cancer Act . . . . 84

NCI Support of Basic Research . . . . . . . . . . 84

NCI Staffing . . . . . . . . . . . . . . . . . . . . . . . . . 86

Addendum B: Questions Posed to Experts

by OTA Staff . . . . . . . . . . . . . . . . . . . . . . 88

Addendum C: Experts Contacted by OTA . . 88

Addendum D: Guidelines for Recognition

of a Cancer Center as Comprehensive . . 89

National and Local Support . . . . . . . . . . . . 89

Research Activities . . . . . . . . . . . . . . . . . . . . 89

Cancer Control Activities . . . . . . . . . . . . . . 90

Training, Education, and Information

Dissemination . . . . . . . . . . . . . . . . . . . . . . 90

Administration . . . . . . . . . . . . . . . . . . . . . . . 90

Geographic Impact . . . . . . . . . . . . . . . . . . . . 90

List of Tables

Table No. Page

14. Estimated New Cancer Cases and

Deaths by Sex for Major Sites, 1981. . . . 57

15.

16.

17,

18.

19.

20.

21.

22.

23.

24.

25.

Death Rates per 1,000 Females, 1935

and 1975. . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Distribution of Commission on Cancer

of the American College of SurgeonsApprovedHospital Cancer Programs

According to the Size of Community

Hospitals in the United States. . . . . . . . . . 65

Five-Year Estimated Survival Rates

After Treatment of Cancer in

Community, University, Veterans

Administration and Military Hospitals,

and Childrens Hospitals. . . . . . . . . . . . . . 65

Comparison of Five-Year Relative

Survival Rates From NCI Studies in

1960-63 and 1970-73. . . . . . . . . . . . . . . . . . 66

Cancer Centers. . . . . . . . . . . . . . . . . . . . . . 72

Authorized, Requested, and

Appropriated Budgets of NCI, Fiscal

Years 1972-81 . . . . . . . . . . . . . . . . . . . . . . . 82

Requested and Appropriated Budgets of

NCI, as Percentages of the Authorized

Budget, Fiscal Years 1972-81. . . . . . . . . . . 83

Annual Percentage Increase in the NCI

Appropriation Compared to Increase in

the Consumer Price Index, 1972-81. . . . . 83

NCI Regular Grant Awards—1974-80. . . 85

Basic and Applied Research and

Development Spending at NCI . . . . . . . . . 86

Comparison of the Increases in NCI

Funding and Changes in the Number of

NCI Personnel Fiscal Years 1971-80. . . . 87

List of Figures

Figure No. Page

3.

4.

5.

6.

Changes in the Percentage of People

Living to Specified Ages, 1900 and 1980. ..63

Authorized, Requested, and

Appropriated Budgets of NCI,

Fiscal Years 1972-81. . . . . . . . . . . . . . . . . . . 82

Requested and Appropriated Budgets of

NCI, as Percentages of the Authorized

Budget, Fiscal Years 1972-81. . . . . . . . . . . . 83

NCI Regular Grant Awards,

Fiscal Years 1974-80.,,.. . . . . . . . . . . . . . . 86
Chapter 6

The National Cancer Institute

INTRODUCTION

In 1979, cancer killed more than 400,00 0

Americans (47) and 815,000 new serious cancers

were diagnosed (1) (see table 14). Over 3 million

Americans alive today have had a diagnosed

cancer. Cancer accounts for about 20 percent of

total U.S. mortality, second only to heart diseases, which are responsible for about 38 percent

of deaths.

Cancer has a major impact on the Nation’s

economy, both from the personal costs of treatment and lost income, and from public expenditures for screening programs, public education,

and cancer research. In 1977, the most recent

year for which information is available, direct

costs for all cancers, including hospital care and

physicians’ services, amounted to about 7 percent of these costs for all illness (33). Indirect

costs, based on a lost earnings approach (discounted at 6 percent), amounted to approximately 19 percent of total indirect costs (33),

The fiscal year 1982 budget for the National

Cancer Institute (NCI) is $986 million.

The costs of cancer are not exclusively economic. Social costs have taken on increasing

prominence in recent years, and include more

than the obvious pain and suffering of the victim, Relatives and friends of victims and caregivers may suffer direct consequences of the victim’s morbidity and mortality. Social isolation,

economic dependence, lost personal and business opportunities, and many undesirable alterations in lifestyle are inevitable. Serious emotional and psychological problems requiring

professional attention are not uncommon

among victims and their family members, often

producing irreversible changes in family structure and relationships.

A common measure of disease impact is the

number of years of life lost due to premature

mortality. This index takes into account both

the number of deaths and the age at which people die. Therefore, the death of a younger person

will contribute more person-years lost than will

the death of a person who is closer to having

Table 14.—Estimated New Cancer Cases and Deaths by Sex for Major Sites, 1981

Females Males

Total cases Total deaths Cases Deaths Cases Deaths

Percent Percent Percent Percent Percent Percent

Site Number of total Number of total Number of total Number of total Number of total Number of total

Lung . . . . . . . . . 122,000 15.0 105,000 25.0 34,000 8.3 28,000 14.5 88,000 21.8 77,000

Colon-rectum. .120,000 14.7 54,900

33.8

13.1 62,000 15.0 28,700 14.9 58,000

Breast. . . . . . . . 110,900

14.4 26,200

13.6 37,100 8.8

11.5

110,000 26.7 36,800 19.1 900 0.2 300

Prostate . . . . . . 70,000 8.6

0.1

22,700 5.4 — 70,000

Uterus. . . . . . . . 54,000a 6.6

— — 17,4 22,700

54,000 –

10.0

10,300 2.5 13.1 10,300 5.4

Urinary . . . . . . . 54,600

— —

6.7

—

18,700 4.5 16,600

—

Oral (buccal

4.0 6,500 3.4 38,000 9.4 12,200 5.4

cavity and

pharynx) . . . . 26,600 3.3 9,150 2.2 8,200 2.0 2,850 1.5 18,400 4.6 6,300

Pancreas . . . . . 24,200 3.0 22,000 5.2

2.8

11,500 2.8 10,500 5.5 12,700 3.2

Leukemia . . . . . 23,400 2.9

11,500 5.1

15,900 3.8 10,400 2.5 7,000 3.6 13,000

Ovary . . . . . . . . 18,000 2.2

3.2 8,900 3.9

11,400 2.7 18,000 4.4 11,400

Skin . . . . . . . . .

5.9

14,300b

—

1.8 6,700

—

1.6 7,300

— —

1.8 2,700 1.4 7,000 1.7

All others . . . . . 177,000 21.7

4,000 1,8

106,150 25.3 80,000 19.4 47,750 24.8 97,000 24.1 58,400 25.7

Total . ......815,000 420,000 412,000 192,500 403,000 227,500

a

lnvaslve cancer only.

bMelanoma only.

NOTE. Estimates of new cancer cases and deaths are offered as a rough guide and should not be regarded as definitive

SOURCE. Office of Technology Assessment, 1981 from American Cancer Society data,

57

91-496 0 - 82 - 5
58

lived to full life expectancy. Cancer accounted

for approximately 19 percent of all deaths in

1975, and about 16 percent of all years of life

lost (104), indicating that the average age of

those who die from cancer is greater than the

average age of those who die from the aggregate

of all other causes of death.

The importance of cancer in U.S. policies

about disease is illustrated by the attention

focused on cancer research. NCI, established in

1937, was the first institute of the U.S. Public

Health Service to be devoted to a single disease.

Initially a freestanding institute, it was incorporated into the National Institutes of Health

(NIH) which was organized in the 1940’s. In

1971, 34 years after NCI’s establishment, an intensive effort was mounted in Congress to separate NCI from NIH and to establish a National

Cancer Authority.

While the National Cancer Act of 1971 was

unsuccessful in establishing a new authority, it

elevated NCI to bureau status, a higher organizational level than any other institute at NIH until the National Heart, Lung, and Blood Institute

(NHLBI) was also made a bureau. The act also

resulted in remarkable growth at NCI (see addendum A).

This chapter was developed by a review of

selected literature and through a number of telephone interviews of experts. The questions that

were mailed to the experts and a list of the addressees are included as addenda B and C. OTA

staff talked with 22 individuals on the list and to

another group of about 15 experts who were

suggested by those on the list.

Throughout this chapter, attribution to

named individuals refers only to published

papers or quotes from news sources. Information obtained during conversations with experts

is so identified, but no specific attributions are

made. Care has been taken to make plain those

cases in which an opinion was heard from more

than one person as opposed to only one person.

CANCER MORTALITY AND INCIDENCE

Nationwide mortality data are used to answer

questions about the number of deaths caused by

cancer in the United States. Without doubt, the

number of Americans dying from cancer has increased during the last century. Paradoxically, a

major part of this increase has resulted from improvements in public health and medical care. In

years past, infectious diseases killed large numbers of people in infancy and during childhood.

Now that advances in health care have softened

the impact of those diseases, many more people

live to old ages when cancer causes significant

mortality.

Deaths from cancer are not evenly distributed

among all body sites; the lung, colon, and breast

account for over 40 percent of the total (see table

14). Discussion of cancer rates at particular

body sites is more revealing than discussion of

overall trends which mask changes at individual

sites. Moreover, some cancer-causing substances

act at specific sites, and more information about

opportunities for prevention is obtained from

the analysis of trends at particular sites. Likewise, survival rates and improvements in treatment vary at different anatomical sites.

The trend that has dominated all others over

the past 50 years is the increase in lung cancer

mortality, largely a result of the widespread

adoption of cigarette smoking earlier in this century. Male lung cancer rates have been rising

steadily for at least half a century. Female lung

cancer rates started to rise about 25 years ago

and are now increasing rapidly. All other

changes are small in comparison with the large

increases in smoking-related cancers, although

the decreases in cancer of the stomach and

uterus are also important.

Currently, there is a general tendency for the

rates of change at each cancer site to be slightly

more favorable for people under 65 than for

those over 65: If the site-specific rate for all ages

is increasing, it is increasing at a slower pace

among the younger group; if the rate is decreasing, the decrease is more pronounced in those

under 65. Two clear exceptions stand out. First,
59

skin cancer is increasing much more rapidly

among males under 65 than among those over

65. Second, mortality rates of brain tumors appear to be moving in opposite directions; despite

falling death rates in middle age, there are large

increases in old age, perhaps because of better

diagnosis for older people which improves the

efficiency of case reporting.

If attention is restricted to those younger than

65, for almost all types of cancer except those

strongly affected by smoking (cancers of the respiratory and upper digestive tracts), the most recent trends in mortality are downward. The

chief exceptions are pancreatic cancer in women,

and melanoma in whites of both sexes.

Incidence rates differ from mortality rates because not all people who contract cancer die of

it. Rates are calculated by relating the number of

cases or deaths to the “population at risk” of

either contracting cancer or dying from the disease. “Crude rates” are the total number of cases

or deaths divided by the total population. Crude

rates are affected by changes in the age structure

of the population, i.e., the fact that there are

more older people in the population today, and

hence more people contracting and dying of

cancer, means that the crude rates will increase.

All of the overall comparisons in this report are

based on rates “age-standardized” to the composition of the population determined in the

1970 census. Changes in these rates occur because of changes in the risk of cancer among

people of a given age; increases or decreases in

the proportion of old people in the population

do not affect age-standardized rates. When a figure or comparison refers to a specific age class,

the rates are based on the cases or deaths as a

proportion of the total number of people in that

class.

Apart from whether or not cancer rates are

changing, many variables contribute to the

greater prominence accorded the disease today

as compared to even a few decades ago. A major

factor in its emergence is the sharp decrease in

deaths from infectious diseases such as tuberculosis, dysentery, and diphtheria over the past

100 years. Before the mid-19th century, these

diseases killed far more people than did chronic

diseases. General improvements in living conditions, public sanitation, and nutrition began to

reduce the rates of infectious diseases, and the

decline was hastened by advances in biology and

medicine early in the 20th century.

As the decades passed, these improvements

have shifted the age structure of the population

upward; as a result, there is a larger proportion

of people over 65. Cancer risks have always

been 10 or 100 times greater among older people

than among younger people. The change in age

structure increases the actual number of cases

and deaths (crude incidence and crude mortality) but not necessarily the age-standardized

cancer rates.

Second, cancer has become relatively more

common as a cause of death because of the prevention or cure of other diseases. This phenomenon is illustrated by the mortality data for

females in 1935 and 1975 (see table 15). Nonrespiratory cancer death rates decreased substantially, but the death rates from all other causes

decreased even more. Therefore, the percentage

of female deaths attributable to nonrespiratory

cancer was greater in 1975 than 40 years earlier,

even though female nonrespiratory cancer

deaths had declined during that period.

Third, many cancers, which might previously

have gone unnoticed or unreported;

Table 15.—Death Rates per 1,000 Females, 1935 and 1975

All causes except All nonrespiratory Respiratory tract

Year cancer cancers cancers All causes

are now

1935

(1933-37) . . . . . 11 .92a (87.6 %)b 1.65 (12.1 %) 0.03 (0.2%) 13,60 (100%)

1975

(1973-77’) . . . . . 4.96 (78.8%) 1.17 (18.6%) 0.16 (2.50/o) 6.29 (100%)

aAll ages, age.standardized to the U S 1970 census Population

b percentage of rate for all causes

SOURCE. Off Ice of Technology Assessment, 1981.
60

diagnosed both during medical treatment and in

death certification. This change is especially pronounced among the elderly who today receive

more medical attention than in premedicare

years.

Finally, cancer is discussed more openly in the

media and among friends and relatives of cancer

patients; public figures no longer try to conceal

their diseases. Previously, such matters were

often hushed up and the diagnosis perhaps withREDUCING CANCER’S IMPACT

There are three approaches to reducing cancer’s impact: prevention, the ultimate goal;

earlier detection; and improved treatment. The

general consensus that most cancers are caused

by extrinsic forces (86) has led to the view that

many cancers are preventable. Estimates of theoretically preventable cancers have reached as

high as 90 percent of the total, though the practical limits undoubtedly will be lower.

Once identified, exposures to carcinogens

may be reduced either through voluntary or regulatory methods. There has been one notable

success among efforts to influence personal behavior—the reduction in cigarette smoking

among adults. The decrease is most notable

among adult males, and can confidently be attributed to the publicity and attention given to

adverse health effects of tobacco. Between 1965

and 1979, the proportion of adult male smokers

dropped from 51 to 37 percent. The decline

among women over the same period was much

smaller, from 33 to 28 percent,

Antismoking efforts on the part of NCI and

other organizations, notably the American Cancer Society, are considered partially successful.

However, many people still smoke and smoking

initiation rates may still be rising in teenage girls.

A number of the people OTA spoke with, in

basic and applied research and administration,

expressed the opinion that, because this is one

area in which there is virtually no serious

disagreement about the cause of a major cancer,

continued smoking is the greatest failure in

cancer control.

held even from the victim. The jump in the reported incidence of breast cancer in 1974 and

1975 is attributed to the publicity surrounding

Happy Rockefeller’s and Betty Ford’s breast cancer surgery. Greater public awareness led to

more women being examined, the detection of

more cancers, and more accurate reporting, but

the reported increase in those years is not considered to reflect a real increase in incidence.

It is generally believed that American eating

habits are healthier than they were early in this

century and that some of the changes, though

not specifically identified, have spurred the decrease in stomach cancer rates. Future cancer-reducing changes in dietary habits may result from

research into mechanisms by which dietary components cause or prevent cancers, or from epidemiologic observations of associations between

dietary components and cancers.

In the last year, NCI approved its first largescale “chemoprevention trial, ” from the Division

of Resources, Centers, and Community Activities (DRCCA), based on the hypothesis that

beta-carotene, the precursor of vitamin A,

reduces cancer rates for at least some sites. The

study is being funded jointly by NCI and

NHLBI, and will also test the effects of aspirin as

a prophylaxis for heart disease.

Early detection of cancers may improve overall survival rates when efficacious treatment is

available. Localized cancers detected before they

metastasize can be excised completely, leaving

the patient with an excellent chance for survival.

The proportion of cancers detected at “early” v.

“late” stages has increased over time. For example, between the early 1950’s and the late 1960’s,

the proportion of prostate cancers diagnosed as

“localized” increased from 48 to 63 percent.

Over that period, the 5-year relative survival for

prostate cancer climbed from 43 to 57 percent.

The overall relative survival rate is the ratio of

the observed survival rate of the treated group

to the expected survival rate for persons of the
61

same age, sex, and race in the general population. Three elements may contribute to the apparent improvement. Part of the improvement

may be artifactual and result from detecting and

reporting less serious tumors in the late 1960’s,

that, had they occurred in the early 1950’s,

would not have been reported. Some of the improvement probably resulted from better treatment. However, a major component of the gain

resulted from detection of tumors at earlier

stages, when they could be more successfully

treated (61). The same pattern has occurred in

some, though not all, body sites.

Surgery, radiation therapy, and chemotherapy are the mainstays of cancer treatment.

There have been advances in all three areas.

Refinements have been made in surgery and in

radiation therapy as technologies have improved. There have been no quantum leaps in

surgery and radiation therapy at least since the

1950’s. This is not necessarily a criticism of NCI,

but a sign that perhaps, particularly for surgery,

there are diminishing returns in efforts to improve survival. In particular, disseminated cancers cannot be treated by excision of all tumor

cells. Improved surgical procedures generally

emphasize doing less surgery with no loss of survival benefit, a move toward improved quality

of cancer treatment.

Some “quantum leaps” have been made in

chemotherapy, and in terms of treatment, this

area still holds the greatest potential, particularly in integrating chemotherapy, surgery, and

radiation into better treatment regimens.

Chemotherapy has had a major impact on

Hodgkins and non-Hodgkins lymphomas, childhood leukemias, testicular cancers, and osteogenic sarcoma, and choriocarcinoma. There is

evidence that, in coming years, survival for certain groups of breast cancer patients may be improved by the use of postsurgery chemotherapy.

Presently, NCI (19) estimates that 46,000 patients yearly are helped by chemotherapy. Scientifically and medically, the successes represent

promising advances. With longer followup periods, more studies might indicate substantial

gains. However, because many people who receive the drugs (which are often accompanied by

undesirable side effects) experience no substantial gain in life expectancy, concern about the

use of chemotherapy has developed in some

parts of the medical profession and in the minds

of the public.

YARDSTICKS FOR MEASURING THE SUCCESS

OF CANCER RESEARCH

The Cancer Control Program at NCI is mandated by the National Cancer Act (69). In addition to that program, the Cancer Centers Program and clinical trials of treatment regimens

promote and facilitate technology transfer. The

basic requirement of any technology transfer

program is a scientific base of knowledge.

NCI research is directed at increasing knowledge about cancer; development, demonstration, and transfer activities, dependent on

research, are aimed at reducing incidence and

mortality.

Increases in Knowledge

In 1973, an Institute of Medicine (IOM) committee (44) suggested that the following avenues

of research were likely to be fruitful in the years

ahead: “DNA replication, the cell cycle, regulation of transcription, regulation of membrane

assembly and function, cell differentiation, regulation of protein synthesis, and all aspects of

cellular immunity. ”

The next paragraph cautioned, however, “The

list should be regarded as flexible, subject to additions or changes depending on the progress of

cancer biology itself. ”

Nine years later, in 1982, a number of experts

contacted by OTA suggested areas of research

most likely to yield important results. Often

mentioned were recombinant DNA research,

hybridomas and monoclonal antibodies, and

better methods for risk assessment. None of
62

these were listed by the IOM committee. Although the basic discoveries about recombinant

DNA were published in 1971, their impact had

not been fully appreciated in early 1973; hybridomas were simply unknown; monoclinal antibodies a hypothesis. Risk assessment was little

discussed and of little perceived importance.

A decade ago, understanding of the possible

mechanisms by which genes regulate and control

cells and how cells synthesize gene products was

based on elegant experiments in bacteria and the

viruses that infect them. The last 10 years have

seen that some of those ideas have much less application to human cells than was expected. Although some scientists have claimed that they

had inklings of the extraordinary differences between production of gene products in bacteria

and mammals, those claims are dismissed. The

new ideas about mammalian cells were forced

on scientists by experimental results. At the

same time, without the bacterial models as a

baseline, little progress would have been made

in understanding mammalian cells. Several experts who talked with OTA emphasized the importance of NCI’S support of basic research,

both intramural and extramural, in these

discoveries.

These examples illustrate the impossibility of

predicting the direction, results, and applicability of basic research. Basic knowledge about

mechanisms important in cancer and in biology

in general has increased greatly in the last

decade, but the productive approaches of the

last 10 years may not be the only ones to pay off

in the years ahead.

There is no yardstick to hold up to basic

research progress that is similar to the actuarial

measurements of cancer incidence and mortality

that are discussed below. The awards of Nobel

Prizes and other trophies are in recognition of

excellence, but they may come soon after or

much after the important discoveries and they

reward only a fraction of outstanding basic

research. Scientists often describe progress in

their own fields, but they face a difficult problem in conveying their excitement and approbation to more lay audiences. Experimental technicalities, laboratory jargon, arcane mathematical

measures, immersion in a sea of details interfere

with the expert’s communication to others not so

expert. (A refreshing contrast to those difficultto-understand measures is provided by Lederberg (41). Even without these problems, some

scientific concepts are difficult to understand.

For many people, the most convincing evidence

of the importance of basic biological research

has been the formation of genetic engineering

companies with large amounts of capital provided by financial organizations that have made

a great deal of money in the past.

A measure of progress in basic research more

directly related to cancer are the reports of experts who teach courses about cancer. The content of those courses has changed dramatically

during the last decade. Such teachers rely on articles in recent scientific publications. Neither

last year’s notes nor textbooks are sufficiently

current,

Reduced Mortality From Some Cancers

The ultimate desired effect of health research

and development programs is longer lives and

more disease-free years. Extending maximum

human lifespans by many years seems unlikely,

but extension of more people’s lifespans to the

biological limit seems attainable. The idea that

humans’ lifespans are fixed by some biological

clock is discussed by Fries (22) and Fries and

Crapo (23). Very, very few people live to ages

much greater than 100; the percentage of centenarians in England’s population has not increased since 1837 despite great changes in average life expectancy. Disappointingly, reports of

people living to very great ages, 110 or more, are

largely from less developed countries. T h e

number of those reports varies directly with the

illiteracy rate, and it is reasonable to conclude

that these reports are the product of faulty recordkeeping.

Fries and his colleagues find that while there

has been little change in the maximum expected

lifespan, more and more people are living to or

almost to what appears to be a maximum expected age (see fig. 3). The maximum expected

age seems to be about 85, with a distribution of

people dying within a few years of that age.
63

Figure 3.—Changes in the Percentage of People

Living to Specified Ages, 1900 and 1980

100

25

0

o 10 20 30 40 50 60 70 80 90 100

Age

The increasingly rectangular survival curve

About 80 percent ( ) of the difference between the 1900 curve

and the ideal curve ( ) had been eliminated by 1980. Trauma is

now the dominant cause of death in early life.

SOURCE: Fries, 1980.

Cancer accounts for about 20 percent of U.S.

mortality (86). Despite that large percentage,

eliminating cancer as a cause of death would

have only a small effect on the average U.S.

lifespan, because cancer is largely a disease

of advanced age. About 90 percent of cancer

deaths occur in persons over 65. While average

life expectancy might be little affected by

preventing cancer deaths, preventing cancer at

whatever age improves the quality of life.

OTA’S Assessment of Technologies for Determining Cancer Risks From the Environment

(86) and Doll and Peto (20) discuss mortality

rates from cancer. Significant decreases have

been seen in mortality from some types of

cancer—stomach, uterine cervix, lung cancer in

men younger than so during the last two decades, and Hodgkin’s disease, other lymphomas,

and some childhood cancers.

The causes of the declines in the first two remain largely matters of speculation. Higher

standards of living, more varied diets, and better

food preservation techniques have been associated with decreases in stomach cancer mortality,

which became noticeable in the 1930’s and have

continued. The downward trend in uterine cancer mortality over the past 50 years is a major

factor contributing to the steady decrease in

death rates from nonrespiratory cancers in

females. Again, the causes are not clear, but improved personal hygiene associated with higher

standards of living may be involved in the

decrease. Decreases in uterine cancer mortality

preceded the development and widespread introduction of cervical cytology screening for

the disease by at least 25 years. The importance

of the screens in the continuing decline is difficult to assess. In the case of stomach and

uterine cancers, for poorly understood reasons,

there have been decreases in incidence that are

translated directly into decreased mortality.

The observed decreases in lung cancer incidence and mortality in young men are directly

related to changes in smoking. Hodgkin’s disease, other lymphomas, and some childhood

cancers differ from the others; mortality from

them has decreased because of better treatment

and increased survival rates.

The examples of declining mortality from

these cancers illustrate the two types of intervention that can reduce cancer mortality: reducing

cancer incidence and improving treatment. The

National Cancer Program Plan recognized the

preferability of reducing incidence. Four of the

seven objectives of the Plan focus on cancer

cause and prevention (69).

Changes in Cancer Incidence

Recent years have seen much progress in identifying environmental agents and personal behaviors that are associated with higher cancer

risks. A thorough examination of epidemiologic

studies of the occurrence of cancer in the United

States (20,86) reaffirms the impression of many

experts that, to a major extent, we have only

clues about what causes cancer. The few positive

exceptions, in which causes are clearly identified, are relatively well known—smoking, exposure to asbestos, radiation, sunlight, some chemicals, and some drugs. More typical of our level

of knowledge is the case of food. Through various methods, a number of different estimates

have been made that suggest that as much as 50

percent of all cancer is associated with elements
64

in the diet. This observation provides a tantalizing lead for further study, but so far few specifics are known (20, 71,86). Finally, there are some

cancers for which there are still no hypotheses

about their causes.

As more specific knowledge is obtained and

prevention activities are increased, measurements of their success in the general population

will depend on obtaining reliable incidence data.

Each new case of cancer, whether it is subsequently cured or results in death, is recorded in

incidence data; mortality data record only

deaths. As is described elsewhere (20,86), mortality data have been collected on a nationwide

basis since 1933. No nationwide incidence data

are collected. The NCI Surveillance, Epidemiology, and End Results (SEER) program now

collects incidence data on about 10 percent of

the U.S. population (see below).

Incidence data have been used in the recent

past, 1980 and 1981, to support arguments that

cancer is rapidly increasing in the U.S. population (112). The most recent summation of SEER

data, released to the press in late 1981, does not

support the idea of rapid increases in cancer occurrence at any major sites except lung.

Prevention, which precludes illness and the

rigors associated with treatment, is highly desirable in cancer. Measuring the effects of prevention programs will require accurate, comparable

incidence data collected from (probably) large

segments of the population.

Changes in Survival

The third actuarial measure of success for the

National Cancer Program are improvements in

treating cancer as measured by more people surviving the disease. This measure, generally expressed as the percentage of newly diagnosed patients surviving years after treatment, after adjustment for “normal” life expectancy, is called

“5-year survival rates.” These data have taken

on more importance with recent announcements

of treatment success from NCI. The most recent

report from NCI (19) depends on incidence data

collected by the SEER program.

One of the seven objectives of the National

Cancer Program (16,44,69) was directed at treatment. As this chapter discusses, and is commonly agreed, NCI has emphasized treatment and

curing cancers. To a major extent, this emphasis

is understandable, because it offers opportunities to help people in need of care now. At the

time of the National Cancer Program Plan’s development, therapeutic advances were in hand

and more were expected (28,64). Exploitation of

those advances is certainly justified, but questions are raised about the balance being struck

between treatment research activities and other

research activities at NCI. An additional, tiger

by the tail, reason for the emphasis on treatment

is congressional pressure. As NCI lauds its treatment advances, the public, through Congress,

demands access to them. In response, NCI bends

more effort to treatment research and cancer

control.

Cancer Treatment and Curing Cancer

At the time the National Cancer Act was being considered in 1970, the National Panel of

Consultants on the Conquest of Cancer reported

(28, quoted in 66).

The cure rate for cancer is gradually improving. In 1930 we were able to cure only about 1

case in 5; today we cure 1 case in 3; and it is estimated that the cure rate could be brought close

to 1 case in 2 by a better application of knowledge which exists today, i.e., detection at an

earlier stage through the more widespread use

of existing techniques (such as the Papanicolaou

test for women and mammography), coupled

with an extension to all citizens of the same

quality of diagnosis and treatment now

available at the best treatment centers.

The last part of this quote touches directly on

cancer control, which includes efforts to move

the best treatment from specialized centers to all

citizens. Increased survival rates are the expected results from such efforts, and, in fact, by

all measures, survival has increased, albeit not

so much as expected in 1970.

Some of the reported improvements in cancer

treatment survival have stemmed from general

improvements in radiotherapy and surgery in
65

the post-World War II years. Improved radiotherapy and surgical techniques, better aseptic

procedures, antibiotics, and better postoperative

and supportive care have contributed to the improving cure rates.

Beginning somewhat later, and well underway

by the late 1960’s, chemotherapy has brought

significant improvements to the treatment of

some cancers. From a compassionate standpoint, these improvements, which were and are

especially pronounced in the treatment of childhood cancers, are gratifying.

The triad of cancer treatments is completed by

radiation therapy. A recent survey (108) shows

that the presence of a radiation therapy unit is

the second most important factor (after having

an American College of Surgeons-approved program) in determining the number of cancer cases

treated by a hospital.

The most encouraging projection about cure

rates has been made by the NCI Director (19).

From examination of data collected through the

SEER program, he concludes that during the

period 1975 to 1979, 46 percent of diagnosed

cancers among whites and 45 percent among all

races were “cur able.” A “more optimistic

calculation from the same data results in a 5 0

percent 5-year survival for white patients and 49

percent for all races. ” To date, the cure rate for

specific sites has not been published. Furthermore, this is the first calculation of survival rates

using SEER data, and the reported rates may not

be directly comparable to data collected earlier

under other systems.

The American College of Surgeons has collected information about cancer cure in community hospitals. Upon presentation of appropriate information about a hospital’s cancer

treatment program, the American College of

Surgeons will approve the program, Approved

programs are found more frequently in larger

hospitals: 14 percent of all acute-care hospitals

have approved programs, and those contain 32

percent of hospital beds (see table 16). The approved hospitals treat a disproportionate number of cancer cases: 60 percent of all newly diagnosed cases are treated in the 14 percent of hospitals with American College of Surgeons-approved programs.

Estimated 5-year survival rates were reported

from four types of hospitals (see table 17), The

rates for community and university hospitals are

quite similar; lung cancer remains intractable to

treatment, and its higher frequency in the Veterans Administration (VA) and military hospitals

Table 16.—Distribution of Commission on Cancer

of the American College of Surgeons-Approved

Hospital Cancer Programs According to the Size of

Community Hospitals in the United States

Number of Number of

hospitals in approved cancer

Bed size of hospital United States programs

501 and over . . . . . . . 385 216 (560/o)

301-500 . . . . . . . . . . . 717 317 (44%)

101-300 . . . . . . . . . . . 2,152 359 (16°/0)

Under 100 . . . . . . . . . 3,285 51 (>1%)

Totals . . . . . . . . . . 6,539 943 (14%)

SOURCE. Smart, 1981

Table 17.—Five-Year Estimated Survival Rates After Treatment of Cancer

in Community, University, Veterans Administration and Military Hospitals,

and Children’s Hospitals

Community University VA and military Childrens

Number of hospitals 555 (840/o) 28 (4°/0) 67 (100%) 9 (2%)

Number of cancers 1,420,213 (820/o) 196,483 (11 0

/0) 114,639 (7°/0) 14,292 (1 0

/0)

5-year estimated

survival 370/0 360/o 30 ”/0 45%

Most frequent Breast Lung Lung Leukemia

cancer sites: Lung Breast Head and neck CNS

Colorectal Cervix Prostate Soft tissue

Prostate Colorectal Colorectal Bone

Cervix Lymphoma Bladder Kidney

SOURCE: Smart. 1981.
—

66

contributes to the lower survival rates in those

institutions.

Overall survival rates from “cancer,” which

includes about 100 different diseases, are not so

informative as rates from particular cancers.

Smart (108) has compared 5-year survival rates

found in whites by NCI in 1965-69 to those

found in the American College of Surgeons’

survey over the period 1973-79 (see table 18).

Improvements are reported for each cancer.

Smart cautions against too detailed comparisons

between the two sets of data, because the data

were collected using different systems during the

two time periods. A more meaningful comparison can be drawn by examining survival data

collected in a standard method by NCI during

two different time periods. Inspection of those

data (table 18) show improvements in survival

from cancer at almost every site, in both races

and sexes. Survival for Hodgkin’s disease and

acute lymphocytic leukemia have shown the

greatest improvements, and stomach, pancreas,

and lung the least. Further improvements can be

expected when details of more recent data collected by the SEER program are published.

A decade after the estimate that 50 percent of

cancers might be curable, the 5-year survival

rate remains below that figure in the American

Table 18.-Comparison of Five-Year Relative Survival Rates From

NCI Studies in 1960-63 and 1970-73

White White Black Black

males females males females

1960- 1970- 1960- 1970- 1960- 1970- 1960- 1970-

Cancer site 1963 1973 1963 1973 1963 1973 1963 1973

Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . 10 12 13 14 5 15 14 10

Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 47 44 50 32 36 35 38

Rectum . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 43 41 48 28 20 27 40

Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 2 2 0 0 3 3

Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 9 11 14 5 6 6 10

Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . 51 62 68 75 ● ● ● ●

Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 63 68 — — 46 51

Uterine cervix. . . . . . . . . . . . . . . . . . . . . — — 58 64 — — 47 61

Uterine corpus . . . . . . . . . . . . . . . . . . . . . — — 73 81 — — 31 44

Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . — — 32 36 — — 32 32

Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . 50 63 — — 35 55 — —

Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 61 53 60 24 38 24 27

Hodgkin’s disease . . . . . . . . . . . . . . . . . . 34 66 48 69 ● ● ● ●

Acute lymphocytic leukemia . . . . . . . . . 4 27 3 29 ● ● ● ●

“ Number of patients too small to yield reliable rates

SOURCE: National Cancer Institute, 1981
67

College of Surgeons’ study (108). In fact, the one

in three cure rate estimated in 1970 is close to

that seen today in that review. NCI’S own estimate of cure rates is higher, 46 to 50 percent,

and it approaches the goal of curing one case in

two. It is likely that more cancers will be cured

as improvements move from NCI to the community. Importantly, of course, within the limits of the improvements that have been made,

lives have been spared and the side effects of

treatment have been reduced. NCI has contributed to these important advances.

Several experts contacted by OTA suggested

that adjuvant chemotherapy (drugs used in association with other treatments) has already contributed to improved cure rates, and more improvements are expected. Not unexpectedly, experts with a background in clinical research and

applications expressed enthusiasm for curative

changes and urged continued emphasis on clinical research. Other people caution that some of

the reported improvements may be artifactual

because of changes in reporting methods and

that additional incremental improvements may

be small.

The proper balance between treatment research and other research efforts is continuously

debated. Whatever the proper balance, the impression left by the following sentence in the

1981 Director’s Report (68) suggests that it has

not yet been struck: “Mortality results not only

from failure to treat adequately but also from

failure to prevent disease. ” Many observers

would order the failures differently,

Surveillance, Epidemiology, and

End Results Program

Measurements of cancer incidence and survival rates depend on data collected by the SEER

program. SEER is the first nationally coordinated, continuous, population-based incidence

registration system and was begun in 1973 by

NCI. SEER is, in part, an expanded sequel to the

successful End Results Program.

In SEER areas, attempts are made to ascertain

every primary cancer, excluding nonmelanoma

skin cancer. All information pertaining to a case

is consolidated into one record to facilitate followup and to correlate survival data with treatment, age, and other variables.

SEER program data are collected from about

10 percent of the total population, but the geographical regions covered by the SEER program

do not closely represent the demographic makeup of the entire country. A SEER report for the

first 4 years of operation compared the demographic characteristics of the population with

the total U.S. population (65):

. . . the participants . . . are fairly representative with respect to age. Blacks are somewhat

underrepresented, while other nonwhite populations (Chinese, Japanese, Hawaiians, and

American Indians) are somewhat overrepresented. Rural populations (especially rural

blacks) are also underrepresented.

The current SEER program costs about $10

million annually out of the total NCI budget of

about $1 billion. Expanding the program to collect more representative data and to validate

data more thoroughly would cost more money

and would also require cooperation of additional local medical organizations to establish

new SEER data collection areas. Balanced

against these costs are opportunities to gather incidence and survival data representative of the

whole country and to learn more about cancer in

the U.S. population.

The two basic SEER program functions—collecting data on incidence and on mortality— are

complementary, and baselines have been established for both measures. However, because the

system is so young at this time, little can be said

about trends in either.

The SEER program plays another important

role in providing information on cancer cases to

be used in epidemiologic case-control studies.

The purpose of such studies is generally the identification of possible causative factors for a particular type of cancer. The largest cancer casecontrol study undertaken by the Federal Government, a study of about 3,000 of bladder cancer uses, relies on cases identified by SEER. Data
68

from the bladder cancer study are still being ana- bling the cases would have been more difficult

lyzed, but already the analysis has produced in- and expensive if any other method had been

formation of great value to cancer researchers used for case-finding.

involved in primary cancer prevention. AssemTECHNOLOGY TRANSFER ACTIVITIES

Clinical Trials

Clinical trials in cancer research have been

used mainly for testing anticancer drugs at varying dose levels and in various combinations.

Multimodality studies, testing combinations of

surgery, radiation therapy, and chemotherapy

are also evaluated in clinical trials. Additionally,

clinical trials have an important role in technology transfer; they demonstrate the usefulness of

treatment regimens, and, increasingly, they involve community physicians in clinical research.

In cancer, perhaps more so than in other diseases, the results of chemotherapy are extremely

variable. Patients with cancers at each stage—

local, regional or advanced—of the approximately 100 types of cancer may react quite differently. This means that large numbers of patients are needed to get meaningful results in a

treatment trial. A test of a promising therapy

might require several hundred patients, which

might require 2 to 4 years of recruitment, even

with multi-institution cooperation. At least 4 to

5 years of followup are necessary before a reasonable evaluation can be made. Unfortunately,

nothing can be done at this time to change those

numbers. The nature of the disease, the state of

the art of treatment, and statistical probability

dictate the limits.

A trial as described above represents a large

investment of money, and it does not promise

any fast answers. A number of people expressed

to OTA the notion that NCI has felt pressure to

produce results in a short time and, perhaps as a

result of that, some clinical trials funded either

directly or indirectly by NCI are short-term,

with few patients and with little chance of producing reliable results. These generally represent

trials carried out in single institutions. Multiinstitution trials generally have larger numbers

of patients and go through the formal review

process, and, overall, meet higher standards

than single-institution trials.

In 1979, a subcommittee of the Board of Scientific Counselors of the Division of Cancer

Treatment conducted a review of the large-scale

cancer therapeutic Clinical Trials Program (67).

The subcommittee found that, “While the clinical trials process has been good, the subcommittee is of the opinion that it can be further improved in preparation for the clinical cancer research era of the 1980’ s.” The subcommittee’s review resulted in four major recommendations

(67):

1.

2.

3.

4.

We recommend that a new study section be

established to review individual investigator

initiated clinical cancer research.

In accord with federal guidelines, a cooperative agreement should be negotiated between the Division of Cancer Treatment

(DCT), NCI and the Cooperative Oncology

Groups.

We recommend that funds from the Cancer

Control Program be transferred to DCT for

cooperative group activities in support of

groupwide Phase III protocols. . . . It is essential that the peer review process for award

of Cancer Control funds be the same as that

applied to the groups as a whole.

We recommend that DCT continue and increase its efforts toward information exchange on cancer therapy evaluation, It

should be extended so that it includes more

input and return to participants in clinical

program projects (PO1’S) as well as to the cooperative clinical trials groups. . . . we recommend that additional government positions be created in DCT to permit expansion

of the Cancer Therapy Evaluation Program.

Each of these four recommendations was addressed by DCT in their September 1980 document, “Future Direction in Extramural Clinical

Trials.” The responses to each are summarized

as follows (66):
69

1.

2.

3.

4.

The Division of Research Grants (DRG) set

up a series of ad hoc study sections to review clinical research proposals. At the

time of the response, NCI’S policy was that,

“If the results of this experimental group

study section are satisfactory, a permanent

study section will be considered by DRG.”

According to recent information from

NCI, * “Data accumulated in the course of

four such ad hoc reviews of RO1 applications for support of clinical research projects suggested that these ‘clinically oriented’

review groups disapproved somewhat

more proposals and voted, on the average,

somewhat higher (worse) priority scores

than had been observed when a similar

body of applications were reviewed by the

most appropriate chartered DRG study section. ”

“DCT plans to convert the cooperative

group program (RO1 grants), the Lung

Cancer Study Group (contract), the Gastrointestinal Tumor Study Group (contract), the Brain Tumor Study Group (contract), the Melanoma Tumor Study Group

(contract), the Head and Neck Cance r

Study Group (contract), and the Parenteral

Nutrition contracts, Phase II GI contracts,

Large Bowel contracts, and the Breast contracts to the cooperative agreement mechanism. These conversions will be implemented within the next year . . . . All clinical trials research supported under cooperative agreements will be reviewed by a

single type of review body. ” According to

recent information from NCI, * the plan

currently underway involves the formation

of review branch, “the specific function of

which will be to assess the scientific merit

of applications of this type requesting support of clinical cooperative groups.”

“Plans for redistribution of control moneys

are being actively discussed with the

DRCCA.”

“Expansion of the Cancer Therapy Evaluation Program (CTEP) staff is being evaluated at present. Funding and position constraints will require careful consideration in

*NCI, persona] communication, Mar. 10, 1982.

making decisions regarding CTEP staff

size. ”

The move to convert most clinical trial research to the cooperative agreement mechanism

appears to be the most significant change to

come from this review and DCT response. NCI

is in the process of converting the currently

grant-supported clinical cooperative groups to

the cooperative agreement mechanism, after

which the contract-supported research will be

converted. NCI sees several advantages to this

mechanism, relating basically to increased input

into and control of clinical trials research, The

cooperative agreement mechanism as defined in

the 1977 Federal Grant and Cooperative Agreement Act is appropriate for funding trials, because “the purpose of the relationship is the

same as that of a grant, but the Federal Government anticipates substantial involvement with

the recipient during the course of the activity”

(66).

The main difference for current grantees is

that the terms of the cooperative agreements

award will specify “substantial Government involvement, ” which is absent from grant awards.

For current contractors, the application and

funding process will change, and “scientific and

administrative direction by NCI staff for these

groups will be diminished” (66). Some of the

specific terms of “substantial Government involvement” include increased participation in

protocol design, protocol review, quality control, data management, the right to terminate a

study, and an increased role in investigational

drug management.

NCI states that “both contractors and grantees

should have to make only minimal adjustments

in their current operating procedures” as a result

of the conversion to cooperative agreements,

and that the conversion simply makes formal a

relationship that already exists (66). The conversion has not gone as expeditiously as expected,

however, and agreements may not have been

worked out with all of the cooperative groups.

One of the people with whom OTA spoke expressed concern over increased control by NCI

over clinical research, particularly the provision

that NCI retain the right to terminate a trial.
70

That decision, he said, should be made by the investigators. A number of other points of concern

about clinical trials were expressed by the individuals with whom OTA spoke; these are described in the remainder of this section.

Many cancer clinical trials are carried out in

single institutions with fewer than so patients,

and many are not randomized trials. An added

concern with small single-institution studies is

that there may be insufficient review of the

study protocol or the data analysis. Unless the

institution has a data collection system in place,

data management may be poor, leading to a

poor analysis. These concerns are particularly

directed at trials funded only indirectly by NCI,

for example, through clinical centers, in which

case the study protocol need not have gone

through peer review. Nevertheless, NCI has

direct involvement in most trials, at least in supplying the necessary drugs.

The opinion was expressed about clinical

trials, as about other aspects of NCI-supported

research, that funding reviews occur at too short

intervals. The cooperative groups have been

reviewed every 3 years or so, barely the recruitment period of a medium to large clinical trial.

The quest for results in a short time has not been

reconciled with the nature of the disease, in

which meaningful results can only be measured

over the long term.

It is estimated that between 6,000 and 10,000

clinical trials are currently being carried out

worldwide, most including a small number of

patients. Statistical analysis shows that several

hundred trials that are in truth negative will appear to be positive based on probability alone

(120). It is impossible in these cases to distinguish between a true positive and a false positive. Because clinical trials in cancer have a fairly

low probability of success to begin with, we may

in fact be overwhelmed by false positives, but

there is no way of knowing this. One step that

could be taken to remedy this is to carry out

confirmatory studies for therapies that are positive in one clinical trial, One of the experts with

whom OTA spoke criticized NCI for giving low

priority to funding such studies because they are

considered to be duplicative. In light of the admittedly low payoff of most cancer clinical

trials, and the importance of introducing only

beneficial therapies into practice, this policy

might be reexamined.

NCI has recognized the need for large-scale

trials for many years and has made improvements in facilitating them. Funding of the Cooperative Oncology Groups Outreach Program

was a step forward in getting the community

hospitals involved, and the incipient Community Clinical Oncology Program (CCOP) is

another (see below). However, the problem is

far from solved. At any time, there will undoubtedly be a number of trials going on of

treatment of any given type of cancer “competing” for patients. One NCI official said that NCI

has failed to act toward supporting the truly

high-priority trials. He felt that NCI could be

more intrusive in channeling patients nationwide into such studies. This may not be welcomed by all members of the clinical research

community, however, who feel that grant-supported investigators should be more and not less

free of NCI control.

A shortcoming of some clinical research in

cancer today is the lack of biological basis for

carrying out studies. Often, a clinical trial is just

another combination of existing therapies, or a

new dose level, and the only outcome measured

is the effect on the tumor. This is, of course, the

ultimate measure, and no trial should be conducted if there is no hope of affecting the state of

the cancer. But clinical research can also be used

to learn more about disease processes, the interactions between the rest of the patient’s body

and cancer, and the effects of therapy aside from

anticancer activity. This is an area where several

of the people with whom OTA spoke noted a

lack of communication and coordination between basic and clinical researchers. If much

more were known about the cancer process, and

if treatment were at a more sophisticated stage,

this might not be as important. As it stands,

there is much that can be gained in the more

basic research area through collaborative efforts

with clinical researchers.
71

Centers Program

Since the early 1960’s, NCI has conducted a

Cancer Centers Program to provide grants for

support of multidisciplinary programs in cancer

research at educational and research institutions

in the United States. Enactment of the National

Cancer Act of 1971 marked the beginning of a

period of rapid growth of the Cancer Centers

Program. In addition to an increased number of

centers, there has been a concomitant growth in

their size and complexity, expansion of their

research programs and activities, and augmentation of their professional staffs.

Cancer centers have developed in a number of

different organizational settings: Some are independent, freestanding institutional entities;

other are under the auspices of universities,

often involving several colleges; and still others

are consortia or multi-institutional in nature.

Although a cancer center needs a certain minimum number of research programs for a “critical

mass, ” existing centers vary greatly in size and

breadth of programs—from rather small, specialized centers to large, complex comprehensive

centers. They have developed from existing

areas of strength at the parent institutions into

coordinated multidisciplinary programs of several

1.

2.

3.

In

types (62):

Laboratory Cancer Research Centers

(LCRC)–centers engaged only in labatory research;

Clinical Cancer Research Centers (CCRC)

—centers engaged only in clinical research;

and

Cancer Research Centers (CRC)—centers

engaged in both laboratory and clinical

research.

addition, a CRC with a funded Cancer Center Support Grant (CCSG) may apply to NCI for

recognition as a Comprehensive Cancer Center.

Such recognition may be granted by the Director

of NCI if evaluation of the center demonstrates

compliance with the guidelines for recognition

of a cancer center as comprehensive. These

guidelines were established by NCAB and were

revised by the Board in 1979 (see addendum D).

In fiscal year 1981, there were 20 Comprehensive Cancer Centers, 23 CCRCs, and 18 LCRCs

(see table 19).

Cancer centers depend heavily on NCI for

research and operational support funds. NCI

contributes an average of 77 percent of total external support funds. Other NIH programs provide an additional 11 percent. The total NIH

contribution is therefore 88 percent of all external financial support. The remaining 12 percent

derives from other Federal, public, and private

sources. Any changes in the NCI budget appropriation and its apportionment can be expected

to have a significant impact on the centers’ research and operational stability.

A number of areas of concern have been identified in the past regarding the centers program,

directed mainly at the comprehensive centers

and how well they carry out their role. From the

beginning, the centers have been individualistic

in organization and in their relation with the

community. All were respected institutions in

cancer research already, all with strengths and

weaknesses in various areas. It is obviously advantageous for such institutions to be recognized

by NCI, both financially and in terms of prestige, but the institutions did not rework themselves into a uniform mold, nor was that ever

the intent of NCI. It does mean that criteria for

naming and evaluating comprehensive cancer

centers are fairly general, though specific requirements can be included.

Centers vary greatly in the degree of integration of basic and clinical research, though that

link appears to be weak in some centers. The degree to which centers serve as focal points for the

community or region also varies, but some are

have a great deal of community involvement.

A longstanding criticism of the program is the

lack of geographic coverage of the centers. One

of the guidelines for comprehensive centers is

“geographic impact. ” A comprehensive center

“should increase the national capability to carry

out regional trials, regional training, education

and information dissemination activities. ” There

are, however, two comprehensive centers each

in Los Angeles and New York, and it appears

that “scientific excellence” overrides concerns of

geographic distribution. One NCI official ex-
72

Table 19.—Cancer Centers

comprehensive cancer centers Clinical cancer Centers Nonclinical cancer centers

Comprehensive Cancer Center

University of Alabama at Birmingham

University of Arizona Cancer Center

Tucson, Ariz.

University of California at San Diego

La Jolla, Calif.

Stanford University Medical Center

Stanford, Calif.

Kenneth Norris, Jr., Cancer Research Institute

University of Southern California

Los Angeles, Calif.

University of California

Berkeley, Calif.

UCLA Jonsson Comprehensive Cancer Center

UCLA School of Medicine

Los Angeles, Calif.

Northern California Cancer Program

Palo Alto, Calif.

City of Hope National Medical Canter

Duarte, Calif.

Colorado Regional Cancer canter, Inc.a

Denver. Colo.

Cancer Center of Hawaii

University of Hawaii at Manoa

Honolulu, Hawaii

Ephraim McDowell Community Cancer

Network, Inc.

Lexington, Ky.

Hubert G. Humphrey Cancer Research

Center

Boston University School of Medicine

Boston, Mass.

Cancer Center, Tufts-New England

Medical Canter

Boston, Mass.

Norris Cotton Cancer Canter

Dartmouth-Hitchcock Medical Center

Hanover, NH.

Cancer Research and Treatment Center

University of New Mexico

Albuquerque, N.M.

Scripps Clinic and Research foundation

La Jolla, Calif.

Yale University Comprehensive Cancer Center

New Haven, Corm

Armand Hammer Center for Cancer Biology

The Salk Institute

La Jolla, Calif.

Georgetown University/Howard University

Comprehensive Cancer Center

Purdue Cancer Center

Purdue University

West Lafayette, Ind.

Vincent T Lombardi Cancer Research Center

Georgetown University Medical Center

Washington, DC.

Worcester Foundation for Experimental Biology, Inc.

Shrewsbury, Mass

Howard University Cancer Research Center

College of Medicine

Washington, D.C.

Center for Basic Cancer Research

Washington University School of Medicine

St. Louis, Mo.

Comprehensive Cancer Center for the State of Florida

University of Miami School of Medicine/

Jackson Memorial Medical Center

Miami, Fla.

St. Louis University

St Louis, Mo.

Illinols Cancer Council

Northwestern University Cancer Center

Chicago, Ill.

Cancer Research Center

Albert Einstein College of Medicine

Bronx. N Y

New York University Medical Center

Institute of Environmental Medicine

New York, N Y

University of Chicago Cancer Research Center

Chicago, Ill.

Hospital for Joint Diseases and

Medical Center

New York, N.Y.

Johns Hopkins Oncology Center

Baltimore, Md.

American Health Foundation

New York, N Y

Grace Cancer Drug Center

Buffalo, N.Y.

Sidney Farber Cancer Institute

Boston, Mass.

Mount Sinai School Of Medicine

New York, N.Y.

New York University Medical Center

New York, N.Y.

University of Rochester Cancer Center

Rochester, N Y

Cancer Research Center, University of

North Carolina

Chapel HiII, N C

Oncology Research Center

Bowman Gray School of Medicine

Winston Salem, N C

Puerto RICO Cancer Center

University of Puerto Rico, Medical Sciences

Campus

San Juan, P R

Roger Williams General Hospital

Providence, R.I.

Comprehensive Cancer Center of Metropolitan Detroit

Detroit, Mich.

Case Western Reserve University

Cleveiand, Ohio

Mayo Comprehensive Cancer Center

Rochester, Minn.

The Pennsylvania State University,

College of Medicine

Hershey, Pa.

Sloan. Kettering Institute for Cancer

Research/Memorial Sloan-Kettering Cancer Canter

The Wistar Institute of Anatomy and Biology

Philadelphia, Pa

Fels Research Institute

Temple University Medical School

Philadelphia, Pa.

Roswell Park Memorial Institute

Buffalo, N.Y

Columbia University, Cancer Research Center,

College of Physicians and Surgeons

New York, N.Y.

The University of Wisconsin,

McArdle Laboratories

Madison, Wis.

Comprehensive Cancer Center

Duke University Medical Center

Durham, NC

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio

Memphis Regional Cancer Center

Memphis, Term

University of Pennsylvania Comprehensive Cancer Center

Institute for Cancer Research

Fox Chase, Pa.

St. Jude Children’s Research Hospital

Memphis, Term.

University of Pennsylvania Cancer Center

Philadelphia, Pa,

The University of Texas Medical

Branch Hospitals

Galveston, Tex.

The University of Texas System Cancer Center

M.D. Anderson Hospital and Tumor Institute

Houston, Tex.

MCV/VCU Cancer Center,

Medical College of Virginia

Richmond, Va.

Fred Hutchinson Cancer Research Center

Seattle, Wash

Vermont Regional Cancer Center,

University of Vermont

Burlington, Vt.

The University of Wisconsin, Clinical Cancer Center

Madison, Wis.

Milwaukee Children’s Hospital

Milwaukee, Wis.

aAlthough this center does not have a current core grant, it iS a recognized NCI Comprehensive Cancer Center

SOURCE: National Cancer Institute, 1981.
73

plained that it was never the intent of the program to achieve geographic distribution of centers. It is understandable that there are no centers in areas where there are few large teaching

or research medical institutions, but it appears

that there is substantial overlap in populations

served. The new CCOP program is intended to

reach into the community with importance given to geographic spread, according an NCI official.

A number of experts contacted by OTA mentioned that the appearance of almost 2,800 oncologists and more than 3,000 oncology nurses

in the past decade has been instrumental in improving care for cancer patients. Part of the expansion in the pool of well-qualified health professionals in this area is credited to the interest

developed in cancer as a result of the National

Cancer Program. In particular, the cancer centers are credited with having made major contributions to professional training.

. . . even under the limited mandate of Cancer

Control, providing for research and demonstration but not for health care, the program

presents great opportunities for the NCPP [National Cancer Program. Plan]. Thus, improvements in today’s methods for the education and

training of all the health professionals in the

cancer fields, technicians, nurses, and physicians, would inevitably result in an upgrading

of the quality of cancer care.

If, as an early outcome of the NCPP, the

country were to be provided with significant

numbers of health professionals, trained in the

use of specialized techniques and facilities, this

would surely be recognized as a valuable product, solid and highly visible (44).

Centralized Cancer Patient Data System

The Centralized Cancer Patient Data System

(CCPDS) began in 1977. The system is a d -

dressed at developing a uniform data system in

the Comprehensive Cancer Centers. At this time

all 20 Comprehensive Cancer Centers have been

awarded grants to participate.

Under this system, 38 items of information are

collected on each patient meeting certain criteria

and reported to the Statistical Analysis and

Quality Control (SAQC) center in Seattle,

Wash. SAQC maintains the system, analyzes

the data and acts as the coordinator for research

activities involving CCPDS. Approximatel y

50,000 new cases are registered annuall y a t

SAQC (62).

Two basic goals of the system were to ensure

that the comprehensive cancer centers used uniform language and procedures in naming and

staging cancers and to develop a resource for cooperative research projects, drawing from all the

centers. The first goal apparently has been

achieved. Toward the second, a number of projects are in various stages of planning, using the

system as a source of cases for case-control studies and studies of rare cancers.

The analyses produced by SAQC will deal

mainly with survival of patients with various

forms of cancer, representing those receiving the

most sophisticated treatment in the country. The

other major system for survival statistics, the

SEER program (see above), differs in that it theoretically represents the survival of all cancer

patients, including those treated in all types of

facilities.

The question that arises is whether enough

new information is gained from CCPDS to justify its existence. The improvements in statistical

capability in the centers and the uniformity of

language are undoubtedly of value. The aspects

that might be seriously questioned are the emphasis on survival rates and the usefulness of a

centralized system for carrying out research.

NCI is conducting a concept review of CCPDS

in the spring of 1982, to be carried out by an outside ad hoc committee. The committee will make

recommendations for the future of the system at

that time.

The Cancer Control Program

At the time of the passage of the National

Cancer Act, “the scientific community and the

Congress thought . . . that many research advances existed which could affect cancer, but

these advances were not being disseminated and

used. The cancer control program was intended

to bridge this gap. ” (28).

The act directed that NCI was to establish

programs with State and other health agencies

91-486 0 - 82 - 6
—

74

that were to demonstrate the best methods to apply the most recent advances in diagnosis, treatment, and prevention. The control program was

not to perform research to develop new knowledge in those fields; rather it was to develop

means for application.

In 1974 and 1978, the act was amended, and

Congress mandated that NCI conduct cancer

control programs aimed at diagnosing uterine

cancer (by use of the “Pap” test). Other specific

diagnostic programs—breast and oral examinations—were also mentioned in the legislative history that accompanied the act. NCI has since

then carried out some demonstration projects

dealing with these subjects. A massive Pap test

demonstration was found to have missed its objectives and to have been poorly managed by

NCI (28).

The cancer control program was administered

from the NCI Director’s Office until September

1974, when it was moved to the newly formed

Division of Cancer Control and Rehabilitation.

In 1980, an NCI reorganization formed the Division of Resources, Centers, and Community Activities (DRCCA), and cancer control was

placed within it. This recent organization

brought to the division all NCI programs connected with control and technology transfer.

From 1976 through 1980, $302 million were

allocated to the cancer control program as a line

item in the NCI budget. More than two-thirds of

that amount has been obligated for contracts.

GAO Review of the Program

A GAO audit (28) of three completed cancer

control contracts found that many specified

tasks were never accomplished. GAO found, to

some extent, that a shortage of NCI staff had

contributed to poor contract supervision and the

subsequent failure of the contracts to reach their

goals. Beyond the staff shortage, GAO found

that poor cooperation among NCI staff and

poor management contributed to the failures of

the contracts.

Two contracts reviewed by GAO were to provide assistance to populations of workers who

had been expected to develop a large number of

tumors because of workplace exposures. In both

those cases, so few tumors developed that there

was no point to the demonstrations. It might be

that more attention to the planning of those

studies would have revealed the likelihood of

there being too few tumors, and the expense of

setting up the demonstrations could have been

avoided.

The GAO audit (28) interviewed a number of

“NCI officials and current and past advisors to

the control program . . . . the individuals said

this assumption [that medical advances in cancer

were slow to get into practice] proved to be incorrect because few cancer advances existed that

the medical community was not using. ” Despite

that conclusion, four out of five advisors expressed opinions that the program in some form

ought to be continued.

An NCI official, interviewed by OTA as part

of this study, said that the cancer control programs in the 1970’s had not been very good.

They were, he said, motivated by a desire to do

good things in the community. However, they

lacked detailed planning, reachable objectives,

and evaluation. The official is confident that recent initiatives (such as the Community Clinical

Oncology Program (CCOP), see below) will improve the performance of the cancer control activities.

A Critical View of the Cancer Control Program

in Contrast to the Success of Cancer Control

The value of NCI programs in cancer control

projects is dismissed in an article by Yarbro that

points to major improvements in the treatment

of cancer in the community (119).

Let’s go back to square one for a

moment . . . to what everyone already knows.

Research is finding out which treatment is best:

Control is making that treatment available.

Now, I submit that we and the NCI know a

great deal about cancer research, but precious

little about cancer control. . . . Why?

To explore the answer to that question, let me

present you with a paradox: The Cancer Control Program of the NCI has been a dismal failure, and yet, the quality of cancer care at the

community level has improved in quantum

leaps every year. How can a program so gener-
75

ally agreed to be such a disaster have succeeded

so magnificently? The answer, of course, is that

what we defined and funded as cancer control

had nothing at all to do with the remarkable

progress in cancer care at the community level.

Yarbro goes on to say that great improvements in the community have occurred in facilities, personnel, and treatment protocols (119).

He says that better facilities have come from

“hospitals and doctors . . . competing with each

other to provide the best. ” This was “competitive cancer control, ” he says, neither planned

nor NCI-funded.

According to Yarbro, “We now have more

than enough oncologists in practice and in the

pipeline to serve cancer patients for years to

come. ” NCI training programs have contributed

to this supply, but they are fading because of

funding cutbacks. However, the university need

for trainees (“the ones to do all the work”) ensures the continued production of trained personnel. Finally, Yarbro concludes (119):

So much for facilities and personnel. What

about new treatment protocols? Surely we need

special people (at Federal expense) to carry these

from the university centers to community hospitals! Here I am forced to admit that the Federal government has been heavily involved. It

does pay such people. They are called postmen

and they deliver medical journals. With few exceptions, new treatment protocols enter community use when oncologists read journals or

attend meetings. This is self-education cancer

control!

Yarbro is positive about enlisting community

physicians in clinical trial programs. It will, he

says, facilitate movement of new therapies to the

community which will benefit patients. At the

same time, it will “unleash the awesome power

of the private practice sector in clinical

research. ”

In addition to the involvement of community

physicians in clinical trials, Yarbro sees a need

for some demonstration projects. The widespread distribution of “hospital cancer programs

with (tumor) registries, tumor boards, and

guidelines” should be a goal for the 1980’s. H e

sees demonstrations of workable methods to

reach that goal as worthwhile projects for cancer

control.

Yarbro’s opinions represent an extreme, but

they illustrate questioning of the basic tenet of

the cancer control program. Is there a lag in

transfer of research information to the community setting? Any answer to that question is likely to be qualified. GAO interviews with NCI officials and advisors were almost consistent in

saying that cancer control programs may have

accelerated the transfer, but that transfer would

have occurred, perhaps more slowly, in their absence (28).

Opposing Views About Technology Transfer

Sharply differing opinions about cancer control were voiced during hearings of the Investigations and General Oversight Subcommittee of

the Senate Committee on Labor and Human Resources on May 21, 1981 (9). Some witnesses

said that publication of research findings does

not constitute effective communication of information and that NCI needed to develop better

means for technology transfer.

Also discussed at those hearings was the role

of clinical trials in technology transfer (9). Methodist Hospital, Indianapolis, Ind., therapist

William Dugan said that it would be “inappropriate to substitute clinical trials for cancer control. ”

An opposing view was expressed by Harold

Amos, a member of the President’s Cancer Panel

and NCAB (9). Amos said, “Clinical trials are

technology transfer. ” The establishment of research advances “as clinical practice throughout

the land, admittedly of utmost importance, must

be the task of some other network already in

place.” Amos viewed suggestions for increased

emphasis on technology transfer “as a threat to

divert NCI from the one thing it was created to

do and can do admirably, i.e., conduct and develop programs in research into the etiology,

diagnosis, prevention, and treatment of cancer.

In that role its resources are already overtaxed. ”

These differences illustrate the varied positions taken on the subject of technology transfer. There is no doubt that research advances
76

need to be applied, but there is disagreement

about whether or not special methods are necessary to transfer those advances. Beyond that, if

methods are needed, there is another question

about whether NCI or some other organization

is appropriate to manage the transfer.

Goals of the NCI Cancer Control

Program

In 1979, NCI described

gram as focused on (28):

identifying, evaluating,

plication of innovative,

cancer control;

he cancer control proand planning the appractical methods of

developing demonstration programs to promote the use of effective cancer control methods by the Nation’s health professionals;

developing training resources for educating

health professionals in the use of cancer control interventions;

developing methods of encouraging beneficial

attitudes and lifestyles as they relate to the

control of cancer with emphasis on hard-toreach populations, such as minority groups

and blue collar workers;

providing mechanisms for organizing the Nation’s resources for an effective, coordinated

attack on specific cancer control problems.

Early in 1982, major attention had been focused on CCOP that will involve community

physicians in trials of new treatment protocols.

This program, described below, is an example of

attention to the second goal in the list above.

NCI is also planning to emphasize education

about workplace exposures that have been associated with cancer. In the past few years, NCI

has had an interagency agreement with the Occupational Safety and Health Administration

(OSHA) for its New Directions Program. That

program funded cancer-related educational efforts by employers, employees, unions, and

academic institutions to improve workplace

health and safety. During 1981, OSHA eliminated its peer review of New Directions grants,

and NCI has decided to fund a limited, similar

program. It is now considering different methods to reach the groups described in the fourth

goal above.

Community Outreach and

Rehabilitation Branch Activities

The Community Outreach and Rehabilitation

Branch supports programs designed to (62):

●

●

●

●

●

increase the transfer of cancer management

technology from research centers to the

community;

develop effective cancer management capabilities within the community;

continue the development of rehabilitation

devices and strategies;

develop new approaches to the management of pain associated with cancer; and

study the problem of optimal care for the

terminally ill cancer patient.

The Community Outreach and Rehabilitation

Branch supports the following programs, which

are described in the sections below (62):

1.

2.

3.

4.

5.

6.

7.

Clinical Cooperative Group Programs.

Clinical Oncology Programs.

Community Hospital Oncology Programs.

Community Clinical Oncology Programs.

Rehabilitation Program.

Pain Programs,

Hospice Program,

Clinical Cooperative Group Programs

According to NCI (62):

The reduction of cancer morbidity and mortality in the community setting is the goal of the

Cooperative Group Outreach Programs. The

objectives of these programs are to upgrade the

skills of community physicians and other health

professionals in the management of cancer patients and to increase the number of these patients receiving the best available care.

The objectives are being fulfilled by the mechanisms of increasing the number of community

hospitals affiliated with the cooperative groups,

expanding the groups’ referral networks, providing support services to the community hospitals, and developing a broad range of profes-
77

sional educational programs at both national

and regional meetings and workshops.

The involvement of community hospitals with

these groups, originally comprised of university

hospitals and other major cancer centers, is a recent phenomenon (see Eastern Cooperative Oncology Group Community Hospital Program,

below). In 1980, six cooperative groups had outreach activities supported by either a grant or

contract.

ECOG Community Hospital Program.—The

Eastern Cooperative Oncology Group (ECOG)

Community Hospital Program is discussed as a

specific example of technology transfer activities. In the early 1970’s, in large part as a

result of the success of NCI-funded training programs, a growing number of cancer patients

were being treated by trained oncologists in

community hospitals, as opposed to being

treated in major teaching or research hospitals.

Recognizing this trend and the importance of involving community hospitals in the cancer control effort, one of the NCI-funded Cooperative

Groups, ECOG, applied for funds to be used for

supporting the participation of community hospitals in clinical trials. The application was rejected on grounds that community hospitals

should not be participating in clinical trial

research. However, the next year NCI initiated a

program to allow for just such involvement of

community hospitals, and in October 1976, NCI

awarded funds to ECOG to begin the ECOG

Community Hospital Programs.

The first 5 years of the ECOG Community

Hospital Program have been a great success in

the participation of community hospitals and in

the quality of data they have submitted (s). At

present, 112 community hospitals are participating, having enrolled in protocol studies over

5,000 patients in 5 years, now averaging well

over 1,200 patients per year. Perhaps more important, the quality of participation in ECOG

clinical trials and the patient outcomes in community hospitals were no different than those

for member institutions. The success of the

ECOG program has been one factor in encouraging NCI to embark on CCOP.

An individual associated with ECOG expressed great dissatisfaction with NCI involvement in the Community Hospital Program.

There was resistance to the program at a time

when it was obvious to the ECOG people that

the community should have been involved.

There seems to be little doubt that ECOG has

taken a successful approach to involving community hospitals in clinical trials (6), and the approach has also worked for some other cooperative groups. NCI is planning to make a very

large investment in CCOP, a program that many

see as competing with the ECOG type programs,

and which will be organized in a manner quite

opposite to them. In CCOP, the community

hospitals (or consortia) will apply directly to

NCI, and it will be each hospital’s (or

consortia’s) responsibility to find a research base

with which to affiliate. Financial incentives and

autonomy for the community hospitals may be

greater in CCOP than through the cooperative

groups, and the possibility exists that the cooperative groups may be irreparably damaged.

The request for applications (RFA) for CCOP

has not yet been released, and the criteria for

awards are not yet fully known, so these potential problems may be ironed out before the program gets underway.

Clinical Oncology Programs

Community hospitals or consortia of hospitals were funded under the Clinical Oncology

Program (COP) to demonstrate that effective

multidisciplinary diagnosis, treatment and rehabilitation services can be provided to patients in

community setting, through small cost-sharing

contracts. Criteria against which community

participation are measured are (62):

involvement of physicians, nurses, and other

allied health professionals in initial planning

of a community treatment and referral system

for the patient;

participation of physicians and allied health

professions in designing multidisciplinary

guidelines for patient treatment, nursing care,

rehabilitation and terminal care;

funding and direction of the cancer programs by a locally accepted hospital or fiscal agent of the regional consortia;
78

● practical relationships concerning patient

treatment that can be developed with regionally appropriate universities or comprehensive cancer centers; and

leadership, in the form of an individual or

group that can motivate a community to

cooperate for the benefit of the cancer patient and family.

Five COPS have completed 3 years of implementation. The final contract year has been

devoted to evaluation with support for operational aspects of the program assumed by the

community. Analysts of the experiences of the

pilot COPS resulted in a model approach to the

development of Community Hospital Oncology

Programs (CHOPS).

Community Hospital Oncology Programs

According to NCI (62):

Twenty-three contracts have been awarded to

field test (in single institutions, community consortia of institutions, and rural institutions) a model

approach to development of a community cancer

program.

The purpose of these CHOPS is to provide

evidence that implementation of the COP model in

a community will improve the scope and quality

of cancer care for cancer patients over that received prior to development of the program.

In the development and implementation of each

program, the cooperating hospitals and health

care professionals will:

●

●

●

●

define criteria for cancer patient care through

the development of management guidelines;

plan and implement a program to encourage

community cancer care practices in accordance with these criteria for care;

use a data management system (e. g., through

upgraded tumor registries) to assess the extent

to which community cancer care practices

correspond to the recommended criteria; and

use the information obtained to correct, modify, and improve the clinical oncology program and to document effective changes in

community cancer care.

The 23 CHOP contractors are in an 18-month

planning phase. Contractors submitting satisfactory implementation plans will be eligible for

a further two-year implementation contract.

Implementation and evaluation plans resulting from the first 12 months planning activities

have been submitted as proposals for peer

review.

Community Clinical Oncology Program

The NCI Director has put a high priority on

funding CCOP, a new program designed to involve small community hospitals and community oncologists in NCI-sponsored clinical trials.

NCI will provide resources for the hospitals to

join forces with large institutions already involved in NCI-supported research. Through this

arrangement, a technology flow from NCI to the

community will be established.

The impetus to initiate CCOP came, in part,

from a directive of Senator Hawkins asking NCI

to upgrade the quality of cancer treatment in

community hospitals. The program was “concept-approved” in the fall 1981 and an RFA was

prepared. The RFA was scheduled for release in

April 1982, but NCAB at its February 1982 meeting expressed interest in knowing the contents of

the RFA before release. An NCAB subcommittee

reviewed a letter from NCI that describes the

contents of the RFA in early March 1982. The

subcommittee has decided to review the CCOP

concept and plan and report to the full NCAB in

May.

Up to 200 CCOP units are expected to be

funded initially. Estimates of the number of applications expected range from 100 to 1,000.

Geographical distribution will be considered

among other factors in making decisions about

where to fund units.

Rehabilitation Program

According to NCI (62):

This program seeks to reduce the morbidity

from cancer and its treatment through stimulating study, demonstration, and research in new

techniques of rehabilitation that have specific

applicability to the physical, cosmetic, and

functional problems associated with cancer.

The comprehensive nature of cancer rehabilitation determines support for a variety of projects that seeks to achieve the cancer patients’

early adjustment and re-entry into the everyday
79

world of work, social activity, and physical

functioning.

The rehabilitation program supports 21

grants which presently investigate six major

areas of cancer rehabilitation, and four contracts to support training for dental personnel

interested in pursuing postsurgical restorations

for cancer patients.

Pain Programs

NCI states (62):

Pain is one of the most feared consequences

of cancer. Severe pain generally occurs in advancing and terminal disease, and pain may

also be an early manifestation of cancer or its

presenting symptoms. Cancer pain has been the

focus of considerable attention and concern for

clinicians, patients, their friends and families,

the general public, and the Government. However, it is now the consensus that no adequate

data base exists from which to determine the

true magnitude of the cancer pain problem.

DRCCA has initiated pilot studies of cancer

pain with the goal of gathering valid data defining the incidence and natural history of pain in

cancer. Under the contract program Pain Control in Cancer, seven institutions are participating in a collaborative study to demonstrate that

pain control for cancer patients is best instituted

PREVENTION PROGRAMS

The goals of the NCI cancer control program

include “developing methods of encouraging

beneficial attitudes and life styles . . . “ A number of experts with whom OTA talked mentioned two areas that may deserve special attention because of their importance to prevention

programs. Those two areas, epidemiology and

nutrition research, are discussed below.

Epidemiology

In 1975, the Environmental Epidemiology

Branch was created in the Division of Cancer

Cause and Prevention, and has expanded in size

and budget. The objective of the branch has

been to attain a comprehensive and balanced

program to enhance our capacity at the national

level to generate fresh ideas and help settle key

early in its onset after careful planning and

evaluation by a multidisciplinary team of experts. This program addresses the management

of pain associated with advanced and metastatic

diseases and chronic pain associated with localized disease.

Hospice Program

According to NCI (62):

Three projects in Implementation of the

Hospice Concept for the Care of Terminal Cancer Patients were implemented with a home care

program and a backup in-house facility. These

projects provided a demonstration of comprehensive terminal care given in three different

settings, i.e., a nursing home, a community hospital, and a health maintenance organization. A

collaborative, descriptive study developed by

the hospice contractors and NCI program staff

was implemented in October 1979 with data

collection ending September 30, 1980. The

study focused on a thorough description of care

in the three settings which included a longitudinal assessment of the patient and the bereaved family members (significant others). In

describing the hospice patient population, age,

sex, socioeconomic status, medical condition,

and other pertinent characteristics were recorded. Data analysis is proceeding and a report

is to be available by the end of this year,

questions in cancer epidemiology and etiology.

Along with expansion of the intramural and collaborative programs, parallel efforts were made

to stimulate and encourage extramural grantsupported programs in epidemiology, including

some support for training in epidemiology and

biostatistics.

The epidemiology and biometry program of

NCI plays a pivotal role in the National Cancer

program. It has responded to requests at all

levels to increase the scope of its work and to

help develop Federal programs and policies in

several areas. NCI efforts have contributed not

only to research in cancer etiology, but also to

our understanding of natural history, end

results, clinical trials, preventive measures, and

strategies involved in administrative planning
80

and decisionmaking. Increasingly, epidemiologic and biometric approaches permeate various

aspects of the National Center Program, and are

fundamental to the design and evaluation of

methods to control cancer. *

In spite of the laudable achievements of the

last few years, a number of people that spoke

with OTA expressed strong feelings that NCI

has failed to emphasize epidemiology sufficiently.

Much of the information available today

about how to prevent cancer has come from

epidemiology. The convincing evidence that

cigarettes, asbestos, radiation, and some

chemicals definitely cause cancer is based on epidemiologic studies. There is a lack of consensus

about whether or not there are many good epidemiologic hypotheses that are going untested

because of lack of support for training in epidemiology and biostatistics. Support for such

training is seen as always having been minimal,

and as being further reduced in recent budget

tightening. The lack of trained people in this

area has been recognized for many years and has

been publicized by the National Research Council.

Primary prevention—preventing cancers from

developing at all—is the ultimate goal, and it depends to a large extent on epidemiology. That is

not, however, a practical short-term goal or

even a foreseeable goal. Epidemiology, however, is a necessary component of other aspects

of cancer control. For example, screening programs, leading to early diagnosis of existing cancers, have been a major thrust of secondary prevention efforts at NCI. Yet, some screening programs have been misapplied. One of the experts

who spoke with OTA claimed that as much was

known about the Pap smear as a successful technique for detecting cervical cancer in 1941 as is

known today. In the 1960’s, as part of the cancer control program, a demonstration screening

program was initiated, but it was directed at a

segment of the population that would benefit little from it. Some experts contend that the same

thing is happening today in breast cancer screening. Increased epidemiologic input would reduce

J. F. Fraumeni, Jr., NCI, personal communication, Mar. 10

1982.

the chances of such misapplications. Epidemiologic guidance could be the integrating factor

between the clinic and the community, identifying the population groups who would derive the

greatest benefit from screening.

Epidemiology might be a unifying force between different phases of research, but in the

past, resources for epidemiology have been relatively small compared to other parts of NCI.

There are hopeful signs at present of expansion

in epidemiologic efforts.

Nutrition Research

Components of diet are associated with cancer

occurrence. During Senate hearings in 1978, a

large number of witnesses referred to estimates

that 60 percent of cancer in females and 40 percent in males were related to diet (115). Relationships are not always clear, but some associations between dietary components and cancer

risks are widely accepted, For instance, high-fat

diets are associated with elevated colon and

breast-cancer rates. Such findings produce immediate suggestions for reducing cancer incidence. The Division of Cancer Cause and

Prevention has been active in looking at dietary

risk factors for cancer in a number of epidemiologic studies.

Within the last year, a number of studies have

contributed to the hypothesis that eating betacarotene, a precursor of vitamin A found in

green, leafy plants and carrots reduces cancer incidence (20,86,96,106). Identification of protective components in the diet may be as important

for prevention as is describing risk factors.

Nutrition has also been studied in relation to

cancer treatment. Many cancer patients have no

appetite and have difficulty in “keeping food

down;” they waste away during treatment. The

term used for providing nutritional support to

the patient is “hyperalimentation.” Although the

Senate heard some presentations about nutritional support of the patient, it is clear from the

hearing record that Congress was most interested in cause and prevention.

Another example of interest in nutrition and

cancer is a major National Academy of Sciences’

study of that subject that is now underway. Its

report is expected in late 1982.
81

At least partly as a result of congressional interest in the nutrition-cancer link, NCI established a program in this area. Many early efforts

of the program were directed at treatment, not

at cause and prevention. Presentations from that

program that are described in the NCAB annual

reports in the late 1970’s discussed hyperalimentation.

A change in direction is now apparent.

NCAB’S Subcommittee on Nutrition and Cancer

has recently examined NCI’S efforts in this field,

and it has recommended a time-limited allocation of funds to stimulate cancer-nutrition research and the establishment of a task force to

coordinate NCI efforts (71).

“Chemoprevention” has become a popular

word in the cancer lexicon. It refers to identification of agents that can be ingested with the expectation of reducing cancer. The NCAB subcommittee published a list of the 10 chemoprevention trials that are ongoing at NCI. Eight of

the 10 trials are being conducted in cancer patients, and, therefore are aimed at prevention of

recurrent or worsening disease. Only one study

of the 10 is directed at primary prevention in

general populations. It is a study to be conducted in a population of 21,900 healthy males,

SUMMARY

Improvements have been made in the control

of cancer. The reasons for some of the improvements are well understood. The reasons for

some others remain obscure.

Some encouraging changes in incidence and

mortality are apparent. Lung cancer mortality

has decreased as a consequence of changes in

smoking patterns in young males. Decreased

stomach and uterine cancer incidence have resulted in declines in mortality. Improved treatment regimens have dramatically reduced mortality from some cancers.

NCI research has played a major role in these

improvements. The role of formal cancer control programs and technology transfer activities

in moving improvements to the community is

less clear. Management of technology transfer is

a difficult task, and NCI is trying a number of

ages 50 to 75. The study is designed to test the effectiveness of beta-carotene in reducing cancer

occurrence and to test the effectiveness of aspirin

in reducing heart attacks. This large-scale study

is being jointly supported by NCI and NHLBI.

The contrast between this chemoprevention

study, involving a large number of healthy people and prevention strategies directed at the

number one and two killers, and the othe r

chemoprevention trials needs no elaboration.

A number of experts who were contacted by

OTA make a point of the difficulties of executing these studies. Such studies involve a large

number of people in making changes, albeit

small ones, in their lifestyles, and the studies will

be difficult. Though it is a first step, merely carrying out such a study is no guarantee that

meaningful results will be obtained.

The NCAB subcommittee, which was critical

of the current efforts in nutrition research,

draws attention to the possible lack of good,

testable ideas in nutrition and cancer, and proposes a number of changes at NCI to promote

better research in this area. Such changes may

lead to better understanding of the connections

between diet and cancer.

activities to decide upon effective strategies. A

related, also difficult task, is the development of

measures for the success or lack of success of

technology transfer programs. A new focus of

cancer control at NCI will be the Community

Clinical Oncology Program (CCOP), which,

like the successful Clinical Cooperative Oncology Group (CCOG) Program, will involve community physicians in NCI-sponsored clinical

trials. These programs directly transfer the most

recent treatment and management methods to

the community through physician participation.

Experts contacted by OTA were complimentary

about NCI’S role in the progress being made

against cancer and in understandin g the disease;

at the same time, some expressed concerns about

some features of its many programs. Those concerns are not definitive opinions, but they identify difficult issues that merit attention.
82

ADDENDUM A: GROWTH OF THE NATIONAL CANCER INSTITUTE

AFTER PASSAGE OF THE NATIONAL CANCER ACT

The NCI Budget

Financial support for NCI more than doubled between 1972 and 1981 (see table 20 and fig. 4), The

budget includes funds for both cancer research and

cancer control; the dollar amounts in this section are

the sums for both activities.

The NCI budget exists in four forms. The annual

authorization figure is the amount specified in the enabling legislation. It and the “bypass request, ” which

is a budget prepared by NCI staff and advisors, have

been for approximately the same amounts each year

and have increased almost in parallel since 1972. By

legislative authority, the bypass request is submitted

directly to the President and bypasses the budget

process imposed on other components of the Public

Health Service (PHS) and the Department of Health

and Human Services (DHHS) by the executive

branch. The Department may comment on the bypass budget but cannot change it.

The “President budget request” is the final amount

proposed by the administration after the President

and the Office of Management and Budget have reviewed and evaluated the bypass request. That mark

has been consistently below the bypass request, and

during 1973 through 1977, it ran between 64 and 82

percent of the authorization (see table 21 and fig. 5).

However, because the percentage increase in the

President’s request in recent years has been greater

than the increase in the authorization, the President’s

budget has been 85 percent or more of the authorized

figure for the last 3 years.

The final budget figure, the continuing resolution

or appropriation figure, is the amount of money

Figure 4.-Authorized, Requested, and

Appropriated Budgets of NCI,

Fiscal Years 1972-81

f

’72 ’73 ’74 ’75 ’76 ’77 ’78 ’79 ’80 ’81

Year

SOURCE: Office of Technology Assessment from NCI data

Table 20.—Authorized, Requested, and Appropriated Budgets of NCI,

Fiscal Years 1972.81

Authorizationa

Bypass

request

1972 . . . . . . . . . .

1973 . . . . . . . . . .

1974 . . . . . . . . . .

1975 ...., . . . . .

1976 . . . . . . . . . .

1977 ......., . .

1978 . . . . . . . . . .

1979 . . . . . . . . . .

1980 . . . . . . . . . .

1981 . . . . . . . . . .

$ 420,000,000

530,000,000

640,000,000

803,500,000

898,500,000

1,073,500,000

1,008,150,000

1,015,000,000

1,030,000,000

1,128,600,000

—

$ 550,790,000

640,000,000

750,000,000

898,500,000

946,000,000

955,000,000

1,036,000,000

1,055,000,000

1,170,000,000

President’s

budget

request

$374,338,000

432,205,000

500,000,000

600,000,000

605,000,000

687,670,000

818,936,000

878,802,000

936,958,000

965,105,000

Continuing

resolution

appropriate ion

$ 378,794,000

492,205,000

551,191,000

691,666,000

761,727,000

815,000,000

872,388,000

937,129,000

1,000,000,000

1,001,330,000

a

lncludes both cancer control authorization and research authorization.

SOURCE: National Cancer Institute, Jan. 4, 1982.
83

Table 21.– Requested and Appropriated Budgets of NCI, as Percentages of the

Authorized Budget, Fiscal Years 1972.81

1972 1973 1974 1975 1976 1977 1978 1979 1980 1981

Bypass . . . . . . . . . — 104% 100% 93% 100% 88% 9570 102% 102% 10470

President’s

budget . . . . . . . 89% 82 78 75 67 64 81 87 91 85

Appropriation. . . . 90 93 86 86 85 76 86 92 97 89

SOURCE: Office of Technology Assessment from data in table 20.

Figure 5.—Requested and Appropriated Budgets of

NCI, as Percentages of the Authorized Budget,

Fiscal Years 1972-81

’72 ’73 ’74 ’75 ’76 ’77 ’78 ’79 ’80 ’81

Year

SOURCE” Office of Technology Assessment from NCI data.

received by NCI each year. Despite the fact that in

some years either the President’s request or the appropriation figure showed little or no increase, the

sum of money received by NCI has increased each

year except in 1981. The overall impression is that,

until 1981, an increase in either the bypass request or

the President’s request signaled an increased appropriation. In 1981, there was hardly any appropriation increase, even though the authorization, the

bypass request, and the President’s request increased.

Appropriations increased most rapidly during the

period 1972 through 1976, the first years of the National Cancer Program. In fact, had the NCI budget

continued to increase at that rate, appropriations

would have doubled every 3 1/2 years. The rate of increase dropped significantly between 1976 and 1980

however, so that the period of very rapid growth in

NCI appropriations occurred over only a few years.

Increases in NCI’S appropriations exceeded the inflation rate for the period 1972 through 1977 but not

since then (see table 22). The impact of inflation has

Table 22.–Annual Percentage Increase in the NCI

Appropriation Compared to Increase in the

Consumer Price Index, 1972.81

(l) Percent change (3) Net change

in NCI (2) Percent change in NCI

appropriation over in Consumer budget

previous yeara

Price Indexb

(1) -(2)

1973 . . . . . . . .

1974 . . . . . . . .

1975 . . . . . . . .

1976 . . . . . . . .

1977 . . . . . . . .

1978 . . . . . . . .

1979 . . . . . . . .

1980 . . . . . . . .

1981 . . . . . . . .

13.9

34.8

20.3

8.8

7.1

7.2

7.4

6.5

O.1c

6.2

11.0

9.1

5.8

6.5

7.6

11.5

13.5

13. 5

d

7.7

23.8

11.2

3.0

0.6

(0.4)

(4.1)

(7.0)

(13.5)

Increase in purchasing power of NCI between 1972 and

1981 after adjusting for inflation:

1972 dollar = 0.798 purchasing power of 1967 dollare

1981 dollar = 0.397 purchasing power of 1967 dollar

1981 dollar = 0.3971972 dollar = 0.498

0.798

1981 appropriation = $1,001 million x 0.498 = $498 million in 1972

dollars.

Therefore, actual increase = $498 million (1981 appropriation in

1972 dollars) -$379 million (1972 appropriation) = $119 million in

crease over period 1972-1981 = $1 19/379 million = 31 percent.

a1980 NCI Fact Book.

bconsumer price Index for urban wage earners and clerical workers, table 22,

Stat/st/ca/ Abstracts of the Urr/ted States, 1981

ccajculated from data in table 20.

dRate for Ig81 is based on the annual rate calculated from changes between

Jan, and May in table 23, Statlstlca/ Abstracts O( lfre Urr/ted States, 1981.

eca[cu(ated is re ciprocal Of “all items” @flSUmer price Index In SfafMf/Ca/

Abstracts of tfre United States, 1981

SOURCE: Office of Technology Assessment.

reduced the purchasing power of the 1981 NCI appropriation to $498 million in 1972 dollars. In other

words, after allowing for inflation, the NCI appropriation increased only about 31 percent between

1972 and 1981.

Research costs are a small part of the national expenditure on cancer. The National Center for Health

Statistics estimates that cancer accounts for 10 percent of the cost of illness in 1977. Assuming that

percentage remained constant, $24.7 billion was

spent on cancer in 1980. During that year, the NCI
84

budget was $1 billion or less than 5 percent of the

total cost of the disease.

Research Support From NCI Since

Passage of the National Cancer Act

The NCI research budget can be divided between

intramural projects and extramural projects (see addendum B). In 1980, about 17 percent of NCI’S expenditures were for intramural research. The amount

spent was $197 million as compared to $802 million

spent extramurally in grants and contracts (see addendum B).

The number of extramural grant applications submitted to NCI, the number of applications approved

for funding, and the number funded are shown in

table 23 and figure 6. “Competing” applications (see

table 23) are those for which no NCI money has been

awarded for the period for which funds are being requested. They can be either of two types. “New”

competing applications describe a project that is not

currently being supported by NCI. In general, grant

applications usually request funds for 3 to 5 years,

and, if an award is made, the award is usually for 3

years. “Renewal” competing applications describe

continuations of currently supported research, but

the current grant period will expire at the time for

which continuing support is sought. For instance,

suppose that Investigator A had submitted a new

competing application in 1977 that was successful

and that a 3-year award was made to begin on January 1, 1978. If the scientist wished to continue that

line of research, sometime late in 1979 or early 1980,

he or she would submit another application. That application, coming from a supported investigator,

would be a “renewal. ”

During the period of Investigator A’s first grant, he

or she would receive two “noncompeting” (see table

23) awards, in 1979 and 1980. This bookkeeping

results from grants being made for more than l-year

periods but dollar allocations having to be made on a

yearly basis.

Competing applications must cross the peer review

hurdle to obtain funding. In this process, they are

either “approved” or “disapproved. ” Approval

means that the research outlined in the application is

worthy of support. Each approved application is

then awarded a numerical score. In general, applications with the best scores are funded.

Renewal applications fare significantly better than

do new ones. The approval rate is higher and the

percentage of approval applications funded is also

higher (table 23 and fig. 6). The better performance

of renewals is to be expected.

The number of awarded grants (both competing

and noncompeting) increased from 1,834 to 2,555

between 1974 and 1980 (table 23 and fig. 6). The bulk

of that increase, from 2,113 to 2,555, came during the

years 1978, 1979, and 1980. Therefore, that increase

occurred after the days of halcyon budget increases

between 1974 and 1977 (see above). The increased

number of regular research grant awards represents a

reprogramming of funds at NCI and increased emphasis on investigator-initiated grants. The percentage of NCI’S extramural support going to

investigator-initiated research grants increased from

52 percent (1974) to 66 percent (1980). The average

value of grant awards has almost doubled during the

7 years 1974 to 1980 (table 23).

In 1974, 18.5 percent of NCI’S extramural expenditures was for research support contracts and interagency agreements. During the next 4 years, the

percentage varied between 17 and 19 percent, and in

1979 and 1980 it increased to 21.9 and then 23.6 percent (62).

NCI Support of Basic Research

NCI expends a smaller proportion of its resources

on basic research than does the rest of NIH as a

whole (see table 24). Its expenditure of 33 percent of

its funds is also the smallest percentage spent on basic

research by any institute. The National Institute of

Dental Research (NIDR) spends the next lowest proportion for basic research, 44 percent. The National

Institute of General Medical Sciences (NIGMS)

spends the greatest proportion, 74 percent.

NCI spends 28 percent of all research and development funds spent by NIH. It spends 18 percent of the

basic research dollars; and 35 and 57 percent, respectively, of applied research and development funds

(table 24).

Because of NCI’S spending distribution, it spends a

larger percentage for “applied research” and “development” than the rest of NIH as a whole (table 24).

Despite NCI’S spending a low proportion of its funds

on basic research, it spends more than any other institute because of its large budget ($382 million from

a budget of $958 million); NHLBI spends the next

largest amount ($302 million from a budget of $530

million) on basic research.

Among the many forces that play on NCI are ones

that urge greater support of basic research, Other opposing forces want greater support for applied research and development. In OTA’S conversations

with experts about NCI, one end of a spectrum was

represented by those who strongly favored investigator-initiated research programs, grant support, and

limited centralized planning. At the other end were
—

85

Table 23.—NCI Regular Grant Awards— 1974-80 (including clinical cooperative groups)

(dollars in thousands)

Requested Approved Awarded Percent

Type award Number Amount Number Amount Number Amount funded

1974

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

55.0%

84.8

63.1—

59.3

81.4

66.1—

42.6

68.4

50.2—

37.2

52.4

42.5—

40.6

61.8

47.5—

40.7

58.6

45.9—

33.5

56.7

40.6—

1,382

379

1,761—

$100,717

33,651

134,368—

$108,621

55,314

163,935—

$113,135

53,992

167,127—

$147,591

87,162

234,753—

$153,528

97,937

251,465—

$177,989

80,521

258,510—

$188,988

89,866

278,854—

909

336

1,245—

979

429

1,408—

910

376

1,286—

1,071

578

1,649—

1,264

617

1,881—

1,414

570

1,984—

1,401

610

2,011—

$ 45,713

22,815

68,528—

$48,023

31,876

79,899—

$ 47,342

28,070

75,412—

$60,155

50,221

110,376

—

$ 75,014

57,131

132,145—

$97,596

52,012

149,608—

$103,389

62,289

165,678—

500

285

785

1,049

Averag e

$27,824

20,413

48,237

62,803

$ 34,200

1975

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

1,509

555

2,064—

581

349

930

1,112

Average

$ 30,605

27,949

58,554

72,917

$35,700

7976

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

1,499

517

2,016—

388

257

645

1,486

Average

$ 22,230

21,236

43,466

106,818

$ 51,100

7977

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total ........, . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

1,756

728

2,484—

398

303

701

1,412

Average

$ 23,781

32,436

56,217

104,431

$ 49,400

1978

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals . . . . . . . . . . . . . . . . . . . . . . . . . . .

Totals . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

1,854

752

2,606—

513

381

894

1,341

Averag e

$32,591

38,905

71,496

111,916

$ 50,100

1979

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

1,950

653

2,603—

576

334

910

1,485

Average

$ 45,287

35,025

80,312

141,198

$ 60,000

7980

Competing

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Renewals ... .. .... . . . . . . .....:...

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncompeting . . . . . . . . . . . . . . . . . . . . . . . .

1,891

632

2,523—

470

346

816

1,739

Average

$ 37,605

39,167

76,772

171,312

$ 67,000

NOTE: Average dollars presented in this column represent the total amount of money expended on grants dlvded by the number of grants That dollar value is expressed in dollars, not in ”dollars in thousands

SOURCE: National Cancer institute, 1981

those who, while acknowledging the importance of cancer problems as being in the “prefeasib]e” stage.

basic research, favored more emphasis on centralized They see an absence of understanding of cancer that

planning and grant and contract support of opportu- can be overcome only by basic research. The second

nities for making improvements in treatment. To a group see many more cancer problems as being in the

major extent, people in the first group view most of “feasible” stage. They see improvements coming
86

Figure 6.—NCI Regular Grant Awards,

Fiscal Years 1974-80

Number of grant applications received and awarded

u

1974 1975 1976 1977 1978 1979 1

Year

SOURCE: Office of Technology Assessment from NCI data.

from empirical studies that can be applied now or in

the near future to treating cancer patients.

There was also a clear division between experts

along the lines in which they view cancer treatment.

Some who are involved in basic research see the

reported improvements in survival rates as limited,

at best. In their eyes, research at the most fundamental level is necessary to provide insight and understanding to break away from methods that have

changed little over the years. Some experts who

argued in support of basic research at the same time

voiced support for epidemiology. In their eyes,

studying cancer in humans identifies “black boxes” of

higher and lower cancer occurrence. Investigating

those black boxes is seen as providing opportunities

to learn about human cancer.

The other group views the reported improvements

as real and clear indications that continual incremental advances will lead to continued betterment of

cancer care.

NCI accommodates both points of view, and it

funds both types of research. The division between

basic and other kinds of research is argued continually.

NCI Staffing

The National Cancer Advisory Board (NCAB) (70)

.

u

has drawn attention to the fact that NCI staff has not

increased in step with its increased budget (see table

25). In particular, the number of personnel declined

Table 24.—Basic and Applied Research and Development Spending at NCI

A. Proportion of budget spent on

1. Basic (o/o)

NCI . . . . . . . . $328 (33)

Others b

. . . . . $1,491 (61)

basic and applied

2. Applied (o/o)

$414 (43)

$776 (32)

research and development, 1982a

Total

3. Development (%) 1 +2+3 (

0

/0)

$215 (22) $958 (100)

$161 (07) $2,427 (100)

B. NCI expenditures as a percentage of all NIHb expenditures

(18) (35) (57) (28)

aDollar amounts are given in millions.

b

other Institutes not Including Fogarty International Center, National Library of Medicine, Office of the Director, Buildings

and Facilities,

SOURCE: Office of Technology Assessment from NIH data.
87

Table 25.—Comparison of the Increases in NCI Funding and Changes in the

Number of NCI Personnel, Fiscal Years 1971-80

Dollars Positions

Percent of Percent of Actual Percent of Percent of

increase increase full-time increase increase

Obligations over over permanent over over

Fiscal year ($000’s) base year prior year employees base year prior year

1971 ... ... .

1972 . . . . . . . . .

1973 ...

1974 ... ... .

1975 . . . . . . . .

1976 ... . . . .

1977 . . . . . . . . . .

1978 . . . . . . . . . .

1979 . . . . . . . .

1980 . . . . . . . . .

232,855

378,636

431,245

581,149

699,320

760,751

814,957

872,369

936,696

998,047

(Base year)

62.6%

85.2

149.6

200,3

226.7

250,0

275.0

302.3

328.6

SOURCE: National Cancer Instltute, 1981

in 1978 and 1980. When a comparison is made between the increase in annual appropriations and the

increases in staff, there is a great discrepancy.

The changes in staff positions can also be compared to the 31-percent increase in the NCI budget

expressed in constant dollars. When that is done, the

10-percent increase from 1,665 positions in 1972 to

l,837 in 1980 does not seem so out of line.

Making comparisons of positions to inflated dollars or to constant dollars is superficial. Conversations that OTA had with non-NCI experts revealed

difference opinions about the number of NCI employees needed. Some NCI grantees (it must be remembered that scientists contacted by OTA were

almost all successful grantees) saw little need for

more NCI staff. The peer review system (see below)

evidently has sufficient staff support, and grantees

see little need for NCI consultation or guidance in

managing their research projects. The number of

competing grant applications received by NCI increased from 1,761 in 1974 to a peak of 2,606 in 1978;

it then declined to 2,523 in 1980 (see table 23). Since

that number has become relatively stable, no increases appear to be needed in that area. NCI notes,

however, that its recent separation of program management activities from review activities will require

additional staff for review activities.

Researchers who depend on individual research

grants or program project grants (see app. B) appear

to favor an NCI largely limited to review, more so

than researchers supported mainly by contracts.

They believe that standard measures of scientific success—publication in professional journals, invitations to speak to scientific meetings, promotion,

etc. —are sufficient to make judgments about a scientist’s progress. Objections to increased demands for

accountability, which involve reports being submitted to NCI, are frequently expressed. The protests

— 1,426 (Base year) –

62.6°/0 1,665 16.80/0 16.80/0

13.9 1,736 21.7 4.3

34.8 1,805 26.6 4.0

20.3 1,849 29.7 2.4

8.8 1,955 37.1 5.7

7.1 1,986 39.3 1.6

7.2 1,969 38.1 – 0.9

7.4 1,973 38.4 0.2

6.5 1,837 28.8 – 6.7

about too many demands for accountability do not

extend to financial affairs. Reporting expenditures

and surpluses is seen as necessary, but accounting for

research results through reports to NCI is seen as unnecessary.

Other experts, particularly those associated with

NCI centers, expressed a desire for more NCI senior

staff. The additional senior-level personnel were seen

as being useful in making decisions about the

management of the centers’ programs and the relationship between NCI and the centers. Some experts

also think that the NCI senior-level officials can take

a more active role in suggesting or targeting research

areas through issuing program announcements or requests for applications in specified areas.

Researchers who run larger enterprises requiring

coordination of several investigators, and, especially, clinical research and community outreach programs which have many special rules, favor more expertise at NCI. They believe that decisionmaking and

advice from NCI would be improved by more staff.

Furthermore, some experts favored more accountability. Currently each grantee submits a progress

report to NCI at the end of each grant year and at the

end of the grant period. By general consensus, hardly

any of the yearly reports are read by anyone. The

response to this observation by some experts is that

the annual reports serve no function and should not

be required. Others believe that the annual reports

should be read and evaluated. The latter procedure

would require more NCI staff.

The differing opinions about the value of annual

reports illustrate that the number of people needed at

NCI depends on what NCI is expected to do. If it is

primarily to provide review services to assure that

the best research gets funded, it would require a

minimum of people in the extramural programs. As

NCI gets more involved in aiding in the management
88

of extramural moneys and in contracts, more people

would be required.

Contracts require more NCI supervision, and the

General Accounting Office (GAO) (25,26,27,28) has

placed part of the blame for poor contract monitoring by NCI on a shortage of personnel. In addition,

however, GAO has faulted some aspects of the NCI

management system.

In contrast to increased numbers of grants and

grant applications, which might require few new staff

positions, increased numbers of contract proposals

and contracts might require much more staff.

Whether or not more staff positions are necessary,

then, depends on perceptions of the role of NCI.

Staffing needs of intramural programs appear to be

straightforward. The budget allows a certain number

of projects; staffing needs are probably directly

related to the number of the projects.

No attempt was made in this study to determine

the staffing needs of NCI. It seems to be a thorny

problem, with experts disagreeing. To some extent

the disagreement reflects the relationships that exist

between different extramural scientists and the Institute.

ADDENDUM B: QUESTIONS POSED TO EXPERTS BY OTA STAFF

1.

2.

3.

4.

5.

6.

7.

8.

What have been the most significant advances in

cancer research and applications of research since

1971? What role has NCI played in bringing them

about?

What have been NCI’S most significant advances?

In what areas will we likely see breakthroughs in

the next decade?

What are appropriate yardsticks by which NCI

success can be measured? Should we expect to see

direct effects of NCI progress in incidence and

mortality statistics?

What are realistic short- and long-term goals for

NCI?

Based on today’s knowledge, which areas of effort should NCI be emphasizing in the next decade? What areas should be cut back or eliminated?

Are there identifiable roadblocks to major breakthroughs in cancer research?

Has an appropriate balance been struck between

9.

10.

11.

tween grants to individual researchers and to institutions? Between program project and center

grants?

Have large NCI center grants to major biomedical research institutions been productive? Is the

mechanism for monitoring the performance of

such institutions adequate?

Can you suggest changes that could be made in

NCI management policies that would accelerate

progress?

Has NCI been successful in technology transfer,

as NCI defines it? Have NCI’S programs had a

positive impact on the community? Are there

problems with the mechanism of technology

transfer? Are there technologies to be transferred

at this time? Are there negative consequences of

attempts at technology transfer? What yardsticks

can be used to measure success in technology

transfer?

NCI intrarnural and extramural programs? BeADDENDUM C: EXPERTS CONTACTED BY OTA

Dr. Harold Amos

Harvard Medical School

Dr. David Baltimore

Massachusetts Institute of Technology

Dr. Lester Breslow

UCLA School of Public Health

Dr. Irwin D. J. Bross

Roswell Park Memorial Institute

Dr. Vincent T. DeVita, Jr.

National Cancer Institute

Sir Richard Doll

Oxford University

Dr. Bernard Fisher

University of Pittsburgh School of Medicine

Dr. James F. Fries

Stanford University Medical Center
89

Dr. Armand Hammer

Occidental International Corporation

Dr. Maureen M. Henderson

University of Washington

Dr. Thomas J. King

Kennedy Institute for Ethics

Mrs. Rose Kushner

Kensington, Maryland

Dr. Joshua Lederberg

The Rockefeller University

Dr. Brian MacMahon

Harvard University School of Public Health

Dr. Elizabeth C. Miller

McArdle Laboratory for Cancer Research

Dr. Marvin Schneiderman

Clement Associates, Inc.

Dr. Guy Newell

M.D. Anderson Hospital & Tumor Institute

Dr. Norton Nelson

New York University

Dr. Frank Rauscher

American Cancer Society

Dr. Frederick Robbins

Institute of Medicine, National Academy of Sciences

Mr. Benno C. Schmidt

J. H. Whitney & Co.

Dr. Irving J. Selikoff

Mt. Sinai School of Medicine

Dr. Charles Smart

American College of Surgeons

Dr. Howard Temin

McArdle Laboratory for Cancer Research

Dr. Lewis Thomas

Memorial Sloan-Kettering

Cancer Center

Dr. Arthur Upton

New York University

Dr. Sidney Wolfe

Public Citizen Health Research Group

Dr. Ernst Wynder

Dr. Henry C. Pitot American Health Foundation

McArdle Laboratory for Cancer Research Dr. John S. Zapp

Dr. David P. Rail American Medical

National Institute of Environmental

Health Sciences

Association

ADDENDUM D: GUIDELINES FOR RECOGNITION OF A

CANCER CENTER AS COMPREHENSIVE

These guidelines describe the qualities and characteristics that the National Cancer Advisory Board

(NCAB) considers essential for recognition of a cancer center as comprehensive. They will be used by reviewers to evaluate centers that are seeking recognition as new comprehensive centers and also to evaluate established centers to determine the advisability

of continued recognition.

In establishing these guidelines, NCAB does not intend that every institution participate in all possible

activities relevant to cancer. For example, although

one of the requirements for recognition as comprehensive center is the existence of high quality

research activities, there is no requirement that all

research areas be pursued at a given center. Rather,

there is the requirement that there be high quality activity in some aspects of cancer control and some

aspects of training, education, and information

dissemination. The term comprehensive is intended

to convey that the cancer center has high quality activities in each of these major areas, but that within

any given area, the center may choose to pursue particular topics and not others.

National and Local Support

The cancer center must have a funded Cancer Center Support (Core) Grant, indicating that center activities are of sufficient quality to achieve funding

from the National Cancer Program. In addition,

there must be evidence of material support for center

activities from the parent institution(s) and the local

community.

Research Activities

The cancer center should support laboratory, clinical, epidemiologic, and evaluative research efforts of
90

the highest quality and should create an environment

which fosters cancer-related information exchange,

cooperation, and collaboration between laboratory

scientists of multiple disciplines and between laboratory scientists, clinical scientists, and epidemiologists. Centers should maintain their own clinical

investigative activities, Those activities should include participation in regional and/or national clinical trials related to the cancers being studied by the

center in question. The center should have available

the personnel and facilities to carry out high quality

diagnostic, therapeutic, and rehabilitative procedures in the interdisciplinary setting most suited to

the cancers being investigated. The center should

make a commitment to participate in uniform clinical

data acquisition and reporting through the Centralized Cancer Patient Data System (CCPDS).

Cancer Control Activities

The cancer center should serve as an important

focal point for local and regional programs designed

to control cancer through research and demonstration activities in areas such as prevention, detection,

diagnosis, treatment, and rehabilitation. The center

should seek the active participation of all sectors of

the professional and lay community in control activities.

Training, Education, and Information

Dissemination

The cancer center should serve as an important

focal point for local and regional information dissemination, as well as for professional and lay education

programs. Programs to assess which methods of information dissemination and education effectively

modify professional and lay behavior patterns are

desirable. Centers should also be actively involved in

training of professional and support personnel.

Administration

The cancer center (or in the case of consortia, the

constituent institutions) should have a formal commitment of support from the parent institution(s),

manifested by the center director having the following: 1) primary control of space and equipment;

2) necessary control over professional and staff appointments to enable the center director to effectively

direct the center and assure accomplishment of its

mission; 3) control of grouped beds and ambulatory

facilities for clinical cancer research; and

4) responsibility for program planning, evaluation,

and implementation, preparation of budgets and

control of expenditures. In addition, the center must

have an administrative structure that will assure

long-term viability, efficiency of operation, and

sound financial practice.

Geographic Impact

Scientific excellence of any center is a primary consideration. The geographic location of the cancer

center, however, should increase the national capability to carry out regional training, education and

information dissemination activities. The location of

other comprehensive centers and the size of the regional population with access to the center are additional factors bearing on recognition.
Chapter 7

Technology Transfer at the

National Heart, Lung, and

Blood Institute
Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

History and Development of Technology Transfer at NHLBI. . . . . . . . . . . . . . . . . . . . 97

Technology Transfer Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............106

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........................111

List of Tables

Table No. Page

26.

27.

28.

29.

30,

31,

32.

33.

34.

35,

36.

Mortality From the Ten Leading Causes of Death, United States, 1979 . . . . . . . . 93

Morbidity From Selected Chronic Conditions, United States, 1979 . . . . . . . . . . . 93

Number of Hospital Discharges and Days for Patients With Cardiovascular

Diseases, United States, 1978 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Number and Percent Distribution of Physics Office Visits for Diseases of the

Circulatory Systern and for Selected Principal Diagnoses, United States, 1978.. 94

NHLBI Program Elements by Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

NHLBI Appropriations, Fiscal Years 1972-82 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

NHLBI Appropriations, Fisca Year 1980 . ................................100

NHLBI Appropriations, Fiscal Year 1982 . ................................100

1980 NHLBI Projected Resource Allocation for Fiscal Year 1982 . .............100

Emerging Technologies Identified by the NHLBI Divisions in 1979 .. ... ... ....104

Emerging Technologies, NHLBI, 1980 Compilation . .......................105

List of Figures

Figure Page

i

8.

9.

10.

11.

12.

13.

14.

Death Rates for Cardiovascular Diseases and Other Causes of Death,

United States, 1960-79 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Trends in Cardiovascular Disease and Noncardiovascular Disease: Decline by

Age-Adjusted Death Rates, 1968-78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Deaths by Cause and Percentage of Total Deaths, 1968 and 1978 . . . . . . . . . . . . . 96

NHLBI Organizational Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Distribution of Fiscal Year 1979 Funding Among Federal Agencies by

Major Areas of the National Program . . . . . . . . ............................101

Fiscal Year 1979 Federal Funding Totals by National Program Area . ..........102

NHLBI’s Conception of the Biomedical Research Spectrum . .................103

NHLBI’s Conception of the Technology Transfer Process . ..................103
Chapter 7

Technology Transfer at the National

Heart, Lung, and Blood Institute

INTRODUCTION

Diseases of the cardiovascular and respiratory

systems account for 5 of the 10 leading causes of

death in the United States. Four of these are

chronic diseases under study by the National

Heart, Lung, and Blood Institute (NHLBI)–

heart disease (ranked first), cerebrovascular disease (third), chronic obstructive lung disease

(fifth), and arteriosclerosis (ninth) (see table 26).

Moreover, hypertension and heart conditions

are among the 10 leading chronic causes of morbidity (see table 27); and cardiovascular diseases

account for nearly 5 million hospitalizations,

with an average length of stay of over 10 days

(table 28), and over 55 million physician office

visits (table 29).

Although cardiovascular diseases remain the

number one cause of mortality, there has been a

continuing decline in age-adjusted mortality

rates since the 1960’s, including a 25-percent

decline between 1968 and 1978 (see figs. 7, 8,

and 9). This decrease in mortality from cardiovascular diseases has been attributed to advances in diagnosis and treatment, preventive

measures, and changes in Iifestyle. The decline

has not been confined to the United States, but

Table 27.—Morbidity From Selected Chronic

Conditions, United States, 1979 (thousands)

Condition Prevalence

1.

3.

4.

5.

6.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

Chronic sinusitis . . . . . . . . . . . . . . . . . . . . .

Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hypertension . . . . . . . . . . . . . . . . . . . . . . . .

Absence of extremities (or parts),

deformities, orthopedic impairments . . . .

Hearing impairments . . . . . . . . . . . . . . . . .

Heart conditions . . . . . . . . . . . . . . . . . . . . .

Hay fever (without asthma). . . . . . . . . . . . .

Digestive conditions ... , . . . . . . . . . . . . . .

Hemorrhoids . . . . . . . . . . . . . . . . . . . . . . . .

Eczema, dermatitis, urticaria . . . . . . . . . . .

Chronic bronchitis. . . . . . . . . . . . . . . . . . . .

Corns, callosities, bunion. . . . . . . . . . . . . .

Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Asthma (with or without hay fever) . . . . . .

Varicose veins . . . . . . . . . . . . . . . . . . . . . . .

Diseases of the urinary system . . . . . . . . .

Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Synovitis, bursitis, tenosynovitis. . . . . . . .

Diseases of nail . . . . . . . . . . . . . . . . . . . . . .

28,054

25,868

23,745

20,213

16,663

16,428

15,620

14,692

8,813

7,754

7,474

6,584

6,450

6,402

6,030

5,602

5,348

5,236

4,637

4,302

SOURCE: National Institutes of Health, derived from unpublished data from

the National Center for Health Statistics.

Table 26.—Mortality From the Ten Leading Causes of Death, United States, 1979a

Rate per

100,000

Cause of death Number population Percent

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,895,380

Heart disease . . . . . . . . . . . . . . . . . . . . . 723,100

Malignant neoplasms . . . . . . . . . . . . . . 401,450

Cerebrovascular diseases. . . . . . . . . . . 167,320

Accidents . . . . . . . . . . . . . . . . . . . . . . . . 102,740

Chronic obstructive pulmonary

disease . . . . . . . . . . . . . . . . . . . . . . . . . . 49,580

Influenza and pneumonia . . . . . . . . . . . 43,770

Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . 32,780

Cirrhosis of the liver . . . . . . . . . . . . . . . . 29,620

Atherosclerosis . . . . . . . . . . . . . . . . . . . 28,410

Suicides. . . . . . . . . . . . . . . . . . . . . . . . . . 25,710

866.2

330.4

183.5

76.5

47.0

22.7

20.0

15.0

13.5

13.0

11.7

100.0

38.2

21.2

8.8

5.4

2.6

2.3

1.7

1.6

1.5

1.4

All other causes . . . . . . . . . . . . . . . . . 290,900 132.9 15.3

aBased on a Io.percen t sample of death certificates for the 12 months of 1979. Causes of death were coded to the Ninth Revision of the International Classification of Diseases.

SOURCE: National Center for Health Statlstlcs, &forrth/y Vita/ Stafistlcs Report 29:1, Apr. 9, 1980.

93
94

Table 28.—Number of Hospital Discharges and Days for Patients With

Cardiovascular Diseases, United States, 1978

Number of Length Number of

discharges of stay days

First-listed diagnosis and ICDA code (thousands) (days) (thousands)

Total cardiovascular 390-458,746,747 . . . . . . . .

Rheumatic fever and rheumatic heart

disease 390-398 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acutemyocardial infarction 410. . . . . . . . . . . . . . . . . .

Other coronary heart disease 411-413. . . . . . . . . . . . .

Hypertensive disease 400-404 . . . . . . . . . . . . . . . . . . .

Cerebrovascular disease 430-438 . . . . . . . . . . . . . . . .

Congenital heart disease746, 747 . . . . . . . . . . . . . . . .

Other cardiovascular diseases 420-429,440-458 . . .

4,828

114

425

1,529

317

648

62

1,733

10.2

10.8

12.5

9.1

6.8

13.4

7.7

10.0

49,163

1,235

5,320

13,989

2,168

8,700

479

17,268

SOURCE: National Heart, Lung, and Blood Institute, based on unpublished data from the Hospital Discharge Survey, National Center for Health Statistics.

Table 29.—Number and Percent Distribution of Physicians’Office Visits for

Diseases of the Circulatory System and for Selected Principal Diagnoses,

United States, 1978

Numberofvisits

Diagnosis and ICDA code (thousands)

Total circulatory 390-458. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Rheumatic fever and rheumatic heart disease 390-398. . . . . . . . .

Hypertensive disease 400-404 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Essential benign hypertension 401 . . . . . . . . . . . . . . . . . . . . . . . .

lschemic heart disease 410-413 . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acutemyocardial infarction and other acute IHD 41O-411 . . . . .

Chronic lHD412 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Angina pectoris413 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other forms of heart disease 420-429 . . . . . . . . . . . . . . . . . . . . . . .

Symptomatic heart disease 427 . . . . . . . . . . . . . . . . . . . . . . . . . .

Cerebrovascular disease430-438 . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of arteries, arterioles, capillaries 440-448. . . . . . . . . . . .

Arteriosclerosis 440 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diseases of veins and other circulatory 450-458 . . . . . . . . . . . . . .

Phlebitis and thrombophlebitis 451 . . . . . . . . . . . . . . . . . . . . . . .

Varicose veins of lower extremities 454 . . . . . . . . . . . . . . . . . . . .

Hemorrhoids 455. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55,167

1,000

24,968a

14,578

4,378

2,270

2,190

5,764

24,068

1,610

11,295

1,674

3,314

740

1,221

988

1.855

aAn estimate of 51 million Is given by the National Disease and Therapeutic Index, which includes visits in all locations (Office, hospital, etc.) and by telephone.

SOURCE: National Heart, Lung, and Blood lnstitute, based on unpublished data from the National Ambulatory Medical Care

Survey, National Center for Health Statistics.

has also occurred in Canada, Australia, and Finland, countries that also have high coronary artery disease death rates. In England, however,

where preventive care in nutrition and hypertension treatment have not been vigorously pursued, mortality from heart disease has remained

constant. In 1968, a middle-aged male American

had a 40-percent higher risk of death than an

Englishman; by 1976 the American’s risk had

fallen below the Englishman’s (37,40).

Improvements in rates of mortality and morbidity are not only desirable from a human wellbeing standpoint. There are also large economic

implications. The economic cost in the United

States of death due to circulatory, respiratory,

and blood diseases was estimated at close to $40

billion, in terms of lost earnings (43). In fact,

diseases of the circulatory system rank first

among all diseases in economic costs of death

(accidents are first overall). These diseases also

rank first in total amount of disability (measured

in number of days) caused by disease, in total

economic cost of morbidity (productivity

losses), and in overall totals of the economic

“burden” of diseases, including the above meas-
95

Figure 7.—Death Rates for Cardiovascular Diseases and Other Causes of Death.

400

380

360

340

320

300

280

260

1960 1965 1970

Year

NOTE: Age-adjusted to U.S. population, 1940.

aEstimated by NHLBI.

SOURCE: Prepared by the National Heart, Lung, and Blood Institute.

1975 1979

Data from the National Center for Health Statistics.

Figure 8.— Trends in Cardiovascular Disease and Noncardiovascular Disease:

Decline by Age-Adjusted Death Rates, 1968-78

0 0

10 10

Heart attack

20 20

30 30

Stroke

I 1 1 I I I I I I I 1

1966 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978

SOURCE: National Heart, Lung, and Blood Institute,
96

Figure 9.–Deaths by Cause and Percentage of Total Deaths, 1968 and 1978

1968

Stroke Cardiovascular

diseases Coronary

heart disease

.

Pneumonia an

influenza

(3.8%) ,

Chronic obstructi

pulmonary disease 7 ,

(1.6°/0) w ., .

Cancer

SOURCE. National Heart, Lung, and Blood Institute,

(16.50/o)

expenditures

through the

ures and others such as health care

(43).

Improvement in treated cases —

combined impact of medical and surgical interventions (e. g., coronary bypass surgery, coronary care units, emergency medical services)

cannot account for the 25-percent decline in ageadjusted mortality rates in the 1970’s. The suggestion, therefore, is that the incidence and

severity of the disease have decreased. Among

the factors cited are greater awareness of overnutrition, increased physical activity, decreased

smoking, and treatment of hypertension. On the

latter factor (37):

The proportion of hypertensive persons

under treatment has doubled in recent years

. . . More effective use of antihypertensive

agents could be responsible for perhaps a third

of the reduction in cardiovascular mortality . . . Evidence that hypertension control is an

important contributor to the decline is especially strong because hypertension is one of the major risk factors for stroke, cardiac failure, and

1978

Stroke Cardiovascular

Chronic obstructive!

pulmonary disease q

(2.40/o) m

coronary disease; hypertension-related deaths

have shown the steepest decline; and declines in

stroke incidence are seen in women who have

shown the greatest improvement in hypertension awareness and treatment (references omitted).

A review of the history and development of

NHLBI would show a concurrent expansion in

its functions and funding at the same time these

decreases in cardiovascular disease mortality

rates were occurring. Determination of a causeand-effect relationship between the rise of

NHLBI and improvement in cardiovascular

mortality is not possible. However, as the

leading research organization against cardiovascular disease, NHLBI influences the direction of

research, development, and application of the

instruments against cardiovascular disease, and

for the past 10 years, it has operated under explicit legislative mandates in technology transfer. Thus, this summary of how NHLBI carries

out its technology transfer responsibilities

focuses on: 1) the administrative structure that
97

NHLBI has developed for technology transfer, tivities have been in concert with the factors that

and 2) the kinds of technology transfer activities are known to have helped to lower cardiovasit has supported to identify whether these ac- cular disease mortality rates.

HISTORY AND DEVELOPMENT OF

TECHNOLOGY TRANSFER AT NHLBI

The National Heart Institute was established

in 1948 under the National Heart Act (Public

Law 80-755). In 1969, it was designated the National Heart and Lung Institute to reflect its expanded responsibilities in diseases of the lung.

And in 1976, its research responsibilities were

recognized to include “the use of blood and

blood products and the management of blood

resources, ” and the institute was redesignated

the National Heart, Lung, and Blood Institute.

Apart from these laws, which recognized

NHLBI’s role in heart, lung, and blood diseases,

the National Heart, Blood Vessel, Lung, and

Blood Act of 1972 (Public Law 92-423) has most

influenced NHLBI’s current role. First, the 1972

legislation established separate funding and renewal periods for NHLB1, as had been established for the National Cancer Institute (NCI) in

the previous year (1971). In contrast, the other

institutes of the National Institutes of Health

(NIH) fall under the general research authority

of the Public Health Service Act, which places

no specific disease category allocations nor time

limits on their authorization. Second, the 1972

act specified the following responsibilities for

NHLBI:

●

●

●

●

research into the epidemiology, etiology,

and prevention of heart, blood vessel, lung,

and blood diseases, including the social, environmental, behavioral, nutritional, biological, and genetic determinants and influences;

research in the basic biological processes

and mechanisms of the heart, blood vessel,

lung, and blood;

development and evaluation of the techniques, drugs, and devices used in the diagnosis and treatment of these diseases;

programs to develop technological devices

to assist, replace, or monitor vital organs;

●

●

●

●

●

●

programs for field studies and large-scale

testing, evaluation, and demonstration of

approaches to these diseases;

research in blood diseases and the use of

blood resources;

education and training of scientists, clinicians, and educators in these fields;

public and professional education in these

diseases;

programs for research of these diseases in

children; and

programs for research, development, demonstration, and evaluation in emergency

medical services.

The 1972 act also specified that:

●

●

●

●

●

an Assistant Director for Health Information Programs be appointed to provide the

public and health professionals with information on these diseases. Special emphasis

was to be placed on disseminating information regarding diet, exercise, stress, hypertension, cigarette smoking, weight control,

and other factors related to prevention;

prevention and control programs be established with other governmental and private

health agencies;

national research and demonstration centers be established in these diseases;

an interagency technical committee be established to coordinate Federal health programs and activities in these diseases; and

no less than 15 percent of appropriated

funds be used for programs in lung diseases,

and 15 percent in programs for blood diseases and blood resources.

Finally, the 1972 act required annual reports

summarizing that year’s accomplishments and

plans for the next 5 years from the director of the

institute and from NHLBI’s National Advisory

Council.
98

In 1974, NHLBI divided its activities into program efforts in: 1) research, and 2) prevention,

control, and education (72):

The Research programs deal largely with the

development of new knowledge and the testing

and evaluation of existing knowledge. The Prevention, Control, and Education programs deal

with the application and dissemination of

knowledge already developed and evaluated

through research, but not yet effectively applied

toward the prevention, control, and treatment

of disease. These Prevention, Control, and Education programs are an essential link between

biomedical research and health care. Their purpose is not to deliver health services but rather

to improve and expedite the transmission of

fundamental research advances to the public

and to medical practitioners and thereby help to

promote the health of our citizens.

The research and prevention, control, and

education activities were to be coordinated within a broad program strategy by (72):

●

●

initiating an ordered sequence of coordinated program activities ranging from the

acquisition of new knowledge to demonstration and control programs in the health

care setting of the community;

providing adequate program evaluation before the application of existing knowledge

to health care delivery systems; and

● evaluating the impact of implemented programs on the health of the American people.

This program strategy was to be applied to

subcategories or elements of heart and vascular

diseases, lung diseases, and blood diseases and

blood resources. The initial elements have remained the same for the Division of Heart and

Vascular Diseases and undergone minor modifications in the Divisions of Lung Diseases and of

Blood Diseases and Resources. Current NHLBI

program elements by division are summarized in

table 30.

The organizational structure of NHLBI is summarized in figure 10, and total appropriations

are summarized in table 31, Fiscal year 1982

marks the second time that NHLBI appropriations have not increased in actual dollars.

Because of overlapping responsibilities between the organizational components shown in

figure 10 (e.g., extramural and intramural research takes place in all three of the categorized

disease divisions), allocation of these funds

among NHLBI’s various activities can be expressed in various parameters, For example,

table 32 summarizes 1980 funds as allocated

among: 1) extramural research in heart and vascular diseases, lung diseases, and blood diseases

Table 30.—NHLBI Program Elements by Division

Division of Heart Division of Blood

and Vascular Diseases Division of Lung Diseases Diseases and Resources

Arteriosclerosis

Hypertension

Cerebrovascular disease

Coronary heart disease

Peripheral vascular disease

Arrhythmias

Heart failure and shock

Congenital and rheumatic

heart disease

Cardiomyopathies and infections

of the heart

Circulatory assistance

Structure and function of Bleeding and clotting disorders

the lung

Red blood cell disorders

Chronic obstructive lung Sickle cell disease

diseases

Pediatric pulmonary disease Blood resources

Fibrotic and immunologic

interstitial lung diseases

Respiratory failure

Pulmonary vascular diseases

SOURCE: National Heart, Lung, and Blood Institute.
99

Figure 1O.—NHLBI Organizational Structure

Office of

Prevention,

Education,

and Control

Office of

Administrative

Management

I I

Office of

Special

Concerns

Division of

Heart and

Vascular Diseases

Office of

the Director

T

Division of

Lung Diseases

Division of

Extramural Affairs

SOURCE. National Heart, Lung, and Blood Institute

Table 31.– NHLBI Appropriations, Fiscal Years

1972=82 (dollars in thousands)

1972 ... ... ... .. .$224,302

1973 . ............290,784

1974 . ............289,550

1975 . ............324,630

1976 . ............370,013

1977 . ............396,661

1978 . ............447,909

1979 , , . ..........510,134

1980 . ............527,488

1981 . ............560,264

1982 . ............559,637

SOURCE: National Institutes of Health.

and resources; 2) intramural research; 3) direct

operations; and 4) program management. Table

33 summarizes 1982 funds in similar fashion, but

with extramural research categorized by research grants (see the table for further subclassiDivision of

Blood Diseases

and Resources

Division of

Intramural Research

fication), research and development contracts,

and training.

NHLBI uses yet another method of categorizing its funding in the 5-year planning requirements of its annual reports. Extramural research

is subclassified into: 1) heart and vascular

diseases; 2) lung diseases; 3) blood diseases and

resources; 4) national research and demonstration centers; 5) prevention, education, and control programs; 6) training; and 7) construction.

Table 34 summarizes NHLBI’s 1980 projections

for 1982, using these categories of extramural

research. (The reader should compare the categories in table 34 with those in tables 32 and 33.

Also note that the actual appropriations for 1982

were $559.6 million, in contrast to projected

needs of $732.4 million or a lowerbound esti-
—

100

Table 32.- NHLBI Appropriations, Fiscal Year 1980 (dollars in thousands)

Grants and contracts

R&D grants R&D Research training

Total Projects Centers Others contracts Individuals Institutions

Extramural research:

Heart and vascular diseases . . . . . $309,913 176,545 33,568 11,479 67,942 3,107 17,272

Lung diseases . . . . . . . . . . . . . . . . . 75,199 44,866 14,022 4,377 4,817 782 6,335

Blood diseases and resources. . . . 72,345 45,485 14,716 1,452 6,232 993 3,467

Intramural research . . . . . . . . . . . . . . 39,040 – — — —

Direct operations. . . . . . . . . . . . . . . . .

— —

25,062 – — — —

Program management . . . . . . . . . . . .

— —

5,532 – — — — — —

Total . . . . . . . . . . . . . . . . . . . . . . . $527,091 266,896 62,306 17,308 78,991 4,882 27,074

SOURCE: National Institutes of Health.

Table 33.—NHLBI Appropriations, Fiscal Year 1982

(dollars in thousands)

Research grants

Research projects:

Noncompeting projects. . . . . . . . . . . . . . . . $211,293

Administrative supplements. . . . . . . . . . . . 1,455

Competing projects:

Competing renewals . . . . . . . . . . . . . . . . 46,007

New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42,672

Supplemental . . . . . . . . . . . . . . . . . . . . . . 2,932

Subtotal, competing projects . . . . . . . 91,611

Subtotal, research projects. . . . . . . . . 304,359

Research centers . . . . . . . . . . . .

Other research:

Research career programs . .

Cooperative clinical research

Minority biomedical support.

Other research related. . . . . .

Subtotal, other research . .

Total, research grants . . . . . . . .

Training

Individual awards . . . . . . . . . . . .

Institutional awards. . . . . . . . . .

Total, training . . . . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

64,808

14,476

4,838

2,112

2,178

23,604

392,771

4,826

22,948

27,774

Research and development contracts . . . . . . $56,050

Intramural research . . . . . . . . . . . . . . . . . . . . . 48,442

Direct operations . . . . . . . . . . . . . . . . . . . . . . . 28,100

Management fund . . . . . . . . . . . . . . . . . . . . . . (26,293)

Program management. . . . . . . . . . . . . . . . . . . 6,500

Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $559,637

SOURCE: National Institutes of Health.

mate of $643.4 million. Projected needs have

always been higher than actual appropriations. )

NHLBI is not the only Federal agency funding

cardiovascular, lung, and blood research. This

was recognized in the 1972 act through the reTable 34.—1980 NHLBI Projected Resource

Allocation a for Fiscal Year 1982

(dollars in millions)

Lowerbound

Allocation al Iocation

Extramural research programs:

Heart and vascular diseases. . . . . .

Lung diseases. . . . . . . . . . . . . . . . . .

Blood diseases and resources . . . .

National research and

demonstration centers. . . . . . . . .

Prevention, education, and

control . . . . . . . . . . . . . . . . . . . . . .

Training . . . . . . . . . . . . . . . . . . . . . . .

Construction . . . . . . . . . . . . . . . . . . .

Total extramural research programs .

Intramural research . . . . . . . . . . . . . . .

Direct operations and program

management . . . . . . . . . . . . . . . . . . .

$294.2

79.2

85.5

50.5

60.0

55.0

0.0

$624.4

56.5

51.4

$283.2

75.8

79.6

14.6

49.1

45.0

0.0

$643.4

50.0

46.1

Total . . . . . . . . . . . . . . . . . . . . . . . . . . $732.4 $643.4

NOTE: The figures in this table were not the actual appropriations. The table is

used to illustrate the various ways allocations can be made. See text for

explanation.

a

Tabulations give the primary thrust of activities, even though the activities

generally involve more than one subprogram.

SOURCE: NHLBI 8th Annual Report, 1980,

quirement that an Interagency Technical Committee (IATC) be established to coordinate

Federal health programs and activities in the cardiovascular, lung, and blood areas. The Director of NHLBI chairs the committee, which includes representatives from all Federal departments and agencies whose programs involve

health functions or responsibilities. IATC’S first

report was issued in 1977, and an update was

provided in 1979,

In fiscal year 1979, NHLBI provided 63.8 percent of Federal funds, with other NIH institutes
101

providing 20.7 percent, and other Federal programs providing the remaining 15.5 percent.

Figure 11 summarizes the distribution of funds

according to disease categories, and figure 12

summarizes the distribution of funds according

to the program elements of NHLBI’s three divisions. These Federal funds were being used to

support nearly 9,000 research projects in fiscal

year 1979 (77).

In implementing its program strategy of initiating an ordered sequence of coordinated program activities, providing adequate program

evaluation before application to health care, and

evaluating the impact of implemented programs

(i.e., NHLBI’s program strategy response to the

1972 act), NHLBI conceptualizes the biomedical

research spectrum as illustrated in figure 13.

NHLBI considers the research spectrum from basic research to demonstration programs (fig. 13)

as comprising the initial knowledge development phase of the technology transfer process

(i.e., the scientific data base shown in fig. 14).

NIH’s research institutes have the primary

responsibility for knowledge development and

the technical analysis phase of the judgment and

decision steps in the technology transfer process

(fig. 14), with the NIH Director’s Office playing

an increasing role as the technology moves toward specific nonscientific issues. NHLBI, because of its broad mandate, not only may take

responsibility for technical analyses, but also

may play a lead role in interface assessment and

knowledge dissemination (76).

NHLBI created a Technical Consensus Development Committee in 1977, which adopted the

following goal (76):

To promote prompt adoption into practice of

approaches that are technically valid, socially

and ethically acceptable, and economically feasible, for prevention or control of heart, lung

and blood diseases.

The Committee, which meets periodically,

has the following agenda (76):

1. definition of process itself, and interaction

with planning and evaluation systems already in place;

2. development of criteria for determining

consensus candidates;

Figure 11.— Distribution of Fiscal Year 1979

Funding Among Federal Agencies by Major Areas

of the National Program (dollars in thousands)

NHLBI 63.80/o

Other NIH

A

Heart and blood

20.70/o vessel diseases

Other Federal 15.5%

aTotal does not include unavailable funding data Indicated in tables.

bDoes not include any projects directly related to Ieukemias, blood cell formation, or the cellular immune system, but only those directly related to blood

diseases and blood resources.

SOURCE: National Heart, Lung, and Blood Institute

3.

4.

5.

development of criteria for determining

relative priorities of consensus candidates;

formulation of a tracking system for technology consensus projects; and

designation of specific points at which to

hold consensus exercises (e.g., completion

of a clinical trial).
—

102

Figure 12.—Fiscal Year 1979 Federal Funding Totals by National Program Area (dollars in millions)

a projects which are directly related to more than one National program area.

SOURCE: National Heart, Lung, and Blood Institute.
103

Figure 13.—NHLBI’s Conception of the Biomedical Research Spectrum

a

I

\

L Non-Federal health organizations

Public

Private

Health care

delivery

Inproved disease

prevention and

treatment

Volunteer

Medical profession

SOURCE: National Heart, Lung, and Blood Institute.

Figure 14.—NHLBI’s Conception of the Technology Transfer Process

Implementation

Assess scientific

data base

Conduct basic

research

Conduct applied

research

Conduct clinical

trials

Conduct demonstration projects

Review technical

findings

●

●

●

Interpret

\

●

scientific

data base

Validate technical findings ●

Initiate

/

nontechnical

review

Evaluate ● Convey results ● Incorporate

social, legal, to health care and utilize

economic, and systems knowledge

ethical aspects within health

Assess overall care systems

merit

● Assess impact of new knowledge

SOURCE: National Heart, Lung, and Blood Institute
104

NHLBI technology transfer activities are

followed by a coordinator in the Office of

Program Planning and Evaluation. In 1978,

concurrent with the establishment of the

Office for Medical Applications of Research

(OMAR) in the NIH Director’s Office,

NHLBI organized its own Medical Applications Program (MAP) in the Office of Program Planning and Evaluation. The MAP

coordinator has the following resources

available: 1) ad hoc MAP-Staff Working

Groups selected from NHLBI’s divisions

and offices, 2) IATC, and 3) an NHLBI Advisory Council Working Group for Medical

Applications.

MAP has two related but functionally

separate sets of objectives. First are medical

applications objectives incorporated within

the program plans for each of the NHLBI

operating units. Second are objectives at the

level of the NHLBI Director’s Office. The

latter objectives are (75):

1. serve as a current source for an inventory

and status information on all high priority

“technologies in transition, ” as identified

and prioritized by NHLBI operating units.

2. insure coordination of technology development, assessment, and dissemination

within NHLBI and between NHLBI and

other portions of NIH or external agencies.

3. assist NHLBI operating units in providing

visibility to their medical applications

plans and accomplishment.

4. assist NHLBI operating units in maintaining awareness of advances in the state-ofthe-science in technology assessment, technology validation, dissemination of technology developments to the clinical community, and diffusion of biomedical

advances into standard clinical practice.

5. insure that a system for identifying and

acting on priority technologies is incorporated into NHLBI’s planning process.

These plans are still under formulation within

NHLBI, with the assistance of a consultant from

the Sloan School of Management at the Massachusetts Institute of Technology. However, the

MAP objectives remain the same, with the overall program strategy still to be worked out.

The first objective is to serve as a source for an

inventory and status information on high priority technologies—classified as emerging, new, or

established technologies in transition—which

NHLBI is actually developing or for which formal evaluations are planned or underway.

An emerging technologies list was generated

by the divisions of NHLBI in 1979. This list (see

table 35) was part of a list of several hundred

technologies compiled by the Public Health

Service Agencies for the (at that time) newly legislated National Center for Health Care Technology (NCHCT). However, the criteria for inclusion were considered too vague, and the purTable 35.—Emerging Technologies Identified by the

NHLBI Divisions in 1979

Heart Division

Clinical trials

Hypertension detection and followup program (HDFP)

Aspirin myocardial infarction study (AMIS)

Multicenter investigation of limitation of infarct size

(MILIS)

Coronary artery surgery study (CASS)

Indomethacin v. surgery for patent ductus

Multiple risk factor intervention trial (MRFIT)

Cholestyramine to reduce lipids

Beta-blocker heart attack trial (BHAT)

Diagnostic/therapeutic technology

Methods for quantifying infarct size

Percutaneous transluminal coronary angioplasty (PTCA)

Circulatory assist devices

Long term

Noninvasive detection of atherosclerotic lesions

Totally implantable circulatory assist devices

Blood Division

Prenatal diagnosis of hemophilia

Prenatal diagnosis of thalassemia

Prenatal diagnosis of sickle cell syndrome

Antiplatelet agents for arterial thrombosis

Fibrinolytic agents

Prophylaxis for deep vein thrombosis (DVT)

Two new iron chelators tested in animals

Activated factor IX for hemophiliacs

Extracorporeal carbamylation of hemoglobin in sickle cell

disease

Granulocyte transfusions

Plasmapheresis and cytapheresis

Fluorocarbons as blood substitutes

Lung Division

Noninvasive assessment of pulmonary hypertension

Noninvasive methods to monitor intracellular events

Noninvasive diagnosis of pulmonary embolism

SOURCE: National Heart, Lung, and Blood Institute.
105

pose of compiling the list was not clear. Thus, in

1980, NHLBI defined an “emerging health care

technology” as:

. . . any technology under development that

appears likely to be used in the practice of medicine within five years. This implies that the

technology has passed a critical point in the development process such that validation of safety

and efficacy in human subjects either has been

initiated or is imminent.

NHLBI also set forth the following criteria for

priority identification of emerging technologies:

1) potential benefit; 2) health risk; or 3) current

or potential social, ethical, legal, or economic

concerns. Finally, NHLBI identified the following uses for the emerging technology list (73):

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

monitoring of the diffusion/development

process;

acceleration of development efforts;

conduct of additional validation studies;

analysis of the state of the science;

development of specific assessments from

certain perspectives such as potential ethical, legal, or economic impact;

development of multifaceted assessments;

initiating consensus development;

development of a strategy for assessing

third-party reimbursement recommendations;

dissemination of information for health

planning;

general dissemination of information (pro

or con); and/or

planning for impact evaluation.

The criteria mentioned above led to a much

smaller list of emerging technologies in the 1980

NHLBI compilation. This list (see table 36) included eight emerging technologies, only four of

which had been on the 1979 list.

In NHLBI’s current compilation, in addition

to emerging technologies, new technologies and

established technologies in transition are also to

be identified (75). Thus, some technologies on

the 1979 list should appear under one of these

two categories—e. g., coronary artery surgery

(46) and beta-blockers for heart attacks (8).

New technologies are “those that may have

passed the stage of clinical trials but are not yet

Table 36.–Emerging Technologies, NHLBI,

1980 Compilation

Therapeutic technologies

Percutaneous transluminal coronary angioplastya

Circulatory assist devicesa

High frequency ventilation

Therapeutic plasmapheresisa

Diagnostic technologies

Ultrasound B-sound imaging

Subtraction radiography

Measurement of high density lipoprotein

Prenatal diagnosis of sickle cell diseasea

a

Technologies which were On the 1979 list.

SOURCE: National Heart, Lung, and Blood Institute

widely disseminated, or those that are moving

into wide scale usage without benefit of clinical

trials. ” Priority for identifying new technologies

is given to “those which affect large population

groups, represent major advances in terms of

improved outcomes, have critical unanswered

safety issues, and have significant economic implications.”

Established technologies in transition are

“those established technologies currently undergoing or likely to undergo major changes in their

extent of usage or costs as a result of new research findings, or for which serious concerns

have been raised concerning safety or effectiveness.” Priority is to be given to “those that are

the most widely used, have the greatest economic implications, or pose grave concerns for

patient safety, and for which significant NHLBI

resources are currently, or are planned, to be

directed at developing or disseminating new

knowledge, or in changing the degree to which

the technology is applied. ”

The year 1982 marked the 10th anniversary of

the National Heart, Blood Vessel, Lung, and

Blood Act of 1972, and NHLBI is currently compiling a list of the most important clinical advances of the past 10 years. Thus, three lists are

being compiled: 1) emerging technologies;

2) more established technologies which warrant

reexamination (new technologies and established technologies in transition); and 3) the

most important clinical advances of the past 10

years.

91-486 0 - 82 - 8
106

TECHNOLOGY TRANSFER ACTIVITIES

NHLBI has sponsored four consensus development meetings for OMAR in the NIH Director’s Office: 1) transfusion therapy in pregnant

sickle cell disease patients (April 1979); 2) improving clinical and consumer use of blood pressure measuring devices (April 1979); 3) thrombolytic therapy in thrombosis (April 1980); and

4) coronary bypass surgery (December 1980).

Since technology transfer involves the translation of basic research into effective and appropriate treatment, management, or prevention of

diseases, much of what NHLBI supports is part

of the technology transfer process. More specifically, the later stages of knowledge development—clinical trials and demonstration programs—are already far down the path toward a

technology’s incorporation into direct health

care delivery and educational programs for the

prevention of diseases. In fact, NHLBI has explicitly recognized the technology transfer functions of clinical trials and demonstration programs:

The large-scale collaborative study or clinical

trial has become an important, indeed, critical

activity in the biomedical research spectrum. It

is the clinical trial that determines most precisely the efficacy of treatment or preventive regimens. These large studies, which may cost tens

of millions of dollars, impact both on research

and medical practice. In testing hypotheses born

from fundamental and clinical research they can

point toward research areas where more work is

required and where the results will have the

most widespread benefit. They have the potential to improve the quality of health care and

control costs through their careful comparison

of alternative treatments (42).

Demonstration programs test methods to introduce or facilitate delivering health care advances to the public. Demonstration activities,

which are a recent addition to the Institute’s

programs, have been implemented to effectively

translate research findings into health practices.

Such programs will be of even greater importance as more clinically applicable information

becomes available for dissemination from ongoing clinical trials (79).

Thus, NHLBI’s technology transfer activities

consist of clinical trials and demonstration programs which “deal with the application and dissemination of knowledge already developed and

evaluated through research, but not yet effectively applied toward the prevention, control,

and treatment of disease” (72). The technology

transfer process previously described might be

thought of as NHLBI’s method of managing

these activities as they apply to specific technologies.

A technology cannot be transferred unless it

exists. When the 1972 act gave NHLBI responsibilities which, a few years later, would coalesce

under the formal rubric of “technology

transfer, ” the technologies that were ripe for

transfer were technologies in cardiovascular diseases and to a much lesser extent in pulmonary

and blood diseases. In the initial program plan

following the 1972 act, the following five areas

were to be given special emphasis (72):

●

●

●

●

●

Thus,

blood

ment,

prevention of heart attacks—the greatest

killer in our nation;

high blood pressure education—millions of

our citizens do not know that they have

high blood pressure, that it may lead to serious complications such as stroke and

death, and that treatment is available;

expansion of the attack on lung diseases—a

heretofore neglected area;

development of a national blood policy—a

critical national need;

methods of controlling sickle cell disease.

the primary emphasis in the lung and

areas had to be on knowledge developwhile knowledge application was a more

immediate reality for cardiovascular diseases.

Furthermore, the two cardiovascular objectives

were linked; hypertension is a major risk factor

for heart failure and coronary disease, as well as

for strokes.

NHLBI’s support of clinical trials generally reflects the situation where knowledge application

is a more immediate reality for cardiovascular

diseases than for lung and blood diseases. Appendix C summarizes NHLBI’s recently com-
107

pleted, current, and planned clinical trials.

Three of these trials will be described shortly.

The demonstration activities in prevention,

education, and control also have a heavy cardiovascular emphasis. These activities are initiated

and/or implemented by the Office of Prevention, Education, and Control (OPEC) or by the

operating divisions. OPEC’s recent activities

have included:

● the National High Blood Pressure Education Program, involving State and Federal

agencies and over 150 private organizations;

● the Foods for Health project, a joint collaborative effort with Giant Foods, that is now

serving as the basis for a number of nutrition education programs;

● the Blue Cross/Blue Shield demonstration

effort to stimulate high blood pressure programs at the worksite (Blue Cross/Blue

Shield has developed a nationwide marketing program in this area following the demonstration project);

● the High Blood Pressure TV Module, an alternative to the Public Service Announcement for conveying educational messages

via TV;

● the Quit Smoking Community Intervention

Program, which uses a series of TV smoking

cessation segments coupled with local

American Lung Association promotion and

materials; and

● the Health Professionals Awareness of High

Blood Pressure Media Messages, a survey of

whether health messages in the lay media

are absorbed by health professionals, to determine whether the lay media might be an

alternative means (e. g., compared to professional journals) of reaching the medical

profession,

Examples of demonstration activities under

the operating divisions are the grant-supported

community intervention programs and the

contract-supported workplace intervention programs of the Division of Heart and Cardiovascular Diseases. The three community intervention programs— the Stanford, Minn., and Pawtucket, R.I. Heart Disease Prevention Programs—are attempting to demonstrate that a

widespread community education and risk reduction effort will result in lowering cardiovascular risk factors that, in turn, will result in

decreased cardiovascular mortality. The three

workplace intervention programs—through the

University of Maryland, Ford Motor Co., and

Westinghouse Corp.—are evaluating the impact

of high blood pressure control in the workplace.

As noted in the introduction to this chapter,

age-adjusted cardiovascular disease death rates

have fallen 25 percent in the decade between

1968 and 1978, compared to a 10-percent decline

in age-adjusted death rates from noncardiovascular causes (see fig. 8). The rate of decrease also

accelerated in 1973, and now there is a 3-percent annual reduction in deaths due to coronary

heart disease and a 5-percent reduction in deaths

due to strokes (105).

In 1972, NHLBI initiated two large programs.

One was the National High Blood Pressure Education Program. The other was the Hypertension Detection and Followup Program.

The National High Blood Pressure Education

Program, coordinated and staffed by NHLBI, involves State and Federal agencies and over 150

private organizations (36). Surveys on public

knowledge about high-blood pressure conducted

in 1973 and in 1979 showed the following

changes. First, the belief that hypertension is a

serious condition increased from 63 percent in

the 1973 survey to 73 percent in 1979. Second,

83 percent of those surveyed in 1979 had had

their blood pressure measured within the past

year, compared to 73 percent in the 1973 survey.

Third, about twice as many people knew in 1979

what a normal blood pressure was. Fourth, 4 0

percent more people understood that hypertension did not have reliable symptoms. And fifth,

in the 1979 survey, more people knew that effective treatment was available, and more were

also following their prescribed therapies (78).

The Hypertension Detection and FOllO Wu p

Program was a community-based randomized

controlled trial involving 10,940 persons with

high-blood pressure, comparing the effects on

5-year mortality of a systematic antihypertensive treatment program (stepped care, or SC)
108

and referral to community medical therapy (referred care, or RC). Stepped care patients were

offered therapy in special centers, and therapy

was increased stepwise to achieve and monitor

reduction of blood pressure to or below set

goals. Referred care patients were referred to

their usual sources of care, with special referral

efforts for those with more severe hypertension

or organ system damage. Patients were apportioned among three diastolic blood pressure

(DBP) strata (subclassified by age, sex, and race)

on entry into the study: 90 to 104, 105 to 114,

and 115 or greater mm Hg.

The study was designed to answer the questions which were unresolved by previous studies

conducted within the Veterans’ Administration’s

medical care system:

1.

2.

3.

4.

5.

Is a systematic approach to

sive therapy (stepped care)

community care effective in

of 5-year mortality for all

adults in the community?

antihypertencompared to

reducing risk

hypertensive

Can a substantial proportion of all hypertensive, detected in general populations,

be brought under pharmacologic management aimed at reducing blood pressure to

normotensive levels and kept under such

management?

Do the benefits of therapy exceed severe

toxicity in the stratum with mild hypertension, as well as in the more severe hypertensive strata?

Is antihypertensive therapy effective in

young adults and in women and equally effective in blacks and whites?

Can morbidity and mortality from coronary artery disease be decreased by antihypertensive therapy?

The results of the clinical trial were as follows

(34,35):

1.

2.

Over the 5 years, 50 to 65 percent of SC patients were at or below the goal DBP, compared to 30 to 44 percent in the RC group.

Five-year mortality from all causes was 17

percent lower for the SC group compared

to the RC group, and 20 percent lower for

the SC subgroup with the lowest entry DBP

of 90 to 104 mm Hg. The latter finding is

3.

4.

5.

particularly significant, because about 70

percent of all hypertensives are in the lower

DBP stratum, and approximately 60 percent of mortality attributable to high blood

pressure occurs in people with this DBP

range.

The 5-year stroke incidence was significantly less in the SC group (1.9 per 100 persons) than in the RC group (2.9 per 100 persons).

The death rate from strokes in the SC

group (1.06 per 1,000 persons vs. 1.91 per

1,000 persons for the RC group) indicated

that the stroke death rate decreased to near

the level of stroke death rate in the general

U.S. population (0.83 per 1,000 persons).

The SC group’s reduction in mortality and

morbidity from strokes occurred in all subsets: a) 45-percent reduction for those with

entry DBP of 115 mm Hg or greater; b) 30-

percent reduction in incidence among white

women and decreased incidence in all subgroups; c) 27-percent reduction even in the

youngest participants (ages 30 to 49 years

at entry); and d) 45-percent reduction in incidence among the oldest participants (ages

60 to 69 years at entry).

Thus, this large clinical trial, with total costs

approaching $70 million, showed more intensive

care with available therapies could lead to a

significant decrease in mortality and morbidity

from hypertension and that these benefits were

found in treating “mild” hypertensives as well.

The results of this study were first published

in the Journal of the American Medical Association in December 1979 (34). In a sampling of

physicians collected to see how timely dissemination of new medical information reached the

practicing physician, 40 percent of family physicians were aware of the study within 2 months

of publication, and 63 percent of internists

learned of it within 6 months. Of the 40 percent

of family physicians aware of the study, 98 percent were able to correctly answer questions

about the reduction in mortality and the benefits

of treating mild hypertension. Eighty percent of

the family physicians and so percent of the internists learned of the study from medical journals,

and 40 percent of the internists learned of it from
109

continuing medical education courses (the remaining percentages learned of the study from

colleagues or the lay press) (110).

In sum, as a result of these activities, the

public is much more aware of hypertension as a

disease with serious but preventable consequences, new information on the effectiveness of

treating even “mild” hypertension has been generated, and this information has disseminated

rapidly to the medical community.

In 1975, the Aspirin Myocardial Infarction

Study (AMIS) was initiated to test whether the

regular administration of aspirin to men and

women who had experienced at least one documented myocardial infarction (heart attack)

would result in a significant decrease in mortality over a 3-year period. Secondary objectives

were to evaluate the effects of aspirin on the incidence of coronary heart disease mortality, coronary incidence (defined as coronary heart disease mortality or definite, nonfatal myocardial

infarction), and the incidence of fatal or nonfatal

stroke.

Previous studies had suggested the possibility

that aspirin use might lead to these effects, and

together with the antiplatelet properties of aspirin, led to NHLBI’s study.

The AMIS study included 4,524 persons between the ages of 30 and 69, randomized over a

13-month period to either 1 gram of aspirin (approximately three aspirin tablets) per day (2,267

persons) or to a placebo (2,257 persons) and followed for 3 years. After the random allocation,

however, a difference (p < 0.05) was found between the two groups in the baseline distribution

of seven characteristics such that the aspirin

group had significantly higher percentages of patients with heart failure, angina pectoris, ECGdocumented arrhythmias, and use of digitalis,

nitroglycerin or long-acting nitrates, propranolol (or other beta-blockers), and “other

drugs.”

The results were as follows:

1. Total mortality during the entire followup

period was 10.8 percent for the aspirin

group and 9.7 percent for the placebo

group. Adjusted for 15 baseline variables,

2

3.

4.

5.

including the seven for which the aspirin

group had significantly higher percentages,

total mortality was 10.5 percent and 10.0

percent, respectively.

Three-year mortality was 9.6 percent for

the aspirin group and 8.8 percent for the

placebo group.

Definite nonfatal myocardial infarction occurred in 6.3 percent of the aspirin group

and 8.1 percent of the placebo group.

Coronary incidence (coronary heart disease

mortality or definite nonfatal myocardial

infarction) was 14.1 percent in the aspirin

group and 14.8 percent in the placebo

group.

Symptoms suggestive of peptic ulcer, gastritis, or erosion of the gastric mucosa occurred in 23.7 percent of the aspirin group

and 14.9 percent of the placebo group.

The investigators reached the following conclusions (2):

The studies that have been cited found trends

in mortality favorable to aspirin. However, in

none of these studies were the differences between aspirin and placebo unequivocally statisticall y significant when all enrolled patients

were included in the analysis . . . The fact re

-

mains that in terms of the primary endpoint,

AMIS found no benefit from aspirin. This trial

is the largest completed and published investigation of aspirin in the post-MI population, and

more weight must be given to its results. These

results indicate that aspirin perhaps is helpful in

reducing the frequency of non-fatal MI but

leads to an increased incidence of side effects.

They clearly indicate that the regular administration of aspirin in this dose does not reduce

three-year mortality in patients with a history

of MI. In summation, based on AMIS results,

aspirin is not recommended for routine use in

patients who have survived an MI.

Soon after publication of this clinical trial, it

and five others (including two other newly published trials)-–which had a total of over 10,000

myocardial infarction patients randomized between aspirin and double-blind placebo controls

and in which over 1,000 patients died—were reviewed by the Society for Clinical Trials. The

consensus that emerged was that aspirin did reduce the risk of death, but that the smallness of
110

the reduction was what had led to difficulties in

interpretation even in the largest trials. It was estimated that, across all six trials, the overall reduction in the odds of reinfarction was 21 percent (standard error +/- 5 percent) and that some

70-odd deaths had been prevented (39).

Recently, NHLBI and NCI have initiated a

clinical trial to test the preventive efforts of both

aspirin (for cardiovascular mortality) and beta

carotene or vitamin A (for cancer incidence).

The study is a double-blind randomized placebo

trial involving 21,500 healthy U.S. male physicians with initial ages of 50 to 75 years.

Policy analysts, preparing for the first renewal

of the 1972 act, asked these questions in 1975

(109):

Is there really anything new, in 1975, about

coronary by-pass except the number of such operations performed? And has the coronary bypass procedure by now been shown to lengthen

lives; or does it still mainly reduce pain symptoms of angina pectoris?

With an average cost of about $15,000 and up to

100,000 coronary bypass procedures performed

annually in the United States (including celebrity

patients such as Secretary of State Alexander

Haig and, more recently, past Secretary of State

Henry Kissinger), the questions being asked

today are basically the same as those in 1975,

with the exception of being more focused. For

example, in what types of coronary artery disease can bypass surgery improve mortality? And

is reducing symptoms a proper use of this technique? These and related questions are still being

addressed in NHLBI’s Coronary Artery Surgery

Study, initiated in 1973 with a goal of 800 randomized patients to be followed for at least 4

years, and including a registry of 25,000 patients

referred for coronary arteriography.

Related to this surgical therapy is the relatively new technique of percutaneous transluminal

coronary angioplasty (PTCA), in which a special catheter with a tiny balloon at its tip is inserted in an arm or leg artery and passed up into

the narrowed coronary artery, where the balloon is inflated to press the atherosclerotic

plaque against the vessel wall to enlarge the narrowed area. The first angioplasty in a peripheral

artery was performed by Dotter and Judkins in

1964, and the first coronary artery procedure

was done in 1977 by Gruntzig.

NHLBI sponsored a workshop in June 1981

for investigators active in this field, and of the

205 procedures reported at the workshop, 116

were considered successful. The technique may

be applicable to no more than 5 percent of patients undergoing coronary bypass surgery at

the present time and is still considered experimental. NHLBI maintains a registry, and by

early 1982, had over 80 centers in the United

States, Canada, and Europe reporting a cumulative total of 3,066 patients (74).

These selected examples show both the extent

and limitations of NHLBI’s influence on the

transfer of technologies under its purview. In the

case of hypertension control, both established

and new applications are converging to produce

not only heightened awareness of the problem

among the public and health professionals, but

also significant effects on cardiovascular-related

morbidity and mortality. In the case of aspirin

use for preventing heart attacks, chance fluctuations in the risk factors of the aspirin v. control

groups of the NHLBI-sponsored clinical trial led

at least one group of reviewers to conclude that

the trial mistakenly indicated no benefit. The

momentum of coronary bypass surgery--reflected in the large numbers of procedures currently being performed—appears to have gone

far beyond the bounds of accepted indications.

Whether the NHLBI clinical trial can cause the

medical community to temper its enthusiasm for

this procedure remains to be seen. Finally, in the

emergence of PTCA, NHLBI’s establishment of a

registry is an example of its monitoring of

emerging technologies and its attempt to steer

this new technology along a rational path of development and dissemination.

The implications of these clinical trials and

demonstration programs and the technology

transfer process adopted by NHLB1 are summarized in the following section.
111

CONCLUSIONS

Under the National Heart, Blood Vessel,

Lung, and Blood Act of 1972, NHLBI operates

under an explicit mandate to help transfer the

results of research in these areas to the public

and health professionals. The 1972 act specified

the kinds of technology transfer activities to be

conducted and the minimal administrative approach which was to be adopted. Among the responsibilities specified in the 1972 act were “programs for field studies and large-scale testing,

evaluation, and demonstration of approaches to

these diseases” and “public and professional

education in these diseases. ” Health Information

Programs were to provide the public and health

professionals with information on these diseases, with special emphasis “to be placed upon

disseminating information regarding diet, exercise, stress, hypertension, cigarette smoking,

weight control, and other factors related to

prevention.” Prevention and control programs

were to be established with other governmental

and private health agencies, and national research and demonstration centers were to be established in these diseases.

In the intervening decade since the 1972 act,

the context in which these transfer activities take

place has expanded to include economic, legal,

social, and ethical issues in addition to the traditional scientific issues of safety and effectiveness. These added emphases have led to organized efforts in the NIH Director’s Office (i. e.,

OMAR activities), and within the Public Health

Service (i.e., the now defunct NCHCT and its

administrative successors). These broadened interests in technology transfer in turn have led to

a parallel broadening of the objectives of

NHLBI’s monitoring of technology transfer activities.

The 1972 act provided direction to NHLBI in

technology transfer through the specific mandates to perform large-scale clinical trials and to

initiate demonstration programs in prevention,

education, and control. When the NIH Director’s Office established a formal technology

transfer focal point in 1978 through OMAR,

NHLBI organized its MAP under a coordinator

in the insititute’s Office of Program Planning

and Evaluation in the same year. These internal

MAP activities have consisted primarily of monitoring technology transfer activities as formulated by the component groups within NHLBI.

MAP has been used for coordinating activities of

groups within and outside of NHLBI and for

summarizing the institute’s activities, as reflected, for example, in the technology transfer

format used in preparing the NHLBI Director’s

annual reports. And until the current, ongoing

revision of MAP, NHLBI’s “medical application

accomplishments have not been synthesized into

a single document, nor has there been a NHLBI

focus to track and facilitate developing, assessing, validating, and transferring medical applications. The MAP plan provides a mechanism

for routinely documenting activities and accomplishments and for the periodic evaluation of the

NHLBI MAP” (75).

The current objectives of MAP are: 1) to serve

as a source for an inventory and status information on all high-priority technologies in transition; 2) to coordinate activities within NHLBI

and between NHLBI and other portions of NIH

or external agencies; 3) to provide visibility to

NHLBI’s transfer activities and their accomplishments; 4) to maintain an awareness of the stateof-the-science of technology transfer methods;

and 5) to ensure that MAP is incorporated into

NHLBI’s planning process (75). Past efforts have

concentrated on objectives 2 through 4. The new

emphases are on objective 1, the inclusion of

new and established technologies in transition in

addition to an emerging technologies list, as well

as more precise criteria for identifying these

technologies; and on objective 5, incorporating

MAP into NHLBI’s planning process. These objectives are to be linked by integrating the identification and tracking of technologies in transition into the NHLBI Implementation Planning

Process.

This linkage raises the familiar issue of

whether emphasizing targeted research and clinical application comes at the expense of basic research, especially at a time of restricted funds.

At the time of the 1972 act, these concerns were

barely raised (109), especially since the transfer
—

112

responsibilities were accompanied by increased

funds. And, as already discussed, NHLBI implemented the legislated programs as additions to

its basic research mission and passively monitored these activities. Currently, NHLBI emphasizes that technologies identified through any

systematic process will originate with the divisions and branches and their advisory groups.

The use of program advisory committees is seen

as a method of identifying technologies that

have reached an appropriate state of development and represent significant needs. Thus,

targeted v. basic research is not a crucial issue,

On the other hand, downplaying a formal system of assessment at the Public Health Service

level may filter down to the NHLBI effort, with

the result that MAP’s purpose remains to monitor and summarize technology transfer activities

instead of being expanded to include it in the institute’s program planning. This effect may be

minimal as long as NHLBI concentrates on efficacy and safety criteria in its transfer functions,

as this role would be consistent with its basic

mission.

There are three other issues of importance for

NHLBI’s technology transfer activities, First, the

formalization of NHLBI’s MAP mirrors closely

the development of technology transfer activities at the levels of the NIH Director’s Office

and of the Public Health Service. With the demise of NCHCT, a focal point for the extrascientific (i. e., economic, legal, social, and ethical)

issues outside of NIH has been lost. But the impact of NHLBI’s activities may be minimal, as

there still exists OMAR in the NIH Director’s

Office to partially insulate NHLBI from being

directly involved in these extrascientific issues.

Second, even if NHLBI continues to try to formalize MAP and integrate it into the institute’s

program plans, this activity may be relatively

low on the institute’s list of priorities. In a period

of fiscal retrenchment, competition for funds

within NHLBI will increase, and MAP may

again revert to its monitoring and summarizing

role.

Third, fiscal retrenchment would directly affect NHLBI’s technology transfer activities. The

medical community regards the large-scale clinical trial as a critical activity in the biomedical

research spectrum and indispensable for determining the efficacy of treatment or preventive

regimens (11,42). But the flow of technology

does not simply proceed in one direction and

along one path from basic research to clinical

application. The Aspirin Myocardial Infarction

Study and the Coronary Artery Surgery Study

represent assessments of technologies already in

use—the first to test a new indication for an old

medicine, and the second to help clarify use of a

surgical technique which is valid but costly.

These evaluations of existing technologies,

although a proper use of NHLBI’s clinical trials

program, compete with evaluations of emerging

technologies for funding.

The research base in areas not yet ripe for

transfer in the past decade—lung and blood diseases and selected areas of cardiovascular disease— is beginning to produce results. There will

therefore be more emerging technologies to evaluate through clinical trials while the interest in

reevaluating existing technologies is maintained.

As long as NHLBI continues as the principal

U.S. source of large-scale clinical trial support

for these diseases, demands on this crucial link

between research and clinical application, and

the underlying competition between evaluations

of emerging v. existing technologies, will increase.

A more immediate effect of fiscal restraints

would be in NHLBI’s demonstration programs.

For example, the National High Blood Pressure

Education Program was initiated in 1972. Ten

years later, it is still funded through NHLBI. The

only way in which new demonstration programs

can occur is through additional funds or through

termination or transfer of existing demonstration programs to other organizations. But demonstration programs often involve the “public

goods” issue; i.e., the majority agree that these

programs are needed, but no other organization

wants to assume responsibility or has the funds

to do SO.

Thus, fiscal restraints may have the effect of

retrenchment both in the management of technology transfer and in the specific activities

which comprise the technology transfer process.
Chapter 8

Findings and Conclusions
Contents

f

Page

Findings Related to the Assessment of Medical Technologies . . . . . . . . . . . . . . . . . . . . 116

Findings Related to the Transfer of Medical Technologies. . . . . . . . . . . . . . . . . . . . . ..117
Chapter 8

Findings and Conclusions

This technical memorandum has described

and examined the role of the National Institutes

of Health (NIH) in the transfer of technologies to

the health care system. Because it is a technical

memorandum and not a full OTA report, it does

not present recommendations or policy options

for congressional consideration.

The major finding of this study is that, despite

some problems relating to the timely transfer of

potentially helpful technologies, the major

weaknesses of the present process for technology

transfer are: 1) inadequate attention as to whether technologies being considered for transfer rest

on sufficient knowledge to justify such transfer,

and 2) insufficient attention to the scientific

evaluation of emerging technologies to determine their potential benefits, risks, costs, and

conditions for appropriate use.

Very importantly, the above finding is a

general criticism of the current process of

medical technology transfer, NIH is only one of

the actors, although it is a crucial and influential

one. And it should be noted that NIH is responsible for much of the evaluation that does take

place and for a great deal of the basic science

knowledge that now exists.

It is also important to realize that “NIH” is not

a single, tightly structured entity. It is a loosely

coordinated collection of semiautonomous organizations— each pursuing related but individual goals, facing different research and public

responsibilities, and under varying types and

amounts of external pressures.

Policies toward technology transfer must try

to satisfy a complex mixture of objectives; they

must blend a concern with basic science research

directed toward eventual application with a concern for science for more immediate practical

purposes. Ultimately, these two concerns may

merge—the knowledge may lead to applications

in health care or even in some other field. Decisions must be made in the present, but they must

take into account both immediate and long-term

implications.

OTA finds that five goals should underlie

policies and activities of technology transfer:

1) the identification of areas where the knowledge base is inadequate to produce effective

technologies, and the setting of priorities among

such areas; 2) the support and encouragement of

basic and applied research in areas of inadequacy; 3) the generation of adequate knowledge

about the readiness for transfer of technologies

under development; 4) the creation of efficient

mechanisms to demonstrate and then transfer

technologies judged to be ready for use; and

5) the creation of mechanisms to monitor the actual use and effects of technologies in the health

care system. Further, each of these five goals

must be supported by a comprehensive and

readily accessible source of information collection and dissemination.

As these five goals indicate, the transfer of

technology is not in itself always a good thing

nor always a bad thing. Unfortunately, however, organizations and individuals very often

divide into two factions: those who believe that

medical technologies should be transferred as

quickly as possible, and those who believe that

the rate of transfer is too rapid already. Such a

generalized position is not helpful. The approach should be to examine each technology,

class of technologies, or disease area and ask

what is known about any technology being considered for transfer or about the knowledge base

being urged for development into technologies.

115
116

FINDINGS RELATED TO THE ASSESSMENT

OF MEDICAL TECHNOLOGIES

NIH’s principal formal activities in the evaluation of medical technologies are its clinical trials

and its consensus development conferences. It is

by far the most important supporter of these

types of activities. With the disappearance of the

National Center for Health Care Technology

(NCHCT), it remains as the only major focus for

such activities.

The arguments in favor of or against NIH’s involvement in evaluating medical technology are

still the same as they were before NCHCT’s

demise. The reasons that argue in favor of its

playing a large, perhaps expanded, role are:

● It has relatively greater fiscal and personnel

resources at its disposal than do other agencies.

● It has strong ties to the academic medical

centers.

● It has a good reputation among practicing

physicians.

● It has a much higher than average institutional ability to accomplish objectives.

● It has experience in assessing medical technologies, especially their efficacy and safety.

The reasons for NIH’s not becoming more involved with technology assessment activities

are:

●

●

●

Evaluation can be expensive in terms of

time, attention, personnel, and, especially,

funds. With a constrained budget, assessment directs resources away from the research mission of NIH.

NIH’s primary orientation is as a developer

of knowledge and technologies, not as a

“gatekeeper” or a critical evaluator of technology.

Its personnel are more appropriate for its

research mission than for technology evaluation. For example, the agency has an inadequate number of assessment methodologists, epidemiologists, and health services

professionals for an expanded role in assessment activities.

● The agency has a large enough and difficult

enough task as it is, without the enlargement and formalization of the complicated

function of evaluation.

Nevertheless, OTA finds that the evaluation

function is so critical to the successful transfer of

appropriate technologies that NIH should approach assessment in a more visible and structured manner and should strongly consider expanding its assessment activities. Funding and

carrying out clinical trials, for example, is a

function already supported by NIH. This function is consistent with the scientific orientation

of NIH. Synthesizing available information on a

particular technology, especially that concerning efficacy and safety, also seems appropriate

for a scientific institution. On the other hand,

considering broader implications of technology

use, such as socioethical and economic factors,

and arriving at policy judgments such as

whether a specific technology should be covered

in the medicare program may be better done by

those more familiar with clinical medical practice and with policies toward technology use.

This function might be better assigned to

another part of the government.

The National Heart, Lung, and Blood Institute

(NHLBI) is an example of an institute where the

assessment and transfer function has been given

much thought, where formal and effective processes have been developed, and where the attention given to such activities seems to be paying

off in terms of successful diffusion of information and technologies.

The identification of emerging or existing

technologies in need of assessment is a crucial

aspect of technology transfer and assessment.

NIH, through the Office for Medical Applications of Research (OMAR), was mandated to develop a yearly list of priority technologies for

NCHCT. With NCHCT no longer in existence,

it will be up to OMAR and NIH whether a list

will be collected in the future. If that activity is

discontinued, there will be no formal procedures

in place, except in NHLBI, to identify technol-
— —

117

ogies in need of assessment. Of particular importance is that NIH assure the evaluation of technologies whose development it has supported.

Not only would such procedures be helpful because they could lead to needed evaluations, but

the process of identification itself may pay dividends in terms of: 1) setting priorities for research, and 2) building a base of experience in

thinking through the criteria by which a technology is judged as ready for transfer. At the same

time, the process of identifying technologies

must not be allowed to become overly burdensome to the institutes and research personnel.

The level of assessment will become even

more critical in future years. Budget pressures

will put even greater demands on each research

dollar. This budget constraint, combined with

an effort to stabilize the number of new competing grants awarded, is likely to influence

negatively the number or size of future clinical

trials.

FINDINGS RELATED TO THE TRANSFER OF

MEDICAL TECHNOLOGIES

Only rarely does NIH actually transfer technologies. In fact, most of the Federal Government’s “technology transfer” activities do not actually involve the transfer of technologies. More

accurately, the vast majority of such activities

are those which: 1) provide information about

technologies, thus encouraging or discouraging

their transfer, or 2) demonstrate in a few selected

settings the potential uses of new technologies.

In the first type of activity, the Government is

not involved in the provision of actual medical

technologies at all. Instead, it is generating,

analyzing, or disseminating information. For example, publication of the results of applied

research or of clinical trials may affect the

transfer of technologies in question.

With the second type of activity, funds and

technical consultation may be provided to support the testing of the performance, acceptance,

etc., of new technologies. Thus, some transfer of

technology takes place, but the extent is usually

small and the conditions of use are relatively

controlled.

At NIH, the institutes that have legislative

mandates to conduct technology transfer activities, especially in the form of demonstration

and control programs, do more of it than do institutes without such mandates. The National

Cancer Institute (NCI), NHLBI, and the National Institute of Arthritis, Diabetes, and

Digestive and Kidney Diseases (NIADDK) are

the clearest examples of this. Thus, it is possible

that if Congress wished to increase this form of

activity it could do so by extending the mandate

to other institutes.

The area of control programs often brings

NIH into the fuzzy interface between biomedical

research and health care delivery. Under most

circumstances, this type of activity bears careful

watching so that NIH is not unintentionally

brought too far into the delivery aspect of health

care. In certain instances, it is imperative that

the agency not get too deeply involved in demonstration and control programs that verge on

health care delivery. That can occur when the

knowledge base is inadequate for the development of effective and safe technologies. Efforts

to transfer technologies prematurely are especially harmful when such transfer is not only to

academic health centers (where conditions m a y

be more controlled) but also into community

hospitals and other medical practice sites, O n e

of these instances may be in the process of occurring if the critics who believe that NCI is moving

too rapidly in its transfer of certain technologies,

primarily through its demonstration and control

programs, are correct. OTA did not have the

mandate to study that specific example; therefore further research may demonstrate otherwise. The situation, however, is worth additional examination.

Note that OTA is not saying that NIH is doing

an inadequate job of developing or keeping

track of the state of basic science. The finding is

simply that in making decisions to support the
118

demonstration and transfer of specific medical

technologies, attention should always be given

to the knowledge base on which those technologies rest, The basic and applied research base is

not at an equal level of development and understanding across all areas of inquiry. Thus, the

priority and funding given to technology evaluation becomes doubly important, for only

through careful scientific evaluation of efficacy

and safety (and at times of cost and social implications) can informed decisions be made about

readiness for transfer and therefore about the

appropriate use of demonstration and control

programs.

The first type of activity mentioned above—

generating and disseminating information—may

not be as obviously seen as transfer supporting,

but it is a crucial aspect of technology transfer

and is actually a far more influential and a much

larger activity than demonstration and control

programs. (It should be noted, however, that in

a very substantial sense, demonstration and control programs are in part also “information-related programs.”)

The current effectiveness of information activities depends on the substance of the information

and the process by which it is gathered and disseminated. OTA finds that the process by which

transfer-related information is disseminated appears to be excellent in most cases. The National

Library of Medicine and its MEDLARS system

have played a key role in information dissemination. Similarly, NIH and its intramural and its

funded researchers have made extensive use of

opportunities for disseminating information

through professional/scientific journals and

other publications and through professional

meetings.

The substance of the biomedical information

generated is generally excellent, although, in

keeping with above comments, more attention

could be given to clinical trials and other assessment results.

In summary, NIH is one of the primary actors

in the assessment and transfer of medical technologies. It is subject to a number of internal and

external constraints and pressures, some of

which urge it to be more active in transfer and

some to be less active. OTA’S conclusion is that

a cautious approach, varying according to the

specifics of each situation, would be more appropriate. NIH could devote more funds and attention to generating information on the potential benefits and risks of technologies, and then,

when sufficient information exists, it could actively utilize its existing, adequate mechanisms

to support appropriate transfer of medical technologies.
Appendixes
APPENDIX A

Glossary of Acronyms

ADAMHA

AHA

AMA

CBA

CC

CCOP

CCPDS

CCRC

CDC

CEA

CEA/CBA

CEAP

CHOPS

COP

CRC

CTEP

DCRT

DCT

DHEW

DHHS

DOL

DRCCA

DRG

DRR

DRS

ECOG

ESRD

FDA

FIC

GAO

HCFA

HEW

HHS

HRA

Alcohol, Drug Abuse, and Mental

Health Administration (PHS)

American Hospital Association

American Medical Association

cost-benefit analysis

Clinical Center (NIH)

Community Clinical Oncology

Program (NCI)

Centralized Patient Data System

(NCI)

Clinical Cancer Research Center

Centers for Disease Control (PHS)

cost-effectiveness analysis

cost-effectiveness analysis/costbenefit analysis (when referred to

as a class of analytical techniques)

Clinical Efficacy Assessment Project

Community Hospital Oncology

Programs (NCI)

Clinical Oncology Program (NCI)

Cancer Research Center

Cancer Therapy Evaluation Program

(NCI)

Division of Computer Research and

Technology (NIH)

Division of Cancer Treatment (NCI)

Department of Health, Education,

and Welfare (now DHHS)

Department of Health and Human

Services (formerly DHEW)

Department of Labor

Division of Resources, Centers, and

Community Activities (NCI)

Division of Research Grants (NIH)

Division of Research Resources (NIH)

Division of Research Services (NIH)

Eastern Cooperative Oncology Group

(NCI)

end-stage renal disease

Food and Drug Administration (PHS)

Fogarty International Center (NIH)

General Accounting Office (U.S.

Congress)

Health Care Financing

Administration (DHHS)

Department of Health, Education,

and Welfare (now DHHS)

Department of Health and Human

Services (formerly DHEW)

Health Resources Administration

HSA

IATC

IOM

I/RDs

IRG

LCRC

MAP

MEDLARS

MI

NAS

NCAB

NCHCT

NCHS

NCHSR

NCI

NEI

NHLBI

NHLI

NIA

NIAAA

NIADDK

NIAID

NIAMDD

NICHD

NIDA

NIDR

NIEHS

NIGMS

NIH

NIMH

Health Services Administration (PHS)

Interagency Technical Committee

Institute of Medicine (NAS)

institutes and research divisions

(NIH)

initial review group

Laboratory Cancer Research Center

Medical Applications Program

(NHLBI)

Medical Literature and Analysis

Retrieval System (NLM)

myocardial infarction

National Academy of Sciences

National Cancer Advisory Board

National Center for Health Care

Technology (OASH)

National Center for Health Statistics

(OASH)

National Center for Health Services

Research (OASH)

National Cancer Institute (NIH)

National Eye Institute (NIH)

National Heart, Lung, and Blood

Institute (NIH)

National Heart and Lung Institute

(now NHLBI)

National Institute on Aging (NIH)

National Institute on Alcohol Abuse

and Alcoholism (ADAMHA)

National Institute of Arthritis,

Diabetes, and Digestive and

Kidney Diseases (NIH)

National Institute of Allergy and

Infectious Diseases (NIH)

National Institute of Arthritis,

Metabolism, and Digestive

Diseases (now NIADDK)

National Institute of Child Health

and Human Development (NIH)

National Institute on Drug Abuse

(ADAMHA)

National Institute of Dental Research

(NIH)

National Institute of Environmental

Health Sciences (NIH)

National Institute of General Medical

Sciences (NIH)

National Institutes of Health (PHS)

National Institute

(ADAMHA)

of Mental Health

121

(PHS)

91-486 0 - 82 - 9
122

NINCDS

N L M

NSF

OAS H

OHRST

OMAR

OSHA

O T A

National Institute of Neurological

and Communicative Disorders and

Stroke (NIH)

National Library of Medicine (NIH)

National Science Foundation

Office of the Assistant Secretary for

Health (DHHS)

Office of Health Research, Statistics,

and Technology (OASH)

Office for Medical Applications of

Research (NIH)

Occupational Safety and Health

Administration (DOL)

Office of Technology Assessment

(U.S. Congress)

PHS

PTCA

R&D

RCT

RFA

RMP

SAQC

SEER

SSA

VA

Public Health Service (DHHS)

percutaneous transluminal coronary

angioplasty

research and development

randomized clinical trial

request for applications

Regional Medical Program

Statistical Analysis and Quality

Center (NCI)

Surveillance, Epidemiology, and End

Results program (NCI)

Social Security Administration

(DHHS)

Veterans Administration
Appendix B

Background Materials: Grants,

Contracts, and Peer Review

The funding mechanisms of the extramural programs of the National Institutes of Health (NIH) have

an impact on the various technology transfer activities. In large part, this impact is due to the way in

which the extramural projects are selected and administered. This appendix describes the awarding

process for grants and contracts, the two primary

funding mechanisms. In addition, it presents a review

of recent studies of the peer review system and a discussion of various grant mechanisms.

Research Grants

The main types of research grants are research

project grants, program project grants, and center

grants. According to the NIH publication NIH Extramural Programs (52), they may be distinguished as

follows:

● Research project grants are awarded to an institution on behalf of a principal investigator to facilitate pursuit of a single scientific focus or objective

in the area of an investigator’s interest and competence. Institutional sponsorship assures the NIH

that the institution will provide facilities necessary

to accomplish the research and will be accountable

for the grant funds. A research grant may occasionally be awarded directly to an individual who

has access to adequate facilities and resources for

conducting the research . . .

● Program project grants are awarded to an institution on behalf of a principal investigator for the

support of a broadly based, often multidisciplinary, long term research program with a particular

major objective or theme, A program project involves the organized efforts of groups of investigators who conduct research projects related to the

overall program objective. The grant can provide

support for the projects and for certain shared resources needed for the total research effort. Each

project supported under a program project grant is

expected to contribute to the overall program objective.

● Center grants, awarded to institutions on behalf of

a program director and a group of collaborating investigators, provide support for long term, multidisciplinary programs of research and develop

ment. The distinction between program project

and center grants is that center grants are more

likely to have a clinical orientation and are usually

developed in response to announcements of the

specific needs and requirements of [an institute or

division]. Center grants support programs in critical health problem areas including: research and

development; demonstration of advanced techniques for the diagnosis, treatment, prevention, or

control of disease; education; and other related

nonresearch components. Although center grants

may support both the projects and the “core” or

shared resources, in some instances, only “core”

costs are provided under the center grant, and

project support must be requested through the

project or program project mechanisms.

Research grants may be used to pay the salaries of

personnel, the purchase of equipment and supplies,

travel, publication, the institution’s direct costs, and

other purposes directly associable with the research.

The award also includes reimbursement for indirect

costs, or overhead, to the investigator’s institution.

Establishing an overhead rate that is equitable to

both the government and the institution continues to

be a problem (114).

Grant applications submitted to NIH are received

centrally in the Division of Research Grants (DRG).

This Divisionf one of the research and support divisions at NIH, has most of the responsibility for administering the grants applications review program,

although each institute’s participation in the process

is essential with respect to grants awarded out of its

individual appropriation. DRG collects, stores, analyzes, evaluates, and retrieves management and program data needed in the administration of these programs. It also provides advisory and consultative

services to grantees relating to grant policy and management matters.

The most important function of DRG, though, is

to screen all incoming grants applications, determine

the relevance of each application to the overall mission of NIH, and assign acceptable applications to an

appropriate initial review group (IRG, or more commonly “study section”) for scientific peer review and

to an appropriate institute for funding review. The

two reviews, referred to as the “dual review system, ”

occur sequentially. DRG does not assign the applications for review arbitrarily. Instead, assignment to an

IRG is based on the match between the subject of a

proposed research project and the review responsibilities and scientific expertise of the IRG’s members;

assignment to an institute is based on the institute’s

legislatively mandated program responsibility. Ap123
124

placations may be assigned to two institutes at once if

the subject matter is pertinent to the program responsibilities of both. Should the primary institute decide

not to provide funding, the other institute may consider it.

Depending on the type of research proposed, the

first level of scientific and technical merit review is by

an IRG located either within DRG or within an institute. IRGs within DRG are called study sections.

Currently, there are four groups of study sections—Behavioral and Neuroscience Review, Biomedical Sciences Review, Clinical Sciences Review,

and Special Review—which contain 55 review

groups representing at least sO disciplines. IRGs in

the institutes are usually multidisciplinary and are

constituted to review more complex program project

and center grant applications.

The IRGs are composed of 10 to 15 highly qualified

nongovernment consultants selected on the basis of

their recognized competence and achievements in

their respective research fields. An NIH health scientist administrator serves as executive secretary of

each group. The executive secretary reads each application and assigns it to two or more members of the

IRG best qualified to judge the application in detail.

When assessing the scientific and technical merit of

an application assigned to their IRG, the members

consider several factors, including: the training, experience, and research competence or promise of the

investigators; the adequacy of the experimental design; the suitability of the facilities; and the appropriateness of the requested budget to the work proposed.

IRG members, who serve up to 4 years per appointment, meet three times a year to review applications. At the meetings, the applications are recommended either for approval, disapproval, or deferral

for more information (which may be obtained using

outside assistance or site visits) by majority vote. In

addition, for applications recommended for approval, each member of the IRG individually and privately assigns a numerical rating that reflects a personal

evaluation of the scientific merit of the proposed

project. The executive secretary then combines these

ratings into one priority score and prepares a written

summary of the considerations, including a project

description and critique, a recommended budget, an

explanation of the IRG’s recommendation, and notations about any special points. Both the priority

scores and the summaries are then forwarded to the

appropriate institutes and other awarding units for

the second level of review.

Each of the awarding units has a national advisory

council or an equivalent unit that reviews and determines approval of grant applications before a grant

can be awarded. These councils are mandated by

law, and some have minimum levels placed both on

the number of times they must meet each year and on

the number of members they must have. Members include authorities in scientific and health fields directly related to the program interests of the institute

or division, as well as lay people noted for their interest or activity in national health problems. Except

for the National Cancer Advisory Board (NCAB)

and the National Library of Medicine Board of

Regents, the council members are selected by the

Secretary of Health and Human Services and serve

4-year terms.

The councils review grant applications in a broader context than the IRGs, because their recommendations are based not only on the IRG scientific and

technical merit evaluations, but also on the needs of

NIH and the missions of the individual institutes, the

need for initiation of research in new areas, the

degree of relevance of the proposed research to the

missions of the institutes, and other policy issues.

The council recommendations are forwarded to the

institute director for funding. The priority scores

assigned to the grant applications by the IRGs serve

as a virtually inviolable guide to the advisory councils and to the awarding units in their decisions regarding the order in which the approved grant applications will be funded. However, while the councils can not change the priority scores, they can recommend that an approved application be classified

to be funded or not to be funded based on program

relevance. The projects approved by the councils are

usually chosen according to rank until the budget is

obligated. An approved grant application is not assured of funding, because there are almost always

more eligible applications than available funds. A

disapproved application, though, can not be funded.

R&D Contracts

The NIH publication NIH Extramural Programs

(52) states that research and development (R&D)

contracts:

. . . are awarded to nonprofit and commercial organizations to foster and direct scientific inquiry toward

particular new areas of research and development and

to utilize advances in knowledge and technology to

search for solutions to specific questions. Contracts

are conducted with close NIH direction and monitoring; negotiations afford the contracting parties flexibility in establishing the details of their relationship at

the outset of the contract work.

The same publication describes several types of

R&D contracts: 1) research contracts focus on a specific research problem that has been identified by an
125

NIH component and requires central direction, control, and management, such as clinical trials of new

and existing therapies; 2) development contracts are

awarded for projects to produce substances, devices,

systems, or other approaches to diagnose, prevent,

treat, or control diseases; and 3) demonstration contracts are awarded when NIH desires to direct, or at

least control closely, opportunities to demonstrate

the feasibility of applying new advances to individual

or community situations to solve certain health problems, such as cancer control programs. Contracts

may also be awarded for certain types of research

support services or resources (e. g., data processing,

collection and distribution of materials needed to

conduct R&D) as well as for conferences and workshops to facilitate scientific communication and evaluation.

The contract mechanism offers more universal

competitive opportunities to all types of scientific

sources. It is used by the Government to fulfill its

specific program objectives. Thus, because the areas

of work to be undertaken are already defined, offerors can compete for a commonly understood objective, and contract proposals received are evaluated

within the framework of criteria announced to all

competing sources.

Each awarding unit (institute or division) has developed slightly different methods to satisfy its research needs. The basic mechanism used to develop

requests for proposals, to review contract applications, and to evaluate the progress and outcomes of

contract products, though, are similar enough to be

summarized in a general description. The scientific

staff members within a given institute, with assistance from standing committees or ad hoc advisory

groups, develop a research project description and

plan. The concept of the project is then evaluated by

a scientific review group composed largely of nonFederal advisors, in compliance with the law that

mandates peer review for NIH contract projects.

Next, the proposed project is released as a request for

proposal (RFP), which specifies the terms, conditions, and provisions for the requested contract. The

RFP appears in several appropriate publications, including the Commerce Business Daily and the NIH

Guide for Grants and Contracts.

Contract proposals, submitted in response to an

RFP, undergo several stages of review. First, they are

reviewed by the institute’s contracting officer and

then by a scientific review group consisting mainly of

nongovernment scientists with expertise in the relevant area. Their recommendations are sent to a contract review committee composed of senior program

staff from the funding institute. During this review,

the various elements of the proposals involving costs

are examined by Government cost analysts in conjunction with technical personnel. Applicants determined to be in the “competitive range” have an op

-

portunity to further defend or clarify their proposals

in written or oral discussion with the contracting officer or senior program staff. Once the applicants

have made their “best and final” offer, the remaining

applications are reevaluated via further negotiations

in order to determine the one to be funded. The ultimate objective of such negotiations is to reach a balanced equitable agreement. Occasionally, unsolicited

contract proposals are received by DRG. They are

forwarded to an appropriate institute, and if relevant

to the institute’s needs, are reviewed in a process similar to that for solicited proposaIs.

Once awarded, the progress and products of contract research are under the supervision and review

of the contracting officer at the funding unit. Informal and formal procedures are used to monitor the

performance of the contract project. A major difference between contract research and grant (and intramural) research, at least in theory, is that contractors

are required to provide an end product based on

specifications established by the institute before the

research begins. With grant-supported and intramural research, requirements for production of a given

outcome are generally much looser. Another difference between the funding mechanisms is that advisory councils or boards are not required to approve

contract awards as they are mandated to do for

grants. Nevertheless, they are usually quite involved

in the awarding unit’s research planning process,

which includes the allocation of resources for both

grants and contracts.

Recent Studies of the

Peer Review System

The peer review mechanism, being at the heart of

the grant-in-aid award system, has been the subject

of a number of recent studies. The General Accounting Office (GAO) (27) compared the operation of the

peer review and progress monitoring systems at NIH

and the National Science Foundation (NSF). In general, GAO found the NIH procedures better. However, GAO’s concern was not, as they stated, with

the quality of the review or the fairness of the review,

but with the process of the review. Examining the

quality of the scientific review is a different problem

and exceeded the resources available to GAO at the

time.

NIH conducted a review of its own peer review

system in the late 1970’s (50,51). Perhaps, not unexpectedly, they found the system to do a good job.

Recommendations on which action have been taken
126

were those directed at the mechanics of the system.

“A few recommendations were made regarding substantive issues of peer review but action on these was

deferred by the NIH Director pending further study”

(27).

The President’s Cancer Panel has announced that it

will host discussions in various cities around the

country during 18 months to begin early in 1982. The

purpose of those meetings is to hear opinions about

the submission and review of grant applications at

the National Cancer Institute (NCI) (announcement

of Dr. Armand Hammer at the NCAB meeting, Feb.

1, 1982).

NSF placed a contract with the National Academy

of Sciences (NAS) for a study of their peer review

system. Two reports from that study have been published. The first (15) appeared in Scientific American.

It reported:

1.

2.

3.

4.

5.

A high correlation between reviewer ratings and

grants awarded.

Absence of a high correlation between grants

awarded and previous scientific performance of

the applicants. (“This result was unexpected.”)

That reviewers from major institutions did not

favor applications from other major institutions.

That length of the scientific career of the applicant had no strong effect on review ratings.

Low or moderate correlation between reviewer

ratings and:

— prestige rank of applicant’s current academic department;

— academic rank;

— geographic location;

— NSF funding history over last 5 years; and

— place of Ph. D. training.

The second paper, published in Science (14)

reported rather more alarming results. Seventy-five

applications from three different NSF programs that

had been reviewed by the NSF peer review system

were subsequently reviewed by other groups of

peers. Surprisingly (to some, at least) and dismayingly (to more, perhaps), the ratings bestowed on about

25 percent of the applications by the two review

groups differed enough to have affected whether or

not the application would have been funded. The

disagreements went both ways. In some cases, the

NSF peer reviewers’ ratings that resulted in a decision

to fund an application was reversed by the second

group. In other cases, an NSF review rating that

would have meant no funding was changed sufficiently that the second rating would have resulted in

funding. The two review groups did not differ in

scientific accomplishments or esteem, and both appeared to be equally “peer.” The authors of the study

concluded that the “luck of the draw” in reviewers

has a significant impact on how an application fares.

The NSF peer review system typically uses some

four or five scientists to review an application. The

luck of the draw might seem more of a factor in that

system than in an NIH study section with 15 scientists. The authors of the paper about NSF review

reached no conclusion about the importance of the

luck of the draw in the NIH system. However, it is

the practice in NIH study sections to assign each application to a primary and a secondary reviewer. If

those two reviewers differ from the other study section members, and the others have read the application less thoroughly, luck of the draw may be important. The probability that members read less carefully applications on which they are neither primary nor

secondary reviewers is almost a certainty. Applications typically run to several score pages, and each

study section considers an average of 80 to 100 applications at each of its three-times-a-year meetings.

One expert contacted by OTA in the course of

writing chapter 6 of this report has served on both

NIH and NSF review groups. He found the NIH system to be more thorough and that the active discussion of applications at study section meetings produced better reviews. He thinks that prejudice, favoritism, and ignorance of a subject show up in study

section discussions and that this assures the applicants fairer consideration.

Some suggestions have been made to institute an

appeals system for applicants whose rating is less

than they think they deserve. Currently, the disappointed applicant must prepare another proposal.

The time necessary to write a new application plus

the time for another review (typically about 9

months from NIH’s receipt of the application to a

decision to fund or not to fund) means a long period

with no decision. Furthermore if a preexisting grant

expires before a new one is secured, part of the scientist’s research program may have to be shut down.

An instititute advisory board can suggest that an

application be sent for a second review to a second

study section. If the applicant has a current grant that

will expire during the second round of study section

review, the board suggestion results in an extension

of the preexisting grant at its current funding level

until the second review cycle is complete. The second

benefit to the applicant is that rereview of an existing

application means that it is unnecessary to prepare a

new application.

Some generalizations can, of course, be made. Scientists who have been successful in the current review system view it more favorably that those who

have not. There are opportunities within the system

for reviewers to play favorites or to discharge ani-
127

mosities, but none of the experts that OTA talked

with offered specific examples. The NIH system

works well (27) in keeping applicants informed of

what is happening to their proposals and of reasons

for the decisions that are made.

Typically, criticisms of the peer review system are

countered by arguments similar to those used to

counter criticisms of democracy: Yes, there are problems, and, indeed, the system may be as bad as can

be imagined, but it’s better than anything else. OTA’S

conversations with experts generated four pointed

criticisms of the NIH peer review system.

1.

2.

3.

4.

The research proposals that project 2, 3, or

more years into the future are not worth the

paper they are written on.

Narrowly focused, “can’t miss” applications

receive better scores than applications that are

broader and, if successful, more important.

“Peers” on study sections are not scientifically

equal to the applicants, and sitting on a study

section allows second-rate scientists opportunities to steal ideas from applicants.

The NIH rules that a scientist can serve only one

term on a study section is resulting in study section membership growing younger and younger. Younger scientists are not familiar with the

difficulties and costs of running large-scale

laboratories.

Directed at points 1 and 2 were comments that

good investigators plan carefully, obtain results, and

follow up leads. Narrow, carefully focused proposals

are most accurate in predicting results. By analogy, it

may also be that the authors of such applications are

least-well prepared to generate or recognize unpredicted leads and follow them down unexpected

courses. Of course, a breakthrough finding might occur in either broadly or narrowly focused research,

but rapid exploitation is thought to be more likely in

the former case.

Suggestions were made that NIH (and NSF) consider attaching greater weight to records of past accomplishments and less to projected research projects. Both the study of NSF peer review (15) and the

GAO study of both NSF and NIH peer review (27)

drew attention to the relatively small weight given to

past performance. The NSF study, as has been mentioned, regarded that finding as “unexpected.”

Published papers, which experts in the field, such

as study section members, will have read anyway,

provide a measure of scientists’ accomplishments.

Reliance on past performance, as judged from the

scientific literature, should reduce the workload on

reviewers, and at the same time, permit ranking of

the applications. A grant supports a scientist’s

research efforts; how the scientist has done in the

past is a guide to future production.

An immediate problem with “review” concentrating on past performance is how to judge the justbeginning investigator. Some experts expressed the

opinion that “new” investigators are now treated differently from “established” ones. Study sections may

be willing to take more of a chance on the new investigators. NIH estimates that one out of four scientists who are awarded an NIH research grant receives

one and only one grant. This 25 percent includes

both one-time grantees who do not submit another

application (“dropouts”) and individuals who resubmit and do not achieve a fundable priority score.

Opinions were expressed to the OTA staff that

reviewers tend to judge more harshly applications

that involve risk in the sense that an experiment may

fail to produce the result that is predicted. Discussions about this point emphasized that poorly

prepared or poorly thought through applications

were not to be favored. “Fishing expedition” applications, which describe experiments to be done with little description of expected results and scanty information about the interpretation that will be placed

on results were not held in high regard. On the other

hand, concern was expressed that applications that

posit a number of possible outcomes, even those

prepared by well-regarded scientists, may not be

given high grades in comparison to near repeats of

already completed studies in which results can be

predicted with greater certainty. The past production

of good results and proper interpretation of those

results, in the eyes of some, are a better guide to the

future than proposed research.

Experts who discussed peer review with OTA staff

pointed out that greater reliance on past performance

would reduce concern about the third point mentioned above. Applications that describe the future in

general terms would be a less rewarding source of intellectual plunder.

Finally, greater reliance on past performance

would provide more time for research on the part of

applicants and reviewers. The application could be

shorter and require less preparation. The reviewer

would have less to read.

Comments Made to OTA About

Various Grant Mechanisms

The research project grant in support of an individual researcher’s activities is the backbone of NIH

research activities and is seen as the essential element

in research support. In addition, some experts con-
128

tacted by OTA expressed great favor for program

project grants. The arguments made for such support

was that it concentrated the talents and experiences

of several individuals on a single project. The common goal is seen as producing a research whole greater than its parts. Review of program projects includes

a site visit by a study section members and NCI staff,

and that activity was seen as making for better

reviews.

The responses concerning center grants varied.

Several experts think that center grant applications

are so large and complex as to be almost impossible

to review. There was also concern that poorer quality research and researchers might shelter inside center grant support. On the other hand, centers—because of their size and complexity—allow some

research projects that cannot be supported by other

mechanisms.

One respondent suggested that center grants might

be made to exceptional scientist-administrators in

much the same way as the Max Planck Institutes in

Germany are funded. The center director would be

responsible for hiring staff, reviewing and approving

research efforts, and the productivity of the center.

At the end of the grant support period, the center’s

performance would be judged by its publications and

reputation. Such an approach would eliminate the

cumbersome and, some suggest, ineffective review of

center grant applications. It would also represent a

giving-up of authority by NCI.

Conclusions. —The peer review and extramural research system, being fundamental to the success of

NIH, have been studied, examined, and discussed.

The result of almost all of the investigations has been

confirmation that the system works. There have been

no suggested alternatives. A contrast to that generally favorable conclusion is the finding about the

“luck of the draw” in the review process.
Appendix C

NHLBI Clinical Trials

Introduction

The National Heart, Lung, and Blood Institute

(NHLBI) has an extensive program of clinical trials

dealing with critical issues in the prevention and

treatment of heart, lung, and blood diseases. These

contract programs now comprise about 9 percent of

the NHLBI’s extramural budget.

The investment in major clinical trials has grown

since the early part of this decade to nearly $42

million for fiscal year 1981 (table C-l).

NHLBI’s complement of clinical trials represents a

balance among several factors. First, the trial must be

in NHLBI’s purview; that is, the design and management of the clinical trial must require NHLBI’s research expertise. Some validation studies may be

aimed at questions that are related solely to health

services delivery, and consequently such experiments

would not fall within NHLBI’s purview, although the

Institute would very likely be involved in an advisory capacity.

Second, the clinical trial must satisfy several requirements related to such factors as the scientific

basis for the trial’s underlying hypothesis and the potential impact of that trial. Through NHLBI’s experience with clinical trials, these factors have been incorporated into a clinical trial decision process that

divides the trial into four distinct phases—initiation,

planning, recruitment and intervention, and analysis

and dissemination of the trial results. Separating each

phase is a crucial decision point at which NHLBI determines either to commit funds to the next stage of

the clinical trial (the first two decision points) or to

conclude the Intervention portion of the trial (the last

decision point).

Tables C-2 and C-3 summarize data on the Institute’s clinical trials. Table C-2 is a fiscal overview of

the clinical trials, with the expected costs of the projects ranging from approximately $1 million to over

$100 million. Table C-3 shows the broad characteristics of the clinical trials. The number of subjects

ranges from very few—even as few as 100—up to almost 13,000 (for the Multiple Risk Factor Intervention Trial). The Institute’s trials are currently in all

phases of the clinical trial decision process; for example, the multicenter investigation of the limitation of

infarct size (MILIS) is now in the recruitment and intervention phase, whereas the Hypertension Detection and Followup Program is in analysis and dissemination.

NHLBI’s complement of clinical trials deals with

both prevention of disease and treatment of disease.

The primary prevention trials are testing interventions to prevent disease before biological onset;

secondary prevention trials are testing intervention

after the disease is detected but before it is symptomatic.

The following sections, taken from NHLBI’s “Clinical Trials Briefing Document” (Jan. 27, 1982), summarize NHLBI’s clinical trials program and are divided into: 1) recently completed trials; 2) recently

initiated trials; and 3) trials in the planning stage.

129
130

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Table C-2e --. Fiscal overview of NHLBI Clinical Trials

PROJECTED

cLINIcAL TRIA L COST TO DATE* TOTAL CoST

Division of Heart and Vascular Diseases

Coronary Drug Project (CDP)

Lipid Research Clinics

Coronary Primary Prevention Trial

(LRC-CPPT)

Multiple Risk Factor Interventio n

Trial (MRFIT)

Hypertension Detection and FollowUP Program (HDFP)

Unstable Angina Pectoris Trial

Coronary Artery Surgery Study

(CASS)

Program on Surgical Control of

Hyperlipidemias (POSCH)

Aspirin Myocardial Infarction

Study (AMIS)

Beta-Blocker Heart Attack Trial

(BHAT)

Multicenter Investigation of

Limitation of Infarct Size (MILIS)

Treatment of Hypertension

Management of Patent Ductus in

premature Infants

Systolic Hypertension in the

Elderly Program (SHEP)

Randomized Trial of Aspirin

and Mortality in Physicians

Primary Prevention of Hypertenslon

Totals

$ 41,760,030

86,727,695

110,833,165

68,174,982

485,849

21,115,333

20,591,097

16,859,386

17,985,327

12,568,841

3,126,004

4,120,095

2,036,251

506,002

1,121,387

$408,011,504

104,420,695

115,769,176

70,541,982

485,849

25,147,393

2Q,750,516

16,859,386

18,200,000

19,437,$341

3,126,004

4,120,095

3,550,000

2,372,155

10,933,260

465,474,382
132

Table c-2 (continued)

PROJECTED

CLINICAL TRIAL COST TO DATE* TOTAL COST

Division of Lung Diseases

Neonatal Respiratory Distress $ 4,892,457 $ 5,567,457

Syndrome

Intermittent Positive Pressure 6,718,975 9,532,975

Breathing (IPPB)

Nocturnal Oxygen Therapy 3,977,382 3,977,382

Extracorporeal Membrane 5,552,340

Oxygenator Study (ECMO)

5,552,340

Totals $ 21,141,154 $24,630,154

Division of Blood Diseases and Resources

Granulocyte Transfusion Study $ 1,635,142 $ 1,635,142

Interruption of Maternal to 113,711 113,711

Infant Transmission of Hepatitis B

by Means of Hepatitis B Immune

Globulin

Cooperative Study of Factor VIII

Inhibitors

Hepatitis B Vaccine Clinical Trial

Totals

782,350

200,000

$ 2,731,203 $ 2,731,203

*AS of September 30, 1981
133

Table c-2 (continued)

PROJECTED

CLINICAL TRIAL COST TO OATE* TOTAL COST

Division of Intramural Research

NHLBI Type II Coronary $ 444,378 $ 444,378

Intervention Study

Diffuse Fibrotic Lung Disease * * * *

Evaluation of Subcutaneous ** **

Desferrioxamine as Treatment for

Transfusional Hemochromatosis

and a Controlled Trial on

Ascorbic Acid

Totals

NHLBI Grand Totals

$ 444,378 s 44,37 8

S432,328,239 $493,390,117

*As of September 3 0, 

1981

.

**The division of Intramural Research is reported in man-years,

not dollars. The NHLBI Type II Coronary Intervention Study is

also supported by a contract.

Source: National Heart, Lung, and Blood Institute
134

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Table c-3 (continued)

PROJECTE COST

CLINICAL TRIAL SUBJECTS STATUS — TOTAL COST

Division of Heart and Vascular Diseases (Continued)

Beta-Blocker Heart Attack Trial

(BHAT):

prevention of myocardial infarction

and death in survivors of myocardial

infarction with the drug propranolol

(a beta-blocker).

Multlcenter Investigation of Limitation of Infarct Size (MILIS):

Treatment of myocardlal infarction

with the drugs propranonlol and/or

hyaluronidase.

Treatment of Hypertension:

Primary prevention of cardiovascular

morbidity and mortality by drug

treatment of hypertension with

chlorothlazide - plus I?auwolfia

serpentina.

Management of Patent Ductus in

Premature Infants:

Comparison of treatment of patent

ductus arteriosus with the drug

indomethacin or with surgery and

conventional medical therapy.

Systolic Hypertension in the

Elderly Program (SHEP):

Prevention of stroke with

standard antihypertensive

agents

3,837 subjects followed

for up to 3.5 Years at

32 clinics.

1,ZNI patients will be

followed for 6 months

in 5 clinics.

389 subjects followed

for up to 11 years at

(i clinics.

400 subjects to he

followed at 12 clinics

for 1 year.

Now in the Analysis

and Dissemination

Phase.

Now in the Recruitment and Intervention Phase, which is

scheduled for completion in June, 1984.

Initiated in 1966.

Recruitment and intervention Phase completed

in 1976. Now in the

Analysis and Dissemination Phase.

tknv in the Intervention

Phase, which is scheduled

for completion in March,

1982.

500 subjects to be Now in the Recruitment

followed at 5 clinics. and Intervention Phase.

Recruitment will Continue throughout June, 1982.

All patients are to be

followed through June, 1983.

19,437,941

3,176,004

4,120,095

3,W),N70
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I I . Recently Completed Trials
142

HYPERTENSION DETECTION AND FOLLOW-UP

Objective

To determine the effectiveness of systematic,

PROGRAM (HDFP)

sustained, antihypertensive therapy in reducing morbidity and mortality from hypertension

in a wide spectrum of persons with elevated blood pressure in 14

communities. During its course, the trial also obtained a direct

measure of prevalence, severity, and current treatment status of

representative white and black populations with high blood pressure

in these 14 communities, and obtained an estimate of the extent of

attainable reduction of complications of high blood pressure bY an

organized screening and blood pressure managenent program.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: May 1971

Total Duration: 11 years (Intervention and Follow-up: 9 years)

Funding:

Total Support Prior to FY 1981 $66,890,877

FY 1981 support 1,284,105

Support Projected Beyond FY 1981 2,367,000

Total Support 70,541,
743

Hypertension Detection and

Follow-up Program (HDFP)

Background

Published data from the Veterans Administration Cooperative Study of

Hypertension denonstrated that reduction in morbidity and mortality could

be attained by treating men with fixed diastolic blood pressure over 105

mm Hg. Similar trends occurred for those with fixed diastolic blood

pressure between 90 and 104 mm Hg. Results and current trends from other

studies supported these findings. However, Prior to inception of the

Hypertension Detection and Follow-up Program (HDFP), it was not known

whether benefits from anti hypertensive therapy applied to all hypertensives

in the general population and whether making use of existing medical

knowledge could significantly reduce morbidity and mortalitv from

hypertension in communities.

Recognizing this need, NHLBI initiated the pilot activities of the HDFP

to characterize Significant Operational, socioeconomic, and motivational or

behavioral factors that would influence the acceptance of antihypertensive

therapy in the defined populations within which the? controlled clinical

trial would take place and to obtain baseline information necessary to

the undertaking of the clinical trial.

The planning of the trial, including the development of a protocol and

manual of operations, began in 1971. Between February 1973 and flay 1974,

158,906 persons were screened for high blood pressure in 14 communities.

A total of 10,940 hypertensive participants were randomized.

The primary hypothesis tested by this clinical trial was that intensive

blood pressure control under stepped care for 5 years can significantly

reduce mortality compared with that under referred care. Stepped care is

the method of treatment in HDFP clinics in which a diuretic is given

initially and additional antihypertensive agents are added in a timestructured, stepwise fashion until goal blood pressure is achieved.

Referred care represents referral to private physicians and other communit y

sources of care. Participating in this study were 14 clinical centers,

a coordinating center, EKG center, central laboratory, and monitorin g

laboratory .

The intervention portion of the trial has been completed. The study is

being extended through May 1982 in order to continue the surveillance of

mortality and blood pressure control.

Trial Results

The following statements have been abstracted from papers appearing in the

Journal of the American Medical Association.*

0 Five-year mortality from all causes was 17 percent lower for the

stepped-care group compared with the referred-care group (see

Figure 3) and 20 percent lower for the steeped-care participants

with “mild” hypertension (diastolic blood pressure 90-104 mm Hg

compared with the corresponding referred-care subgroup.
144

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Hypertension Detection and

FOllOw-UP Program (HDFP)

o Preliminary data on cause-specific mortality indicate that

the number of deaths from Cerebrovascular disease was smaller

by almost 45 percent for the steeped-care group. There were

26 percent fewer deaths from acute myocardial infarction in

the stepped-care group. Death rates from other ischemic

heart disease were similar in both groups. Nine deaths in

the stepped-carp group were certified to hypertension compared

with 14 in the referred-care group. For all cardiovascular

causes, there were 19 percent fewer deaths for the steppedcare group than for the referred-care group.

0 For white men, black men, and black women and for age subgroups 50 to 59 and 60 to 69, 5-year all-cause death rates were

substantially lower-- by 15 percent to 28 percent--for the

stepped-care subgroups compared with the referred-care subgroups.

Blood pressure control was consistently better for the steppedcare group than for the referred-care group. After 5 years,

64.9 percent of the stepped-care participants had reached goal

diastolic blood pressure versus 43.6 percent of the referrd-care

participants. Goal diastolic blood pressure was defined as

90 mm Hg for those entering with DBP equal to or greater than

100 or receiving anti hypertensive therapy, and a 10 mm Hg decrease

for those entering with DBP 90-99. After 5 years, 63.8 percent

of those stepped-care participants in stratum I (DBP 90-104)

achieved goal diastolic blood pressure versus 43.0 percent of

those in referred-care. Also, after 5 years, 69.6 percent of

stepped-care participants in stratum 11 (DBP 105-114) achieved

goal diastolic blood pressure versus 48.3 percent of those in

referred-care and 63.6 percent of stepped-care participants in

stratum III (DBP 115 or higher) achieved goal diastolic blood

pressure versus 39.1 percent of referred-care participants.

0 Systematic, effective management of hypertension has great

potential for reducing mortality for the large numbers of

people with hypertension in the population, including those

with “mild” hypertension.

*Hypertension Detection and Follow-up Program Cooperative Group:

Five-year Findings of the Hypertension Detection and Follow-up

Program: I. Reduction in Mortality of persons with High Blood

Pressure, Including Mild Hypertension. JAMA 242:2562-257l, 1979.

Hypertension Detection and Follow-up Program Cooperative Group:

Five-Year Findings of the Hypertension Detection and Follow-up program:

I I . Mortality by Race-sex and Age. JAMA 242:2572-2577, 1979.
146

ASPIRIN-MYOCARDIAL INFARCTION STUDY (AMIS)

Objective

To determine whether the daily administration of 1 gm of aspirin to

individuals with a documented myocardial infarction will result in a

significant reduction in mortality over a 3-year period.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: October 1974

Total Duration: 6 years (Intervention: minimum 3 years)

Funding:

Total Support Prior to FY 1981 $16,859,386

FY 1981 Support o

Support Projected Beyond FY 1981 0

Total Support $16,959,386

Subjects

Males and females, ages 30-69, not stratified as to ethnic groupx with a

documented myocardial infarction.

Experimental Design

Randomized, double-blind, fixed sample. Eligible patients were assigned

to a treatment group receiving 1 gm of aspirin daily (the equivalent of

three standard aspirin tablets) or to a control group receiving a placebo.

Current Phase (As of October 1981): Analysis and Dissemination

Background

It has been postulated that thrombosis plays a major role in the late

stages of coronary artery occlusion. Platelet aggregation is a large

component in the formation of arterial thrombi. Theoretically, an agent

which prevents the aggregation of platelets would be of value in people

with coronary artery disease. Aspirin, in small doses, inhibits platelet

aggregation for prolonged periods of time, and therefore might be expected

to prevent or retard the occlusion of coronary arteries. This would be

reflected in a decrease in the incidence of myocardial infarction and a

decrease in mortality due to coronary artery disease.

Several studies had given preliminary evidence that regular administration

of aspirin may be of benefit to patients with known the Coronary Drug

Project, ran a pilot trial of aspirin and placebo in men with previous

myocardial infarctions. Preliminary results from this trial demonstrated

its feasibility and led NHLBI to sponsor a more definitive controlled

study of the benefit of aspirin in the secondary prevention of coronary

heart disease.
147

Aspirin-Myocardial Infarction Study (AMIS)

An Institute Planning Committee developed a protocol, manual of

operations, and data collection forms. Recruitment of patients

began in June 1975, with the first patient randomized on July 2,

1975. Patients who were randomized had been seen at the AMIS Clinical

Center for two initial visits and one baseline visit and were free

of any reasons for exclusion, such as the current use of anticoagulants

and a history of adverse reactions to aspirin. Patients took acetaminophen

at times when they would normally take aspirin.

Follow-up was for a minimum of 3 years, with each patient seen at 4-

month intervals and monitored for side effects and various nonfatal

events, including cardiovascular problems. The primary endpoint was

mortality. Annually, a detailed history was obtained and a complete

physical examination performed. The study involved 30 clinical

centers, a coordinating center, and a central laboratory.

The study completed patient recruitment in the scheduled l-year

period. A total of 4,524 post-MI patients were enrolled by the 30

clinical centers. Three-year minimum patient follow-up ended in

June 1979.

Trial Results

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Total mortality during the entire follow-up period was 10.8

percent in the aspirin group and 9.7 percent in the placebo

group.

Three-year mortality was 9.6 percent in the aspirin group and

8.8 percent in the placebo group.

The rate of definite nonfatal MI was 8.1 percent in the placebo

group and 6.3 percent in the aspirin group.

Coronary incidence (coronary heart disease mortality or

definite nonfatal MI) was 14.1 percent in the aspirin group

and 14.8 percent in the placebo group.

Symptoms of peptic ulcer, gastritis, or erosion of gastric

mucosa occurred in 23.7 percent of the aspirin group and

14.9 percent of the placebo group.

Based on AMIS results, aspirin is not recommended for routine

use in patients who have survived a myocardial infarction.
148 — .

BETA-BLOCKER HEART ATTACK TRIAL (BHAT)

Objective

To determine whether the regular administration of the beta-blocker

drug propranolol to people who have had at least one documented

myocardial infarction will result in a significant reduction of

mortality from all causes over the follow-up period. A total of

3,837 eligible volunteer patients were recruited to participate in a

double-blind clinical trial within 5 to 21 days after the onset of the

acute event. One-half of the patients were randomly assigned to a

beta-blocking drug (propranolol) and one-half to a placebo. The trial

also evaluated the effect of propranolol on incidence of coronary

heart disease mortality, sudden cardiac cleat?, and nonfatal myocardial

infarction plus coronary heart disease mortality in persons with

documented previous myocardial infarction.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: September 1977

Total duration: 7 years (Intervention: 1-3.5 years)

Funding:

Total Support Prior to FY 1981 S14,098,633

FY 1981 Support 3,886,694

Support Projected Beyond FY 1981 214,673

Total Support 18,200,000

Subjects

Males and females, ages 30-69, who have had at least one myocardial

infarction. Subjects were not stratified as to ethnic group and were

drawn from various locations in the United States. Total sample size

equaled 3,837. Individuals were randomized to treatment and control

groups.

Experimental Design

A randomized, double-blind design with single experimental and control

groups. Patients were recruited while in the hospital for an acute

myocardial infarction and enrolled in the study before discharge.

Eligible patients fulfilled the study definition of an acute myocardial

infarction. The diagnosis was based either on electrocardiographic

records showing evolving QRS segment changes or on ST segment and T

wave changes together with enzyme changes and appropriate clinical

history. One-half of the patients were placed on therapy using a

beta-blocking drug (propranolol). The other half received a placebo.

Intervention duration was 1-3.5 years.

Current Phase (As of October 1981): Analysis and Dissemination
149

Beta Blocker Heart Attack Trial (BHAT)

Background

Coronary heart disease and its complications account for over 600,000

deaths in the U.S. each year. Survivors of a documented myocardial

infarction are recognized as having a high risk of dying relative to

the general population. Serious arrhythmias, occurring with or

without evidence of new infarction, are a common cause of death in

this population. Theoretically, an agent which (1) can block the

sympathetic nervous activity thought to be involved in precipitating

sudden death and (2) has non-neurogenic antiarrhythmic properties

would be of value to people with coronary heart disease. Propranolol,

like other beta-blocking agents, has these as well as other properties

and therefore might be expected to prevent or retard complications of

coronary heart disease such as serious arrhythmias. This would be

reflected in a decrease in mortality due to coronary heart disease.

A workshop on chronic antiarrhythmic therapy held in 1976 reviewed

contemporary experimental data and clinical practice and recommended

that a clinical trial be undertaken to clearly show the effects of

beta-blocking drugs on mortality. Subsequently, such a trial was

approved by the Clinical Applications and Prevention Advisory

committee, by the Cardiology Advisory Committee, and by the National

Heart, Lung, and Blood Advisory Council.

The study protocol was reviewed in February 1978 and recommended for

approval by the policy-data monitoring board and ad hoc members. The

protocol was approved by the Director of NHLBI in March 1978.

Recruitment started on June 19, 1978 and ended in October 1980. A

total of 3,837 patients were randomized. Participating in the trial

were 32 clinical centers, an EKG center, a central laboratory, a

coordinating center, a l-hour ambulatory EKG center, a 24-hour

ambulatory EKG center, and and EKG tape quality control center.

Trial Results

On the recommendation of the Policy and Data Monitoring Board,

intervention was ended in October 1981 instead of in June 1982.

Mortality was 9.5% in the placebo group and 7.9% in the propranolol

group, a reduction of 26% (see Figure 4). Preliminary results of

the trial indicate that the beneficial efforts of propranolol occur

primarily in the first year after a myocardial infarction.
— —

150

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151

PREVENTION OF NEONATAL RESPIRATORY DISTRESS SYNDROME

WITH ANTENATAL STEROID ADMINISTRATION

Objective

To determine the effect of corticosteroids, administered 24 to 48

hours before parturition, on the incidence of neonatal respirator

distress syndrome (RDS) and to determine whether the therapy has any

adverse short- or long-term (up to 36 months) effects on the infant.

Secondarily, to determine whether the therapy has any adverse shortterm effects on the mother and to determine whether morbidity rates

for neonatal respiratory distress syndrome as well as total and causespecific infant mortality rates differ between mothers who received

antenatal steroids and those who received conventional medical care.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: June 1976

Total Duration: 6 years (Intervention: 48 hours; Follow-up:

36 months)

Funding:

Total Support Prior to FY 1981 $4,438,366

FY 1981 Support 454,091

Support Projected Beyond FY 1981 675,000

Total Support s 5,567,457

Subjects

Male and female fetuses and infants; pregnant women with anticipated

premature delivery and gestational age between 26 and 37 weeks.

Experimental Design

Randomized, double-blind, fixed sample. Six hundred and ninety-six

patients were randomized to four doses of dexamethasone every 12

hours or to placebo. Endpoints were the incidence of respiratorv

distress syndrome and abnormality of motor-neuro-intellectual

development.

Current Phase (As of October 1981) Intervention (Follow-up)

Background

Neonatal respiratory distress syndrome is one of the leading causes

of disability and death in the newborn. In the United States,

approximately 10 percent of all infants are premature, and each year

about 50,000 cases of neonatal respiratory distress syndrome occur.

Hospital costs at the onset of the trial averaged $5,000 per patient,

with an average stay of 23 days.
—

152

Prevention of Neonatal Respiratory Distress Syndrome

with Antenatal Steroid Administration

Extensive studies in animal models on respirator distress syndrome

have demonstrated that antenatal administration of synthetic

(dexamethasone) and natural (cortisol) corticosteroids accelerates

lung maturation and significantly diminishes the occurrence of RDS.

Only one large, controlled, double-blind clinical trial on antenatal

corticosteroid therapy has been published to date, although this

therapy is beginning to be widely used in the United States. In that

trial, which was conducted in New Zealand, it was reported that there

is a lower-than expected incidence of neonatal RDS when betamethasone

is given to mothers for at least 24 hours after the onset of premature

labor and not later than the 32nd week of gestation. No follow-up

data, however, have been published. Although a variety of conditions

in newborn infants have been treated with steroids over the past 20

years without adverse effects, investigations have been needed on the

short-term effects of corticosteroids administered antenatally on

neonate and mother and on the long-term effects on the infants.

The Planning Phase of this trial was completed in March 1977, with

formulation of a common protocol and manual of operations. Patient

screening and enrollment began in May 1977 and ended on March 1,

1980. Follow-up will continue for 36 months after the entrance of

the last patient. At the present time, there are five clinical

centers and a coordinating center in the trial.

Preliminary Trial Results

Fetal and neonatal death rates were not significantly altered by

treatment. Fetal death rate was 1.6% in the treatment group and 2.2%

in the placebo group. Neonatal death rate before 40 weeks of age was

9.3% in the treatment group and 8.8% in the placebo group. The overall

incidence of RDS was different between control subjects (18.0%) and

treated mothers (12.6’%). This effect was mainly due to the pronounced

beneficial effect of treatment on singleton female infants. No

treatment effect was observed in male infants. Non-Caucasians were

improved, whereas Caucasians showed little benefit.
153

CORONARY DRUG PROJECT

Objective

To determine whether the regular administration of lipid modifyinq drugs

(clofibrate, nicotinic acid, estrogen, dextrothyroxine) to men with a

documented myocardial infarction would result in significant reduction

in total mortality over a 5-year period. Secondarily, to determine whether

the degree to which these drugs change serum lipids is correlated with any

effect on mortality and morbidity rates; to gain further information on

the long-term prognosis of myocardial infarction (by studying the control

group as intensively as the treatment group); to acquire further experience

and knowledge concerning the techniques and methodology of long-term

clinical trials; to determine, in a substudy, the effectiveness of aspirin,

a platelet inhibitor, in reducing recurrences of myocardial infarction.

Summary Data

Mechanism: Grant (Investigator

Initiation: April 1965

Total Duratfon: 16 years (Interventi

Funding:

Total Support Prior to FY 1981

FY 1981 Support

Support Projected Beyond FY 1981

Total Support

Subjects

Initiated Clinical Trial)

on: 5-8.5 years*)

$41,590,050

169$980

0

$41, 760,030

Males, ages 30-64, not stratified as to ethnic group, who were 3 months

beyond their most recent myocardial infarction.

Experimental Design

Randomized, double-blind, fixed sample. A total of 8,341 patients were

randomly assigned to six treatment groups consisting of ‘2.5 mg/day of

conjugated estrogens, 5.0 mg/day of conjugated estrogens, 1.8 gm/day of

clofibrate, 6.0 mg/day of dextrothyroxine sodium, 3.0 gin/day of niacin, or

3.8 gin/day of lactose placebo.

Current phase (As of October 1981): Nearly concluded, small Analysis and

Dissemination effort underway.

Background

Correlation of high levels of serum cholesterol with an increased incidence

and prevalence of coronary heart disease (CHD) was demonstrated--prior to

the inception of the Coronary Drug Project--repeatedly in prospective and

cross-sectional epidemiological surveys (e.g., the Tecumseh Study, the

Framingham Heart Disease Study). These findinqs led to the question of

*Applies to clofibrate and niacin therapy. Estrogen and dextrothyroxine

treatments were discontinued early.

91-486 9 - 82 - 11
154

Coronary Drug Project

whether long-term lowering of serum lipids in individuals both with and

without CHD would have a beneficial effect on morbidity and mortality.

The Coronary Drug Project was designed to answer the question of secondary

prevention. In 1961, Dr. Robert Wilkins (Boston University School of

Medicine) chaired an ad hoc committee which determined the desirability

and feasibility of the conduct of this study. Following National Heart

Advisory Council (NHAC) support, a study Policy Board, Steering Committee,

and Coordinating Center were established and a detailed protocol was

written. In 1964, NHAC approved the project and the NHI recommendation

for implementation; the study was begun in 1965. Supported by the grant

mechanism, the trial involved 53 participating clinics, a coordinatinq

center, central laboratory, ECG center, drug procurement and distribution

center, and NHI medical liaison office, and a policy board, steering

committee, and 12 other committees (e.g., a data and safety monitoring

committee).

The first patient was randomly allocated to treatment in March 1966 and

the last in October 1969. Each patient reported to the clinic every 4

months for a follow-up visit,

Trial Results

Three drug regimens were discontinued before the scheduled completion of

the project. The 5.0 mg/day estrogen regimen was discontinued in 1970

because of the number of nonfatal cardiovascular events when compared

with placebo and lack of evidence of efficacy with respect to the primary

endpoint of total mortality. Dextrothyroxine sodium was discontinued in

1971 because of excess mortality in the treatment group as compared with

the placebo group. The third regimen 2.5 mg/day of estrogen, was

discontinued in 1973.

Findings in the nicotinic acid and clofibrate treated groups were that

O both drugs produced modest reduction in serum cholesterol

concentrations,

O neither significantly decreased mortality compared with

that of patients receiving placebo, and

0 both drugs were associated with unpleasant and hazardous

side effects* which affected both the cardiovascular anti

digestive systems.

These negative findings refer only to secondary prevention--to patients

who have had one or more previous heart attacks--and do not indicate

whether either clofibrate or nicotinic acid is useful for individuals

who have not had a heart attack (i.e., for primary prevention).

*C loflbrate was associated with a high degree of cardiovascular

morbidity. Nicotinic acid decreased angina and new heart attacks,

but was associated with frequent side effects.
——.—

155

Coronary Dug Project

The study was extremely worthwhile in several respects:

O The trial established the hazardous side effects of the

lipid-lowering drug s

de effects might still be attributed to

the natural course of the disease rather than to the drugs.

O The information obtained on the natural history of myocardial

disease is extremely valuable and useful.

The trial also serves as the foundation for the primary prevention

trials now underway.

The vital status as of March 1, 1980 of all Participants alive at the

end of the Coronary Drug Project is currently being examined. The

objective is to confirm or refute reports of continued adverse effects

on mortality of clofibrate years after cessation of use OF the drug.

This mortality surveillance will be conducted from June 1981 - June

1982 by the Coordinating Center.
156

UNSTABLE ANGINA PECTORIS TRIAL

Objective

To compare the efficacy of medical or surgical (coronary artery bypass

graft) therapy with regard to survival and quality of life in patients

with unstable angina and requisite coronary anatomy as defined by

angiography.

Summary Data

Mechanism: Contract and Grant (Institute Initiated Clinical Trial)

Initiation: January 1972

Total Duration: 10 years (Intervention: 2 years)

Funding:

Total Support Prior to FY 1981 $485,849

FY 1981 Support o

Support Projected Beyond FY 1981 0

Total Support $485,849

Subjects

Males and females, ages 21 to 65, from selected sites across the United

States. All subjects had class III or IV angina pectoris in which nain

occurred at rest or with minimal exercise.

Experimental Design

Randomized, non-blind, sequential design with a control group and an experimental group. The patients in the experimental group were treated with

coronary bypass surgery. Patients in the control group received intensive

medical management. Endpoints were mortality and morbidity measures, such

as incidence of myocardial infarction and persistence of angina.

Current Phase (As of October 1981): Analysis and Dissemination

Background

Angina pectoris is a symptomatic condition of attacks of chest pain, often

debilitating. It is caused by a decreased supply of blood to the heart,

such as that which might occur in coronary artery disease. The usual

treatment of angina pectoris is designed to relieve the symptoms. It

includes avoidance of activities that produce the discomfort and the use

of nitroglycerin and beta-blocking drugs. Soon after the introduction of

coronary bypass surgery, many doctors enthusiastically adopted this approach

in treating patients with unstable angina.

In 1972, emphasizing that there was no definitive evidence showing the

superiority of intensive medical management or coronary bypass surgery in

determining mortality and morbidity in patients hospitalized with unstable

angina, some of the participating groups in the NHLBI Myocardial Infarction

Research Units developed a cooperative clinical trial to compare these

medical and surgical approaches to therapy.
157

Unstable Angina Pectoris Trial

From 1972 through 1976, 288 patients were entered into this randomized clinical trial. One hundred forty-seven patients received

intensive pharmacological medical therapy, and 141 comparable patients

underwent coronary artery bypass surgery. Careful follow-up studies

were performed on patients in both groups, in-hospital and during the

post-hospital phase. These studies included, apart from routine

physical examinations, resting electrocardiograms, chest x-ray films,

and grade exercise tolerance tests at six months and twelve months.

Unstable Angina Pectoris Trial

Trial Results

During the study period, the hospital mortality rate was 5 percent in

the surgical group and 3 percent in the medical group (difference not

significant).* The rate of in-hospital myocardial infarction was 17

and 8 percent in the respective groups (P<O.05). In the last 4 years

of the study (1973 to 1976), the hospital mortality rate decreased to

3 percent in the surgical group and to 2 percent in the medical group

(difference not significant). Durinq the last 3 years of the study

(1974 to 1976), the rate of in-hospital myocardial infarction was 13

percent in the surgical group and 10 percent in the medical group

(difference not significant). There were no differences in the subsets of patients with one-, two-, or three-vessel disease.

In the first year after hospital discharge, class III or IV angina

(New York Heart Association criteria) was more common in medically

than in surgically treated patients with one-vessel disease (22 percent versus 3 percent, P<O.05), two-vessel disease (40 percent versus

13 percent, P<O.01), and three-vessel disease (40 percent versus 15

percent, P<.01). During an average follow-up period of 30 months, 36

percent of the medically treated patients later underwent surgery to

relieve unacceptable angina. Late mortality was comparable in the

two groups, but the large number of medically treated Patients who

later underwent surgery prevents definitive conclusions about the

relative effect of medical and surgical therapy on long-term mortality.

However, the patients who responded to medical therapy did not have a

higher rate than surgical patients.

The results indicate that patients with unstable angina pectoris can

be managed acutely with intensive medical therapy, including the

administration of propranolol and long-acting nitrates in phamacologic

doses, with adequate control of pain in most patients and no increase

in early mortality or myocardial infarction rates. Later, elective

surgery can be performed with a low risk and good clinical results if

the patient’s angina fails to respond to intensive medical therapy.

*Unstable Angina Pectoris Study Group: Unstable Angina Pectoris

National Cooperative Study Group to Compare Medical and Surgical

Therapy. I I . In-Hospital Experience and Initial Follow-up Results

in Patients with One-, Two-, and Three-Vessel Disease. Am. J.

Cardiol. 42:839-848, 1978.

91-486 0 - 82 - 1?
158

NOCTURNAL OXYGEN THERAPY

Objective

To compare the efficacy of long-term use of nocturnal oxygen therapy (12

hours) with that of continuous, low-flow oxygen therapy (24 hours) in

patients with chronic hypoxic lung disease.

Summary Data

Mechanism:

Initiation:

Total Duration:

Funding:

Total Support

Contract (Institute Initiated Clinical Trial)

July 1976

4 years

,, Prior to FY 1981 $3,977,382

FY 1981 Support o

Support Projected Beyond FY 1981 0

Total Support S3,977,382

Subjects

Males and females, ages 35-70, not stratified as to ethnic group, who

have severe chronic obstructive lung disease requiring supplemental oxygen

therapy.

Experimental Design

Randomized, fixed sample. Two hundred and three patients were randomly

assigned to at-home treatments of continuous oxygen therapy or nocturnal

oxygen therapy. Endpoints related to quality of life, neuropsychological

function, and respiratory function and capacity. Intervention lasted

for 6 months to 3 years, with an average intervention of 19.3 months.

Current Phase (As of October 1981); Concluded

Background

Chronic obstructive pulmonary disease is a major health problem in the

United States. In 1975, it was the sixth leading cause of death. The

economic impact of the disease in 1972 amounted to $803 million in the

direct costs of disability treatment, $3.05 billion in disability costs,

and $645 million in lost earnings clue to premature death.

Motivated in part by the significant toll of this disease, a conference

on the Scientific Basis of Respiratory Therapy, co-sponsored by the

American Thoracic Society and the Division of Lung Diseases, examined

the current status of the use of oxygen therapy in chronic lunq disease.

The proceedings of the conference, published in the American Review of

Respiratory Disease (Vol. 110, No. 6, December 1974), included a

recommendation for clinical studies that would provide a critical

assessment of the role of nocturnal oxygen therapy in the treatment of

patients with chronic obstructive pulmonary disease. Low-flow oxygen,

administered continuously, is known to benefit some patients with chronic

hypoxic lung disease. However, low-flow oxygen administration for long
159

Nocturnal Oxygen Therapy

periods of time is cumbersome, confining, and expensive. If nocturnal

oxygen administration could be unequivocally demonstrated to be

efficacious, then the advantages of convenience and cost would have a

favorable impact on treatment of patients, and a rationale could be

developed for testing this therapy in a larger group of patients.

The Planning Phase of the trial was initiated in September 1976. Patient

recruitment began in May 1977. The Recruitment Phase lasted 24 rnonths.

The 203 patients in the trial were assigned randomly to home treatments

with nocturnal oxygen therapy or continuous low-flow oxygen therapy. The

Recruitment and Intervention Phase has ended. The trial has now concluded.

Trial Results

Mortality in the nocturnal oxygen therapy group was nearly twice that in

the continuous oxygen therapy group.* Sixty-four patients died, 41 in

the nocturnal oxygen therapv group and 23 in the continuous oxygen therapy

group. The 12-month mortality rate was 20.6 percent in the nocturnal

oxygen therapy group and 11.9 percent in the continuous oxygen therapy

group; 24-month mortality was 40.3 percent and 22.4 percent, respectively.

Overall mortality was 31.5 percent for all patients.

The reason for the decreased mortality associated with continuous oxygen

therapy is unclear . Only two of the numerous physiological and psychological

variables showed a significant treatment-related change with time. Hematocrit

value decreased in patients on continuous oxygen therapy, but not in those

on nocturnal oxygen therapy. Although continuous oxygen therapy decreased

hematocrit values and increased survival, there is no evidence that these

results are related to one another. Pulmonary vascular resistance also

showed a differential effect of treatment. However, the data suggest that

although continuous oxygen therapy reduced both mortality and pulmonarv

vascular resistance, the two phenomena were not related.

*Nocturnal Oxygen Therapy Trial Group: Continuous or Nocturnal

Oxygen Therapy in Hypoxemic Chronic Obstructive Lung Disease: 4

Clinical Trial. Ann. Intern. Med. 93:391-398, 1980.
160

EXTRACORPOREAL SUPPORT FOR RESPIRATORY INSUFFICIENCY (ECMO)

Objective

To evaluate indications for the use and efficacy of extracorporeal

membrane oxygenators (ECMO’S) for the support of patients with potentially

reversible acute respiratory failure.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: June 1974

Total Duration: 3 years

Funding:

Total Support Prior to FY 1981 S5,552,340

FY 1981 Support 0

Support Projected Beyond FY 1981

Total Support $5,552,34;

Subjects

Males and females, ages 12 to 65, not stratified as to ethnic group,

who had potentially reversible acute respiratory failure.

Experimental Design

Randomized, non-blind, fixed sample; 90 eligible patients were randomly

assigned to a group receiving extracorporeal membrane oxygenation plus

conventional therapy or to a group receiving conventional therapy.

Current Phase (As of October 1981): Concluded

Background

The report of the Task Force on Respiratory Diseases identified a

clinical syndrome of acute respiratory insufficiency (ARI) and estimated

that approximately 60,000 Americans die of ARI yearly. ARI was not

precisely defined; indeed, the Task Force realized that pathologists do

not recognize ARI. The Task Force pointed out that no diagnostic tests

for early detection of ARI exist, that the incidence and prevalence of

the disease are not known, and that existing therapy is supportive and

nonspecific (diuretics, corticosteroids, etc.). The pathogenesis of

the syndrome, the mechanism of interstitial edema, the defenses of the

lung against agents causing ARI, and the ultrastructural pathology and

natural history of the disease were virtually unknown. The Task Force

indicated a need for Respiratory Care Centers with highly trained

personnel that could reduce mortality from ARI.

This clinical trial grew out of the Task Force report. Nine participating

centers defined ARI in clinical and physiological terms and agreed to a

prospective randomized control study for 3 years to compare treatment

of severe ARI by conventional means with treatment by extracorporeal

membrane oxygenators.
161

Extracorporeal support for

Respiratory Insufficiency (ECMO)

Animal studies have shown that ECMO’S can provide one to two WeekS

1

support for the lungs without serious blood damage, in contrast to

bubble oxygenators, which allow complete pulmonary bypass for

approximately 6 hours, after which severe blood damage occurs at the

direct blood-gas interface. If patients with hypoxia secondary to

acute reversible lung injury can be supported with ECMO’S until the

lung lesion heals, improvement in survival rates and avoidance of the

hazards of conventional therapy may result. The trial, now completed,

was conducted at nine clinical centers in the United States.

Trial Results

Among the 90 patients in the randomized study, mortality for all

groups was over 90 percent, and there were an equal number of survivors

in the group receiving conventional therapy alone and in the group

receiving extracorporeal membrane oxygenation plus conventional

therapy. Morphological studies of biopsy and autopsy material from

the study group support the view that, despite sophisticated technology,

the progression of lung disease in patients with severe acute

respiratory failure cannot be arrested by the use of ECMO.
162

GRANULOCYTE TRANFUSION STUDY

Objective

To evaluate granulocyte transfusion therapy with respect to its prophylactic

and therapeutic effectiveness to prevent and aid recovery from infection.

The study trials were conducted simultaneously.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: September 1976

Total Duration: 4 years

Funding:

Total Support Prior to FY 1981 $1,635,142

FY 1981 support o

Support Projected Beyond FY 1981 o

Total Support $1,635,142

Prophylactic Trial: males and females, 12 years or older, who were i n

the first induction phase of chemotherapy for acute leukemia, who had

severe neutropenia, and who did not have documented infection.

Therapeutic Trial: males and females, any age who were receiving

chemotherapy for acute leukemia or who may have had aplastic anemia,

who had severe neutropenia, and who had documented infection.

Experimental Design

Prophylactic Trial and Therapeutic Trial: randomized, non-blind,

sequential. eligible patients were randomized to daily granulocyte

transfusions or no granulocyte transfusions.

Current Phase (As of October 1981): Analysis and Dissemination

Background

Infection remains a major cause of death in patients receiving chemotherapy

for malignant diseases. One approach to the problem of septicemia and

high mortality in these patients is the therapeutic use of granulocyte

transfusions. Recent improvements in collection techniques, employinq

continuous flow centrifugation, now permit the collection of granulocytes

from a single, normal donor in sufficient numbers to study their application

in the treatment of infections in granulocytopenic patients. Recent

studies have demonstrated the efficacy of granulocyte transfusions as an

adjunct in the therapy of septicemia due to gram negative microorganisms

associated with granulocytopenia.

The aims of the study were to determine (1) whether infections Can be

prevented in patients who receive granulocytes prophylactically and (2)

whether recovery from infection is aided in patients who receive granulocytes

therapeutically . Both trials utilized controls who received no qranulocytes.
163

Granulocyte Transfusion Study

Four contracts were awarded in September 1976. The protocol designed to

evaluate the efficacy of prophylactic granulocyte transfusions was

completed at the close of 1977. The protocol for the therapeutic trial

was completed in April 1978. 102 patients were randomized in the

Prophylactic trial and 51 in the therapeutic trial. The Recruitment and

Intervention Phase ended in February 1980. The trial is now in the

Analysis and Dissemination Phase.

Trial Results (Prophylactic Transfusion Study)

54 patients were randomized to receive daily granulocyte transfusions and

48 were randomized to the control group. Granulocyte transfusions were

given for 28 days. The primary end-point was the occurrence of documented

infection during the study period. Patients were monitored and data

collected daily. Additional evaluations were performed 35 and 60 days

after randomization and at six month intervals thereafter. The incidence of

bacterial septicemia was significantly lower in patients given transfusions

(9 per cent) than in controls (27 percent). The incidence of pneumonia

was twice that in transfused patients than in controls. Granulocvte

transfusion did not reduce the incidence of other infections or improve

hone-marrow recovery, remission rate and duration, or survival . Seventy-two

percent of the patients given transfusions had transfusion reactions and

fifty-seven percent had pulmonary infiltrates versus twenty-seven percent

of the controls. Thirty-five percent of the patients with pulmonary

infiltrates died versus five percent of those without infiltrates. It

was concluded that prophylactic granulocyte transfusions should not be

used during remission-induction chemotherapy in acute myelogenous Ieukemia

because the risks outweigh the benefits.
164

COOPERATIVE STUDY OF FACTOR VIII INHIBITORS

Objective

To test the efficacy of prothrombin complex concentrates (Factor IX) in

the treatment of hemophiliac patients who have inhibitors to Factor VIII.

Summary Data

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: July 1978

Total Duration: 2 years (Intervention: 1 year)

Funding:

Total Support Prior to FY 1981 $782,350

FY 1981 Support o

Support Projected Beyond FY 1981 0

Total Support $782,350

Males, not stratified as to ethnic group, who had hemophilia.

Experimental Design

Double-blind study; patients served as their own controls. A total of

51 patients. Each patient received a single large dose of Konyne, Proplex,

or diluted albumin (as a control). Joint bleeding of the elbow, knee, and

ankle were evaluated 6 hours after each dose.

Current Phase (As of October 1981): Concluded

Background

Despite major advances in the treatment of patients with hemophilia, a

serious remaining challenge is presented by the occurrence of circulating

inhibitors to Factor VIII. Because of lack of information on the natural

course of patients with Factor VIII inhibitors, the relative efficacy of

various modes of therapy is not established. The Division of Blood Diseases

and Resources decided to sponsor a clinical investigation which would

evaluate populations of hemophilia patients for Factor VIII inhibitors,

follow up these patients to provide information on the natural history of

the inhibitor in the hemophilia patients, and make available a reference

center to monitor results and attain uniformity.
165

cooperative -Study ‘

f

Factor VIII Inhibitors

Treatment of a patient with a severe inhibitor and consequent bleeding

remains a problem. Management includes protracted treatment with

Factor VIII, use of immunosuppressive agents, and most recently, the

use of prothrombin complex (or Factor IX) concentrates. The rationale

for Factor IX is that it bypasses the defect in Factor VIII caused by

the inhibitor. This method of therapy has attracted wide popularity,

but the success is greatly debated. It was intended at the very

outset of the Factor VIII study that therapeutic trials involving

patients with inhibitors would not be a prime function, but that such

studies would be monitored if necessary. A control trial of Factor

IX concentrates therrapy Was strongly advised by the DBDR Advisory

Committee. Accordingly, during fiscal year 1978, a protocol for a

double-blind control study was developed by the Factor VIII inhibitor

group. The trial began in the spring of 1978, and the intervention

concluded about 1 year later. The trial has been concluded.

Trial Results

Results were published in August 1980 indicating that although Factor

IX, when used in a single dose, is only partially effective in the

treatment of joint hemorrhage in hemophiliacs with inhibitors, its

continued use for acute hemarthrosis is justified in the absence of

any other effective and readily available therapy for this disorder.*

*L h JM, Sh apiro, SS, Palascak, JE, et al.: Efficacy of

P~~t;~~mbin-Complex Concentrates in Hemophiliacs with Antibodies

To Factor VIII. N Enql J. Med. 1980; 303:421-425.
166

MANAGEMENT OF PATENT DUCTUS IN PREMATURE INFANTS

Objective

To evaluate the effects (up to one year of age) of indomethacin on the

clinical course of patent ductus arteriosus in premature infants (24 hours

old or less) and to assess the relative merits of indomethacin and surgery

in infants with persistent respiratory distress who were not treated

early with indomethacln. Two concurrent trials are to he performed.

Summary Data

Nechanism: Grant (Investigator Initiated Clinical Trial)

Initiation: September 1978

Total Duration: 4 years (Intervention and Follow-up: 2 years)

Funding:

Total Support Prior to FY 1981 $3,543,332

FY 1981 Support 576,763

Support Projected Beyond FY 1981 0

Total Support $4,120,095

Subjects

Premature infants with patent ductus arteriosus, males and females,

with birth weights of 1,750 gm or less, admitted to the participating

institutions within the first 24 hours of life. Total sample size was

400 for Trial A and 140 for Trial B.

Experimental Design

Trial A was a randomized, double-blind trial in which indomethacin plus

usual medical therapy was compared with a placebo plus medical therapy.

Where this regimen was unsuccessful, the code was broken, and infants who

received Indomethacln were treated surgically. Infants who had received

placebo in Trial A were entered, if there are no contraindications to

indomethacin, into Trial B. In Trial B, infants were randomized to

immediate surgery or indomethacin therapy. Those in whom indomethacin

treatment is unsuccessful were be treated surgically.

Current Phase (As of October 1981): Intervention (Follow-up)

Background

The incidence of patent ductus arteriosus is higher in premature

infants than in full-term infants and is highest in premature infants

who have respiratory distress syndrome. It is generally agreed that

intervention in an asymptomatic infant with a small left-to-right

shunt is unnecessary, since the patent ductus almost invariably closes

spontaneously and thus does not require surgery. A few infants will

demonstrate signs of a large shunt during the course of respiratorv
167

Managenent of Patent Ductus in

Premature Infants

distress syndrome. Many of these infants will improve with medical

management of congestive heart failure, but others require surgical

closure. A third group of babies with respiratory distress have

severe progressive pulmonary disease requiring ventilator support.

There is disagreement as to whether elimination of the patent ductus

in these infants results in decreased mortality. A variety of

therapeutic approaches is being used, and there is no convincing

evidence of the superiority of one treatment over another.

The Recruitment and Intervention Phase began in April 1979. Recruitment

was completed March 31, 1981 with the recruitment goal of 400 patients

met.

PreliminaryTrial Result s

At the time of hospital discharge, mortality and morbidity was very

similar in the early indomethacin group, the delayed indomethacin

group, and the usual medical therapy plus surgery group. However, in

the two groups who received indomethacin, surgery was necessary to

close the ductus in only 30% of cases, as opposed to 70% in the group

who did not receive indomethacin. Thus, it appears that the use of

indomethacin eliminates the need for surgery in 40% of the infants

with this condition. All patients will be followed for one year

after hospital discharge, with these results to he released in 1982.
168

Hepatitis B VACCINE CLINIcAL TRIA L

Objective

To determine the efficacy of a new vaccine to prevent hepatitis B.

Summary Data

Mechanism: Grant (Investigator Initiated Clinical Trial)

Initiation: November 1978

Total Duration: 3 years (2 years Intervention and Follow-Up)

Funding:

Total Support Prior to FY 1981 $100,000 estimated

FY 1981 Support 100,000 “

Support Projected Beyond 1981 o

200000 It ~t

Subjects

Males at high risk for hepatitis B virus infection, 36 years of age or

younger, no recent symptoms of hepatitis, blood specimen negative for

HBsAg, anti-HBs and anti-HBe.

Experimental Design

Randomized, double blind, fixed-sample. Total sample size was 1083.

549 subjects were allocated to the vaccine group in which they were treated

with highly purified formalin-inactivated virus subunits derived from the

plasma of chronic carriers of hepatitis R. 534 were allocated to the

placebo group. Both groups received injections at 0, 1 month, and 6 months

unless evidence of infection developed before the series was completed.

Current Phase (As of October 1981): Concluded

Background

Although most carriers of HBsAq are asymptomatic, a substantial proportion

eventually develop chronic active hepatitis and cirrhosis. There is also

overwhelming evidence that the hepatitis B virus is the single most important

causative factor of hepatocellular carcinoma. Thus, mass immunization proqrams

against HBV infection may ultimately affect not only the incidence of acute

hepatitis B and the pool of chronic carriers but may also reduce the morbidity

and mortality from chronic active hepatitis, cirrhosis, and hepatocellular

carcinoma.

Krugman and his co-workers laid the groundwork for active immunization

against hepatitis B in 1970 to 1973. They discovered that a 1:10 dilution

of hepatitis B infective serum lost its infectivity when boiled for one minute

but retained its antigenicity and prevented hepatitis B in 70% of vaccinated

subjects. Hilleman and his colleagues at the Merck Institute of Therapeutic

Research developed a more sophisticated vaccine consisting of highly
169

Hepatitis B Vaccine Clinical Trial

purified, formal in-inactivated HBsAq particles derived from the plasma of

chronic carriers of the antigen. By 197Q, data were sufficient to permit

testing in a clinical trial.

The first subject was inoculated in November 1978, and by December 1979,

recruitment had ended. In May 1980, all trial events were reviewed

and classified by an expert panel. In June 1980 the code of vaccine

and placebo allocation was broken.

Trial Results

Within one month of the first vaccination, 31.4 percent of persons

receiving the vaccine developed antibody agqainst hepatitis B; within

two months, this rate increased to 77 Percent; within three months,

to 87 percent; and within six months, but before the third injection,

to 90 percent. The booster injection increased the antibody-response

rate to 96 percent. Antibody-response rates then remained essentially

unchanged for the rest of the 18-month followup period. The incidence

of chemical or serologic evidence of hepatitis R in vaccine recipients

varied between 1.4 percent and 7.6 percent compared with 18.1 percent

and 35.0 percent in placebo recipients.
170

III : Recently Initiated Trials (FY 1981)
171

A RANDOMIZED TRIAL OF ASPIRIN AND MORTALITY IN PHYSICIANS

Objective

To assess the effect on cardiovascular mortality of alternate-day

consumption of 325 milligrams of aspirin and, secondarily, the effect

on cancer incidence of alternate-day consumption of 30 milligrams of

beta-carotene.

Summary Data

Mechanism: Grant (Investigator Initiated Clinical Trial)

Initiation: September 1981

Total Duration: 5 years (Intervention 4.5 years)

Funding:

Total Support Prior to FY 1981 $

FY 1981 Support 505,00:*

Support Projected Beyond FY 1981 1,866,153

Total Support $2,372,155

Subjects

Male physicians, age 50 to 75, who report no history of stroke,

myocardial infarction, cancer, or renal disease, who indicate no

contraindications to aspirin or beta-carotene and who report no

current usage of aspirin or Vitamin A tablets greater than once per

week. Sample size is estimated to be 21,900.

Experimental Design

Randomized, double-blind, fixed sample. Participants are to be

randomized into one of four treatment groups: one 325 milligram

aspirin tablet ever other day, alternating with one 30 milligram

capsule of beta-carotene; one aspirin every other day, alternating

with one capsule of beta-carotene; and one aspirin Placebo tablet

every other day, alternating with one capsule of beta-carotene placebo.

Major endpoints for the cardiovascular component of the study are

cardiovascular mortality, total mortality, and coronary events.

Current Phase (As of October 1981): Planning

Thrombosis plays a major role in the late stages of coronary occlusion.

Platelet aggregation is a large component in the formation of arterial

thrombi. In pharmacologic studies, aspirin has been shown to inhibit

platelet aggregability and, therefore, might be expected to prevent

coronary occlusion. These effects are apparent in the dose range of

100-1000 mg/day, and may be most evident at 160 milligrams daily.

Higher doses seen to be no more effective in either inhibition of

platelet aggregability or prolonged bleeding time.

*Joint funding by NHLBI and NCI. Total dollars spent in FY 1981 were

$843,336. NHLBI financed $506,002 and NCI $337,334. Total dollars, including

estimated indirect costs, committed through FY 1985 are S3,110,254, of which

NHLBI is to fund $1,866,153 and NCI to fund $1,224,101.
172

PRIMARY PREvENTION OF Hypertension (FEASIBILITY STUDY)

Objective

To determine whether hypertension can be prevented by dietary interventions

in a population of 19-40 year old high risk men and women.

Summary Data

Mechanism: Grant (Investigator Initiated Clinical Trial)

Initiation: September 1981

Total Ouration: 5 years (Feasibility Study)

Funding:

Total Support Prior to FY 1981 $

FY 1981 Support 1,121,38?

Support project Beyond FY 1981 9,811,873

Total Support 10,

Subjects

Mlales and females, ages 18-40, first degree relatives of hypertensive patients

in the HDFP study, first degree relatives of clinic hypertension patients, and

patients identified through screening. Patients will have initial home

diastolic blood pressure between 78-96 mm Hg, subsequent clinic readings

between 80-89 mm HG and Quetelet body mass index of more than 0.035 and less

than 0.061. 800 patients will be required.

Experimental Desiqn

Randomized, non-blind, with five groups of 160 patients each. The groups

include: a control group with no intervention; a low sodium group with a goal

of 70 milliequivalents sodium intake per day; a low sodium, high potassium group

with a goal of 70 milliequivalents sodium and 100 milliequivalents potassium per

day; a weight reduction group with a goal of more than five percent reduction

in body weight; and a body weight reduction and low sodium intake group.

Current Phase (As of October 1981): Planning

Background

Animal studies conducted over recent decades have shown that excess dietary

sodium chloride induces hypertension in a large fraction of most mammalian

species and that excess dietary potassium chloride protects against the

hypertensigenic action of excess sodium chloride. Human population groups

which consume less than three grams of sodium chloride per day do not show

the rise in blood pressure with increasing age that occurs in populations

in industrial nations. A variety of studies have shown the relationship of

body mass to blood pressure, leading many investigators to believe excess

weight to be the leading risk factor for high blood pressure. Intervention

trials have demonstrated that weight reduction in the absence of substantial

change in sodium excretion results in reducing blood pressure in hypertensive.

The study is in the Planning Phase, in which the protocol will be refined and

the manual of operations developed. Included in the study are four clinical

centers, a coordinating center, and a nutrition and education resource center.
173

IV: Trials in the Planning Stage

91-486 0 - 82 - 13
174

ANTIARRHYTHMIC AGENTS IN THE PREVENTION OF SUDDEN DEATH: PILOT STUDY

Objective

To conduct a pilot study in order to compare the effectiveness of various

drugs and drug combinations in suppressing ventricular arrhythmias, and

to evaluate their safety. This pilot study will also assess the feasibility

of carrying out a full scale clinical trial. The objective of the full

trial, if it is conducted, will be to determine if the suppression of

ventricular arrhythmias in people with coronary heart disease will result

in reduction in sudden cardiac death.

Proposed:

Mechanism: Contract (Institute Initiated Clinical Trial)

Initiation: September 1982

Total Duration: 4 years (Pilot Study)

Funding:

Total Support $8,000,000

Subjects

Patients in the post-MI period who have major ventricular arrhythmias.

Experimental Design

About 500 patients would be enrolled and randomized to five groups.

About 100 patients per group is required in order to obtain reliable

information on toxicity and to analyze results by subgroups.

The drugs studied will be chosen from among amiodarone, aprindine,

disopyramide, encainicle, flecainide, lorcainide, mexiletine, procainamide,

quinidine, and tocainide. Each group will follow a pre-determined

treatment strategy. Initially, patients will be prescribed one of five

drugs. After a three month interval, efficacy in decreasing ventricular

arrhythmias will be assessed. Then, depenriinq on the degree of arrhythmia

suppression and occurrence of side effects, a second drug will supplement

or replace the first drug.

Background

Approximately 400,000 people in the U.S. die suddenly every year,

most of them presumably from cardiac arrhythmias. Three quarters of

this population has known heart disease. Epidemiologic studies have

indicated that complex ventricular premature beats make an independent

contribution to risk of sudden death in survivors of myocardial infarction

and do not appear to be merely a reflection of their association with
175

Antiarrhythmic Agents in the Preventing

of Sudden Death: Pilot Study

relatively severe myocardial damage. The potential for reduction in

mortality by identification and administration of drugs capable of

safely suppressing ventricular arrhythmias is tremendous. Currently,

there is incomplete knowledge regarding which types of ventricular

arrhythmias respond to various kinds of drugs. This pilot study of

antiarrhythmic agents would help clarify this issue.
176

ISOLATED SYSTOLIC HYPERTENSION IN THE ELDERLY

Objective

To determine the effect of treating isolated systolic hypertension

(ISH) in persons over 60 years of age.

Proposed

Mechanism: Contract (Institute Initiated Clinical Trial

Total Duration: 7 years (Intervention 3 years)

Funding:

Total support $70,000,000

Subjects

Males and females, over 60 years of age and with systolic blood pressure

greater or equal to 160 mm Hg and a diastolic blood pressure less than 90

mm Hg. Total sample size is 4,000.

Experimental Design

Randomized, double blind, placebo controlled. All patients would be treated

and followed for three years, the primary endpoint being the occurrence of

stroke, or other cardiovascular events.

Background

The classical form of essential hypertension is a relative increase in both

the systolic and the diastolic components of the blood pressure. Attention

so far has primarily focused on elevated diastolic pressure and it has been

shown, beyond doubt, that effective treatment of this condition results in not

only reduced mortality, but also in a lesser risk of subsequent cardiovascular

and renal complications. The prevalence of combined systolic-diastolic hypertension tends to stabilize in late middle age. However, with increasing’years

the systolic pressure continues to rise out of proportion to any concomitant

rise in the diastolic component. Hence the emergence in the elderly population

of the condition known as isolated systolic hypertension (ISH).

It was once believed that the complication of hypertension could be completely

accounted for by the diastolic elevation alone. There is now abundant evidence

that the systolic component is at least as equally predictive of future

morbidity and mortality. Therefore effective treatment of ISH in the elderly

population might reduce premature mortality and the occurrence of disabling

cerebrovascular, cardiovascular and renal disease. ISH may also play an

important part in the etiology of senile dementia.

To determine whether a large study is now feasible the National Heart, Lung,

and Blood Institute is sponsoring, in conjunction with the National Institute

on Aging, a pilot study of systolic hypertension in the elderly. This will

recruit a total of 500 patients from five centers and treat and follow them

all for at least one year. This small pilot has specific objectives each

designed to test and evaluate critical components of a future full-scale

endeavor directed at the consequences of treating ISH in the elderly.
177

STREPTOKINASE IN THE TREATMENT OF MYOCARDIAL INFARCTION

The use of intracoronary or intravenous streptokinase in the treatment

of acute myocardial infarction is showing dramatic effects upon

relieving acute coronary obstruction. This trial will assess the

effectiveness of streptokinase under controlled clinical procedures

in order to prevent inappropriate widespread clinical use without

inadequate validation of net benefit. Details of this trial are

under development.
178

EVALUATION OF VENTILATION-PERFUSION SCANS AND PULMONARY ANGIOGRAPHY FOR

DIAGNOSIS OF PULMONARY EMBOLISM

Objective

To evaluate the effectiveness of ventilation-perfusion scans as a

less dangerous and less costly alternative and adjunct technique to

pulmonary angiography, for the diagnosis of pulmonary embolism. The

outcome is expected to solve a major medical controversy with important

implications for reducing the risks associated with the diagnosis and

treatment of pulmonary embolism.

Proposed

Mechanism: Contract (Institute Initiated Clinical Trial)

Total Duration: 4 years (Recruitment 2 years)

Funding:

Total Support $70,000,000

Subjects

Patients suspected of having pulmonary embolism. Total sample size is 700.

Experimental Design

Non-randomized, non-blind, fixed sample. The trial would involve 700 patients

who would receive ventilation perfusion scans; negative scans would result in

detailed followup; equivocal and positive scans would lead to pulmonary

angiography for definitive diagnosis and followup.

Background

Pulmonary embolism refers to a blood clot blocking one or more arteries in the

lung. The problem is associated with patients recovering from major surgery,

patients with poor circulation, childbirth, women taking oral contraceptives,

and patients with underlying cancer. In the last decade despite diagnostic

advances the condition remains difficult to diagnose. Postmortem exams have

shown a high incidence of undiagnosed pulmonary emboli, conditions that in many

cases may have been associated with the patient’s death. Recent estimates

indicate that pulmonary embolism may account for 50,000 deaths each year. If

less than one embolic event in 10 is fatal, there are an estimated half a

million episodes of pulmonary embolism each year in hospitalized patients in

the United States.

The primary immediate hospital treatment for pulmonary embolism, anticoagulation

therapy with heparin is dangerous, being the leading cause of adverse drug

reactions in hospitalized patients. Moreover, the followup treatment with the

oral anticoagulant coumadin represents some risk since that drug is one of the

eight drugs most commonly responsible for hospital admission.

This trial will assess the accuracy of ventilation-perfusion scans, a radionucleide imaging technique, in diagnosing pulmonary embolism, comparing this

technique to the more invasive and more dangerous, standard technique of pulmonary

angiography.
179

SLOW CHANNEL CALCIUM BLOCKER IN PATIENTS WITH

CORONARY ARTERY SPASM

Objective

To evaluate the efficacy of a slow channel calcium blocker in patients

with coronary artery spasm.

Proposed

Mechanism: Contract (Institute Initiated Clinical Trial)

Total Duration: 6 years (Recruitment 2 years)

Funding:

Total Support $8,000,0Q0

Subjects

Patients with coronary artery spasm. These patients would be identified

primarily on the basis of angina at rest. However, a number of

patients with chronic stable angina and acute myocardial infarction

may also be shown to have coronary artery spasm and would be eligible

for the study. The primary endpoint would be death plus nonfatal

myocardial infarction. Reduction in angina would also be measured.

Total sample size is 650.

Experimental Design

Double blind, multicenter, controlled trial.

Background

In recent years, there has been a resurgence of the concept that coronarY

artery spasm plays a major role in cardiac disease. The major area is

thought to be unstable angina. However, there is some evidence that

some people with chronic stable angina also have coronary artery spasm.

In addition, studies have shown that of those with acute myocardial

infarction, perhaps 5% have no evidence of vessel disease and 25% have

evidence of only one vessel disease. Coronary artery spasm may play a

role there as well.

Slow channel blockers (calcium antagonists) have received recent attention

in the relief of the symptoms of coronary artery spasm. A number of

small or uncontrolled studies have been done in patients with spasm and

have shown promising results in relief of variant angina and ventricular

arrhythmias (which often accompany variant angina). However, a large

controlled study is needed to demonstrate whether these agents are indeed

beneficial in reducing mortality and morbidity.

Previous studies have demonstrated the feasibility of identifying eligible

patients and extended treatment with acceptable compliance and toxicity levels.

A trial with about 10 centers is necessary to recruit the 650 patients necessary

for a two-arm study. Recruitment would take two years, with one additional

year of follow-up.
180

PHYSICAL EXERCISE IN SURVIVORS OF MYOCARDIAL INFARCTION

Objective:

To test the effect of physical exercise in survivors of myocardial

infarction.

Proposed

Mechanism: Contract (Institute Initiated clinical Trial)

Total Duration: 7 years (Recruitment 2 years)

Funding:

Total SuPport $50,000,000

Subjects

Post-myocardial infarction patients.

Experimental Design

Randomized, controlled trial. Four thousand subjects would

allocated either to Special Intervention, comprising an inddesigned training program and risk factor counseling, or to

Care from their primary physicians.

Background

he

vidually

usual

One third of all deaths in the United States are the direct result of

coronary heart disease (CHD), making it the leading cause of death.

The patient who survives an MI has not only an increased chance of

dying but also risks significant morbidity from cardiovascular and

renal complications. Myocardial infarction often comes at a time

when a subject has significant responsibilities both at home and at

work.

Of the approximately one million persons suffering their first coronary

event each year, roughly 400,000 of them die in the acute phase. The

600,900 who survive face a 10% chance of dying in the first year

after the event, resulting in an additional 50,000 deaths. Therefore

a reduction of even twenty percent would result in a substantial saving

of lives. In five exercise trials to date, while none demonstrated a

significant reduction in mortality (perhaps because of inadequate

sample size), all had a positive trend favoring the exercise group

ranging from 18.8% to 37.0%. Any new trial undertaken in this area

would need to be sufficiently large to permit a true beneficial effect

on mortality to detected. To date, exercise appears to be one of the

most promising interventions in a post-MI population. Increasing

interest in this field by practicing physicians and the general

population would most likely encourage participation in a post-MI

clinical trial of physical exercise.
181

PREVENTION OF SUDDEN DEATH IN SURVIVORS

OF OUT-OF-HOSPITAL VENTRICULAR FIBRILLATION

Objective

To evaluate an antiarrhythmic agent in patients who recover from outof-hospital ventricular fibrillation.

Proposed

Mechanism: Contract (Institute Initiated Clinical Trial)

Total Duration: 5 years (Recruitment 2 years)

Funding:

Total Support $5,000,000

Patients who have recovered from out-of-hospital ventricular

fibrillation. Total size is 400.

Experimental Design

Randomized, multicenter trial.

Background

The number of community programs aimed at reducing heart disease

mortality in the pre-hospital phase is increasing. The greater

sophistication of ambulance and other rescue services plus the spread

of cardiopulmonary resuscitation programs are likely to result in

many more survivors of ventricular fibrillation. Recurrence of

fibrillation is extremely likely in this population, especially in

those without a demonstrable myocardial infarction accompanying the

fibrillatory episode. In fact, there is often an absence of any

other identifiable cardiac pathology. Therefore, if the ventricular

fibrillation could be prevented, a major increase in life span might

be expected. Currently, there is no accepted therapy which will

prevent recurrence of fibrillation. At the same time, there are a

number of promising, new antiarrhythmic drugs. Therefore, the time

is appropriate to assess one or more of these drugs.
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