HE 26 1),

F/ INAL REPORT

of the

Tuskegee Syphilis Study

Ad Hoc Advisory Panel

Southeor Iffu li Un mrs gSStoc Of M c R" Library

Spr,ng`iesd, iU#hiois

U .S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFAREPUBLIC HEALTH SERVICE

April 28, 1973

Dr. Charles C . EdwardsAssistant Secretary for HealthU.S. Department of Health, Education, and WelfareWashington, D .C .'20202

Dear Doctor Edwards :

The final report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel is transmittedherewith . The Chairman specifically abstains from concurrence in this final report butrecognizes his responsibility to submit it .

Broadus N . Butler, Ph .D .PresidentDillard University

TABLE OF CONTENTS

PANEL CHARTERSFirst Panel Charter 1Second Panel Charter 2

PANEL MEMBERS 3

DATES AND PLACES OF MEETINGS 4

FINAL REPORTSection I - Report on Charge I 5

Addenda to Charge I 14

Section II - Report on Charge II 16Addenda to Charge II 20

Section III - Report on Charge III 21

Southern Illinois UniversitySchool of Medicine Library

Springfield, Illinois

DEPARTMENT OF HEALTH, EDUCATION, ANDWELFARE

CHARTER

Tuskegee Syphilis Study Ad Hoc Advisory Panel to theAssistant Secretary for Health and Scientific Affairs

Purpose

To fulfill the public pledge of the Assistant Secretary forHealth and Scientific Affairs to investigate . thecircumstances surrounding the Tuskegee, Alabama,study of untreated syphilis in the male Negro initiatedby the United States Public Health Service in 1932 .

Authority

The committee is established under the provisions ofSection 222 of the Public Health Service Act, asamended, 42 US Code 217a, and in accordance with theprovisions of Executive Order 11671, which sets forthstandards for the formation and use of advisorycommittees .

Function

The committee will advise the Assistant Secretary forHealth and Scientific Affairs on the following specificaspects of the Tuskegee Syphilis Study :

Determine whether the study was justified in 1932and whether it should have been continued whenpenicillin became generally available .

Recommend whether the study should be continuedat this point in time, and if not, how it should beterminated in a way consistent with the rights andhealth needs of its remaining participants .

Determine whether existing policies to protect therights of patients participating in health researchconducted or. supported by the Department ofHealth, Education, and Welfare are adequate andeffective and to recommend improvements in thesepolicies, if needed .

Structure

The committee will consist of nine members, includingthe Chairman, not otherwise in the full-time employ ofthe Federal Government. Members will be selected bythe Assistant Secretary for Health and Scientific Affairsfrom citizens representing medicine, law, religion, labor,education, health administration, and public affairs .The Panel members will be invited to serve for a periodnot to extend beyond December 31, 1972, unless anextension beyond that time is approved by the AssistantSecretary for Health and Scientific Affairs . The Assistant

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Secretary for Health and Scientific Affairs will designatethe Chairman .

Management and staff services will be provided by theOffice of the Assistant Secretary for Health andScientific Affairs .

Meetings

Meetings will be held at the call of the Chairman, withthe advance approval of a Government official who shallalso approve the agenda . A Government official will bepresent at all meetings .

Meetings shall be conducted, and records of the pro-ceedings kept as required by Executive Order 11671 andapplicable Departmental regulations .

Compensation

Members who are not full-time Federal employees willbe paid at the rate of $100 per day for time spent atmeetings, plus per diem and travel expenses inaccordance with Standard Government TravelRegulations .

Annual Cost Estimate

Estimated annual cost for operating the committee,including compensation and travel expenses of membersbut excluding staff support, is $74,000 . Estimate ofannual man years of staff support required is one year atan estimated annual cost of $16,000 .

Report

A final report based on the committee's investigationwill be made to the Assistant Secretary for Health andScientific Affairs . A copy of this report shall be providedto the Department Committee Management Officer .

The Tuskegee Syphilis Study Ad Hoc Advisory Panel tothe Assistant Secretary for Health and Scientific Affairswill terminate on December 31, 1972, unless extensionbeyond that date is requested and approved .

FORMAL DETERMINATION

By authority delegated to me by the Secretary onSeptember 29, 1969, I hereby determine that theformation of the Tuskegee Syphilis Study Ad HocAdvisory Panel to the Assistant Secretary for Health andScientific Affairs is in the public interest in connectionwith the performance of duties imposed on the Depart-ment by law, and that such duties can best be performedthrough the advice and counsel of such a group .

8/28/72

(sgd.) Merlin K . DuVal, M .D.Date

Assistant Secretary for Healthand Scientific Affairs

DEPARTMENT OF HEALTH, EDUCATION,AND WELFARE

CHARTER

Tuskegee Syphilis Study Ad Hoc Advisory Panel to theAssistant Secretary for Health

Purpose

To fulfill the public pledge of the Assistant Secretary forHealth to investigate the circumstances surrounding theTuskegee, Alabama, study of untreated syphilis in themale Negro initiated by the United States Public HealthService in 1932 .

Authority

The Panel is established under the provisions of Section222 of the Public Health Service Act, as amended, 42 USCode 217a; the Panel is governed by provisions ofExecutive Order 11671, which sets forth standards forthe formation and use of advisory committees .

Function

The Panel will advise the Assistant Secretary for Healthon the following specific aspects of the TuskegeeSyphilis Study :

Determine whether the study was justified in 1932and whether it should have been continued whenpenicillin became generally available .

Recommend whether the study should be continuedat this point in time, and if not, how it should beterminated in a way consistent with the rights andhealth needs of its remaining participants .

Determine whether existing policies to protect therights of patients participating in health researchconducted or supported by the Department ofHealth, Education, and Welfare are adequate andeffective and to recommend improvements in thesepolicies, if needed .

Structure

The Tuskegee Syphilis Study Ad Hoc Advisory Panel tothe Assistant Secretary for Health consists of ninemembers, including the Chairman, not otherwise in thefull-time employ of the Federal Government. Membersare selected by the Assistant Secretary for Health fromcitizens representing medicine, law, religion, labor,education, health administration, and public affairs . TheChairman is designated by the Assistant Secretary forHealth .The Panel members are invited to serve for a period notto extend beyond March 31, 1973, unless an extension

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beyond that time is approved by the Assistant Secretaryfor Health .

Management and staff services will be provided by theOffice of the Assistant Secretary for Health whichsupplies the Executive Secretary .

Meetings

Meetings will be held at the call of the Chairman, withthe advance approval of a Government official who shallalso approve the agenda . A Government official will bepresent at all meetings .

Meetings are open to the public except as determinedotherwise by the Secretary ; notice of all meetings isgiven to the public .

Meetings are conducted, and records of the proceedingskept, as required by applicable laws and Departmentalregulations .

Compensation

Members who are not full-time Federal employees willbe paid at the rate of $100 per day for time spent atmeetings, plus per diem and travel expenses inaccordance with Standard Government TravelRegulations .

Annual Cost Estimate

Estimated annual cost for operating the Panel, includingcompensation and travel expenses of members butexcluding staff support, is $74,000 . Estimate of annualmanyears of staff support required is one year, at anestimated annual cost of $16,000 .

Report

A final report based on the Panel's investigation will bemade to the Assistant Secretary for Health, not laterthan April 30, 1973, which contains as a minimum a listof members and their business addresses, the dates andplaces of meetings, and a summary of the Panel'sactivities and recommendations . A copy of this reportshall be provided to the Department Committee Manage-ment Officer .

Termination Date

Unless renewed by appropriate action prior to itsexpiration, the Tuskegee Syphilis Study Ad HocAdvisory Panel to the Assistant Secretary for Health willterminate on March 31, 1973 .

APPROVED:

1/4/73

(sgd.) Richard L. SeggelDate

Acting Assistant Secretary for Health

PANEL MEMBERS

Chairman :

Broadus N . Butler, Ph.D .President, Dillard University2601 Gentilly BoulevardNew Orleans, Louisiana 70122

Members :

Mr. Ronald H. BrownGeneral CounselNational Urban League55 East 52nd StreetNew York, New York 10022Vernal Cave, M .D .Director, Bureau of Venereal

Disease ControlNew York City Health Department93 Worth StreetNew York, New York 10013

Jean L . Harris, M.D ., F.R .S .H .Executive DirectorNational Medical Association

Foundation, Inc .1150 17th Street, N .W .Washington, D.C. 20036

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Seward Hiltner, Ph.D ., D.D .Professor of TheologyPrinceton Theological SeminaryPrinceton, New Jersey 08540

Jay Katz, M .D .Professor (Adjunct)

of Law and PsychiatryYale Law School127 Wall StreetNew Haven, Connecticut 06520

Jeanne C . Sinkford, D .D .S .Associate Dean for Graduate and

Postgraduate AffairsCollege of DentistryHoward University600 W Street, N .W .Washington, D.C. 20001

Mr. Fred SpeakerAttorney at Law2 North Market SquareHarrisburg, Pennsylvania 17108

Mr. Barney H . WeeksPresident, Alabama Labor CouncilAFL-CIO1018 South 18th StreetBirmingham, Alabama 35205

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MEETINGS

TUSKEGEE SYPHILIS STUDY AD HOCADVISORY PANEL

1 . September 22, 1972Subcommittee Meeting on Charge IIIHoliday Inn - La Guardia AirportNew York, New York

2. September 27, 1972Panel MeetingNational Institutes of HealthBethesda, Maryland

3 . October 25, 1972Panel MeetingNational Institutes of HealthBethesda, Maryland

4. November 2, 1972Panel MeetingNational Institutes of HealthBethesda, Maryland

5. November 30, 1972Panel MeetingNational Institutes of HealthBethesda, Maryland

6. December 18, 1972Subcommittee Meeting on Charge I

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Subcommittee Meeting on Charge IIINational Institutes of HealthBethesda, Maryland

7. December 19, 1972Panel MeetingNational Institutes of HealthBethesda, Maryland

8. January 24, 1973Subcommittee Meeting on Charge III55 East 52nd StreetNew York, New York

9. February 23, 1973Subcommittee Meeting on Charge INational Institutes of HealthBethesda, Maryland

10. March 1, 1973Panel MeetingParklawn BuildingRockville, Maryland

11 . March 20, 1973Subcommittee Meeting on Charge III26 Federal PlazaNew York, New York

12. March 28, 1973Panel MeetingNational Institutes of HealthBethesda, Maryland

REPORT ON CHARGE I

April 24, 1973

Tuskegee Syphilis Study Ad HocAdvisory Panel

Acknowledgements

Subcommittee for Charge I

The Co-Chairmen wish to acknowledge the input ofmembers of the subcommittee and panel members whoseinput and deliberations were essential to the final report forCharge I :

Members of'the Subcommittee for Charge I

Mr. Ronald H. BrownDr. Vernal CaveMr. Barney H . WeeksDr. Jean L . Harris, Co-ChairmanDr. Jeanne C. Sinkford, Co-Chairman

and

Mr. Fred Speaker, Panel Member

Also, our sincere appreciation to staff members whoassisted in editing, typing and distributing the final report :

Dr. Robert C . BackusMrs. Bernice M. LeeMrs. Jacqueline Eagle

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FINAL REPORT

TUSKEGEE SYPHILIS STUDY AD HOCADVISORY PANEL

REPORT ON CHARGE I-A

Statement of Charge I-A : Determine whether thestudy was justified in 1932 .

Background Data

The Tuskegee Study was one of several investigationsthat were taking place in the 1930's with the ultimateobjective of venereal disease control in the UnitedStates. Beginning in 1926, the United States PublicHealth Service, with the cooperation of other organiza-tions, actively engaged in venereal disease control work .'In 1929, the United States Public Health Service enteredinto a cooperative demonstration study with the JuliusRosenwald Fund and state and local departments ofhealth in the control of venereal disease in six southernstates 2 : Mississippi (Bolivar County); Tennessee (TiptonCounty); Georgia (Glynn County); Alabama (MaconCounty) ; North Carolina (Pitt County) ; Virginia(Albermarle County) .IThese syphilis control demonstra-tions took place from 1930-1932 and disclosed a highprevalence of syphilis (35%) in the Macon Countysurvey. Macon County was 82.4% Negro . The culturalstatus of this Negro population was low and theilliteracy rate was high .

During the years 1928-1942 the Cooperative ClinicalStudies in the Treatment of Syphilis3 were taking placein the syphilis clinics of Western Reserve University,Johns Hopkins University, Mayo Clinic, University ofPennsylvania, and the University of Michigan . TheDivision of Venereal Disease, USPHS provided statisticalsupport, and financial support was provided by theUSPHS and a grant from the Milbank Memorial Fund .These studies included a focus on_ effects of treatment- in .latent, syphilis which had not been clinically documentedbefore- 1932 . A report issued in 1932 indicated asatisfactory clinical outcome in 35% of untreated latentsyphilitics .

The findings of Bruusgaard of Oslo on the results ofuntreated syphilis became available in 19 a The Oslostudy was a classic retrospective study involving theanalysis of 473 patients at three to forty years afterinfection. For the first time, as a result of the Oslostudy, clinical data were available to suggest the proba-bility of spontaneous cure, continued latency, or seriousor fatal outcome . Of the 473 patients included in theOslo study, 309 were living and examined and 164 weredeceased . Among the 473 patients, 27 .7 percent wereclinically free from symptoms and Wassermann negative ;

14.8 percent had no clinical symptoms with Wassermannpositive ; 14 .1 percent had heart and vessel disease ; 2 .76percent had general paresis and 1 .27 percent had tabesdorsalis . Thus in 1932, as the Public Health Service putforth a major effort toward control and treatment, muchwas still unknown regarding the latent stages of thedisease especially pertaining to its natural course and theepidemiology of late and latent syphilis .

Facts and DocumentationPertaining to Charge I-A

1 . There is no protocol which documents the originalintent of the study . None of the literature searches orinterviews with participants in the study gave anyevidence that a written protocol ever existed for thisstudy. The theories postulated from time to time includethe following purposes either by direct statement orimplication : 5-7

a. Study of the natural history of the disease .

b . Study of the course of treated and untreatedsyphilis (Annual Report of the Surgeon General ofthe Public Health Service of the United States1935-36) .

c. Study of the differences in histological and clinicalcourse of the disease in black versus whitesubjects.

d . Study with an "acceptance" of the postulate thatthere was a benign course of the disease in laterstages vis-a-vis the dangers of available therapy .

e. Short term study (6 months or longer) of theincidence and clinical course of late latent syphilisin the Negro male (From letter of correspondencefrom T. Clark, Assistant Surgeon General, to M .M .Davis of the Rosenwald Fund, October 29, 1932)- Original plan of procedure is stated herein .

f. A study which would provide valuable data for asyphilis control program for a rural impoverishedcommunity .

In the absence of an original protocol, it can only beassumed that between 1932 and 1936 (when the firstreports of the study was made) the decision was madeto continue the study as a long-term study . The AnnualReport of the Surgeon General for 1935-36 included thestatement: "Plans for the continuation of this study areunderway. During the last 12 months, success has beenobtained in gaining permission for the performance of,autopsies on 11/15 individuals who died ."

2. There is no evidence that informed consent wasgained from the human participants in this study . Suchconsent would and should have included knowledge ofthe risk of human life for the involved parties and

information re possible infections of innocent, non-participating parties such as friends and relatives .Reports such as "Only individuals giving a history ofinfection who submitted voluntarily to examinationwere included in the 399 cases" are the only ones thatare documentable .5 Submitting voluntarily is notinformed consent .

3. In 1932, there was a known risk to human life andtransmission of the disease in latent and late syphilis*was believed to be possible . Moore 3 1932 reportedsatisfactory clinical outcome in 85% of patients withlatent syphilis that were treated in contrast to 35% if notreatment is given .

4 . The study as announced and continually described asinvolving "untreated" male Negro subjects was not astudy of "untreated" subjects . Caldwell8 in 1971reported that : All but one of the originally untreatedsyphilitics seen in 1968-1970 have received therapy,although heavy metals and/or antibiotics were given fora variety of reasons by many non-study physicians andnot necessarily in doses considered curative for syphilis .Heller6 in 1946 reported "about one-fourth of thesyphilitic individuals received treatment for their infec-tion. Most of these, however, received no more than 1 or2 arsenical injections ; only 12 received as many, as 10 ."The "untreated" group in this study is therefore a groupof treated and untreated male subjects.

5 . There is evidence that control subjects who becamesyphilitic were transferred to the "untreated" group .This data is present in the patient files at the Center forDisease Control in Atlanta . Caldwell a reports 12 originalcontrols either acquired syphilis or were found to havereactive treponemal tests (unavailable prior to 1953) .Heller,6 also, reported that "It is known that some ofthe control group have acquired syphilis although theexact number cannot be accurately determined atpresent ." Since this transfer of patients from the controlgroup to the syphilitic group did occur, the study is notone of late latent syphilis . Also, it is not certain that thisgroup of patients did in fact receive adequate therapy .

6. In the absence of a definitive protocol, there is noevidence or assurance that standardization of evaluativeprocedures, which are essential to the validity andreliability of a scientific study, existed at any time . Thisfact leaves open to question the true scientific merits ofa longitudinal study of this nature . Standardization ofevaluative procedures and clinical judgment of theinvestigators are considered essential to the validinterpretation of clinical data . 9 It should be noted that,in 1932, orderly and well planned research related tolatent syphilis was justifiable since a . Morbidity and

*Vonderlehr to T . Clark - Memorandum - June 10, 1932 .

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mortality had not been documented for this populationand the significance of the survey procedure had justbeen reported in findings of the prevalence studies for 6southern counties;' b. Epidemiologic knowledge ofsyphilis at the time had not produced facts so that itcould be scientifically documented "just how and atwhat stage the disease is spread ."* c. There was apaucity of knowledge re clinical aspects and spontaneouscure in latent syphilis 3 and the Oslo study4 had justreported spontaneous remission of the disease in 27 .7%of the patients studied . If perhaps a higher "cure" ratecould have been documented for the latent syphilitics,then the treatment priorities and recommendations mayhave been altered for this community where funds andmedical services were already inadequate .

The retrospective summary of the "Scientific Contribu-tions of the Tuskegee Study" from the Chief, VenerealDisease Branch, USPHS (dated November 21, 1972)includes the following merits of the study :

"Knowledge already gained or potentially able to begained from this study may be categorized as con-tributing to improvements in the following areas :

1 . Care of the surviving participants,2. Care of all persons with latent syphilis,3 . The operation of a national syphilis control

program,4. Understanding of the disease of syphilis,5 . Understanding of basic disease producing

mechanisms."

Panel Judgments on Charge 1-A

1 . In retrospect, the Public Health Service Study ofUntreated Syphilis in the Male Negro in Macon County,Alabama, was ethically unjustified in 1932 . This judg-ment made in 1973 about the conduct of the study in1932 is made with the advantage of hindsight acutelysharpened over some forty years, concerning an activityin a different age with different social standards .Nevertheless one fundamental ethical rule is that aperson should not be subjected to avoidable risk ofdeath or physical harm unless he freely and intelligentlyconsents. There is no evidence that such consent wasobtained from the participants in this study .

2. Because of the paucity of information available todayon the manner in which the study was conceived,designed and sustained, a scientific justification for ashort term demonstration study cannot be ruled out .However, the conduct of the longitudinal study asinitially reported in 1936 and through the years is

*Letter from L. Usllton, VO Program 1930-32 and memo-randum from Vonderlehr to T . Clark (Assistant SurgeonGeneral) June 10, 1932 .

judged to be scientifically unsound and its results aredisproportionately meager compared with known risksto human subjects involved . Outstanding weaknesses ofthis study, supported by the lack of written protocol,include lack of validity and reliability assurances ; lack ofcalibration of investigator responses ; uncertain quality ofclinical judgments between various investigators ;questionable data base validity and questionable value ofthe experimental design for a long term study of thisnature .

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The position of the Panel must not be construed to be ageneral repudiation of scientific research with humansubjects . It is possible that a scientific study in 1932 ofuntreated syphilis, properly conceived with a clearprotocol and conducted with suitable subjects who fullyunderstood the implications of their involvement, mighthave been justified in the pre-penicillin era. This isespecially true when one considers the uncertain natureof the results of treatment of late latent syphilis and thehighly toxic nature of therapeutic agents then available .

REPORT ON CHARGE I-B

Statement of Charge I-B : Determine whetherthe study should have been continued when penicillin

became generally available .

Background Data

In 1932, treatment of syphilis in all stages was beingprovided through the use of a variety of chemothera-peutic agents including mercury, bismuth, arsphena-mine, neoarsphenamine, iodides and various combina-tions thereof. Treatment procedures being used in theearly 1930's extended over long periods of time (up totwo years) and were not without hazard to thepatient.' ° As of 1932, also, treatment was widelyrecommended and treatment schedules specifically forlate latent syphilis were published and in use . 3 10 Therationale for treatment at that time was based on theclinical judgment "that the latent syphilitic patientmust be regarded as a potential carrier of the disease andshould be treated for the sake of the Community'shealth.s 3 The aims of treatment in the treatment oflatent syphilis were stated to be : 1) to increase theprobability of "cure" or arrest, 2) to decrease theprobability of progression or relapse over the probableresult if no treatment were given and 3) the control ofpotential infectiousness from contact of the patient withadults of either sex, or in the case of women with latentsyphilis, for unborn children .According to Pfeiffer (1935)," treatment of latesyphilis is quite individualistic and requires thephysician's best judgment based upon sound funda-mental knowledge of internal medicine and experience,and should not be undertaken as a routine procedure .Thus, treatment was being recommended in the UnitedStates for all stages of syphilis as of 1932 despite the"spontaneous" cure concept that was being justified byinterpretations of the Oslo study, the potential hazardsof treatment due to drug toxicity and to possibleJarisch-Herxheimer reactions in acute late syphilis . 12

Documented reports of the effects of penicillin in the1940's and early 1950's vary from outright support andendorsement of the use of penicillin in late and latentsyphilis, 13-15 to statements of possible little or novalue,' 6"' 7 to expressions of doubts anduncertainty 18-19 related to its value, the potency ofpenicillin, absence of control of the rate of absorption,and potential hazard related to severe Herxheimereffects .

Although the mechanism of action of penicillin is notclear from available scientific reports of late latentsyphilis, the therapeutic benefits were clinically docu-mented by the early 1950's and have been widely

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'reported from the mid 1950's to the present . In fact, theCenter for Disease Control of the USPHS has reportedtreatment of syphilitic mothers in all stages of infectionwith penicillin as of 1953 20 and has demonstrated thatpenicillin is the most effective treatment yet known forneurosyphilis (1960) . 21

Facts and Documentation re Charge I-B

1 . Treatment schedules recommending the use ofarsenicals and bismuth in the treatment of late latentsyphilis were available in 1932 .3 Penicillin therapy wasrecommended for treatment of late latent syphilis in thelate 1940's' 4"15 which was before it became readilyavailable for public use (estimated to have been1952-53) .

2. It was "known as early as 1932 that 85% of patientstreated in late latent syphilis would enjoy prolongedmaintenance of good health and freedom from disease asopposed to 35 percent if left untreated .i3 Scientists inthis study, 5 reported in 1936, that morbidity in maleNegroes with untreated syphilis far exceeds that in acomparable nonsyphilitic group and that cardiovascularand central nervous system involvements were two tothree times as common . Moreover, Wenger,22 in 1950,reported : "We know now, where we could only surmisebefore, that we have contributed to their ailments andshortened their lives . I think the least we can say is thatwe have a high moral obligation to those that have diedto make this the best study possible ." The effect ofsyphilis in shortening life was published from observa-tions made by Usilton et al. in 1937 .23 The study byRosahn24 at Yale in 1947 reported strong clinicalevidence that syphilis ran a more fatal course in Negroesthan in Caucasians .3 . Reports regarding the withholding of treatment frompatients in this study are varied and are still subject tocontroversy . Statements received from personal inter-views conducted by Panel members with participants inthis study cannot be considered as conclusive since thereare varied opinions concerning what actually happened .In written letters and in open interviews, the panelreceived reports that treatment was deliberatelywithheld on the one hand and on the other, we weretold that individuals seeking treatment were not deniedtreatment (in transcript and correspondencedocuments) .

What is clearly documentable (in a series of lettersbetween Vonderlehr and Health officials in Tuskegeetaking place between February 1941 and August 1942)is that known seropositive, untreated males under 45years of age from the Tuskegee Study had been calledfor army duty and rejected on account of a positiveblood . The local board was furnished with a list of 256

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names of men under 45 years of age and asked that thesemen be excluded from the list of draftees needingtreatment! According to the letters, the board agreedwith this arrangement in order to make it possible tocontinue this study on an effective basis . It should benoted that some of these patients had already receivednotices from the Local Selective Service Board "to begintheir antisyphilitic treatment immediately ."

According to Wenger,22 the patients in the study"received no treatment on our recommendation," At thepresent time, we know that most of the participants inthis study received some form of treatment with heavymetals and/or antibiotics . 8 Although the adequacy oftreatment received is not known, it is clear that thetreatment received was provided by physicians who werenot a part of the study and who were individually soughtby the individual patients related to their own medicalsymptoms and pursuit of treatment .4. The five survey periods in this study occurred in1932, 1938-39, 1948, 1952-53 and 1968-70 .8 "25 Thisstudy lacks continuity except through the public healthnurse and at these isolated survey periods . In 1969 anAd Hoc Committee reviewed the Tuskegee Study withthe purpose : to examine data from the Tuskegee Studyand offer advice on continuance of this study .

Participants of the February 6, 1969 meeting included :

Committee Members :

Dr. Gene StollermanChairman, Dept . of MedicineUniversity of Tennessee, Memphis

Dr. Johannes Ipsen, Jr .ProfessorDept. of Community MedicineUniversity of Pennsylvania, Philadelphia

Dr . Ira MyersState Health OfficerMontgomery

Dr. J. Lawton SmithAssociate Professor of OphthalmologyUniversity of Miami

Dr. Clyde KaiserSenior Member Technical StaffMilbank Memorial FundNew York City

Resource Persons :

Dr. Bobby C . Brown, VDRL, NCDCMrs. Eleanor V . Price, VD Branch, NCDCDr. Joseph Caldwell, VD Branch, NCDCDr. Paul Cohen, VDRL, NCDC

Dr. Sidney Olansky

Professor of MedicineDept. of Internal MedicineEmory University Clinic, Atlanta

Recorders :Dr. Leslie C. NorinsChief, VDRL, NCDC

Mrs. Doris J . SmithSecretary to Dr. Norins, VDRL, NCDC

Attending :

Dr. David J . SencerDirector, NCDC

Dr. William J . BrownChief, VD Branch, NCDC

Dr. U.S.G. Kuhn j III, VDRL, NCDCMiss Genevieve W . Stout, VDRL, NCDC

Dr. H. Bruce DullAssistant Director, NCDC

The meeting was convened at 1 :00 p.m. and adjournedat 4 :10 p.m .

A summary report of the meeting includes thefollowing :

The purpose of the meeting was to determine if theTuskegee Study should be terminated or continued .Considerations were :

1 . How the study was setup in 19322 . Are the participants all available3 . How are the survivors faring

At the time of this study there were only sevenpatients whose primary cause of death was ascribedto syphilis .It was determined that benefits to be achieved fromthe study at this time were :

1 . Relationship of serology to morbidity fromsyphilis

2. Relationship of known pathology to syphilis3.' Various epidemiological considerations

Full treatment of the survivors was also consideredand the following liabilities listed .

Danger of late Herxheimer's reaction which wouldworsen or possibly kill those syphilitic patientssuffering from cardiovascular or neurological con-ditions.

At this time it was mentioned that both MaconCounty Health Department and Tuskegee Institutewere cognizant of the study .

The meeting was terminated with several salientpoints .

1 . This type of study would never be repeated .2. There were certain medical facts to be learned

by continuing the present study .3 . Treatment for these patients was not indicated

unless they had signs of active syphilitic disease .4. More contact should be established between

PHS and Macon County Health Departmentand Medical Society so they would cooperate inthe continuance of the study .

It should be noted that the Committee was eminentlyrepresented from the medical community . However,legal representatives and others from the non-medicalcommunity of scholars were not adequately representedfor so sensitive a study . This is especially true since theTuskegee Study was being continued at a time whenDepartment of Health, Education, and Welfare guide-lines for the Protection of Human Subjects were beingwidely disseminated for compliance by all institutionsreceiving grant support . The three hours and ten minuteswere not adequate for in-depth study of the broadissues, implications and ramifications of this study .

In 1970, Drs. Anne Yobs and Arnold L . Schroeter inseparate memoranda (to the Director, Center for DiseaseControl and to the Chief, Venereal Disease Branch)recommended procedures for orderly termination of thisstudy . Dr . James Lucas, Assistant Chief of the VenerealDisease Branch, in a memorandum to the Chief of theVenereal Disease Branch dated September 10, 1970

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states: It must be fully realized that the remainingcontribution from this study will be largely of historicalinterest . Nothing learned will prevent, find, or cure asingle case of infectious syphilis or bring us closer to ourbasic mission of controlling venereal disease in theUnited States.5 . There is a crucial absence of evidence that patientswere given a "choice" of continuing in the study oncepenicillin became readily available . This fact serves toamplify the magnitude of encroachment on the humanlives and well-being of the participants in this study . Thisis especially significant when there- is uncertainty as tothe whole issue of "consent" of the participants .

Panel Judgments on Charge I-B

The ethical, legal and scientific implications which areevoked from the facts presented in the previous sectionled the Panel to the following judgment :

That penicillin therapy should have been made availableto the participants in this study especially as of 1953when penicillin became generally available .

Withholding of penicillin, after it became generallyavailable, amplified the injustice to which this group ofhuman beings had already been subjected. The scientificmerits of the Tuskegee Study are vastly overshadowedby the violation of basic ethical principles pertaining tohuman dignity and human life imposed on theexperimental subjects .

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REPORT ON CHARGE I

SUMMARY

This section of the Advisory Panel's report dealsspecifically with Charge Codes I-A and I-B .

Statement of Charge Codes

Charge I-A. Determine whether the study was justifiedin 1932, and

Charge I-B . Determine whether it should have beencontinued when penicillin becamegenerally available .

Introduction

The Background Paper on the Tuskegee Study, preparedby the Venereal Disease Branch of the Center for DiseaseControl, July 27, 1972, included the followingstatements :

"Because of the lack of knowledge of the patho-genesis of syphilis, a long-term study of untreatedsyphilis was considered desirable in establishing amore knowledgeable syphilis control program ."

"A prospective study was begun late in 1932 inMacon County, Alabama, a rural area with a staticpopulation and a high rate of untreated syphilis . Anuntreated population such as this offered an unusualopportunityy to follow and study the disease over along period of time . In 1932, a total of 26 percent ofthe male population tested, who were 25 years of ageor older, were serologically reactive for syphilis by atleast two tests, usually on two occasions . The originalstudy group was composed of 399 of these men whohad received no therapy and who gave historical andlaboratory evidence of syphilis which had progressedbeyond the infectious stages . A total of 201 mencomparable in age and environment and judged byserology, history, and physical examination to be freeof syphilis were selected to be the control group ."

Panel Conclusions re Charge I-A andI-B of the Tuskegee Study

After extensive review of the available documents,interviews with associated parties and pursuit of variousother avenues of documentation, the Panel concludesthat

1 . In retrospect, the Public Health Service Study ofUntreated Syphilis in the Male Negro in Macon County,Alabama was ethically unjustified in 1932 .

2 . Because of the paucity of information available todayon the manner in which the study was conceived,designed and sustained, scientific justification for ashort-term demonstration study in 1932 cannot be ruled

12

out . However, the conduct of the longitudinal study asinitially reported in 1936 and through the years isjudged to be scientifically unsound and its results aredisproportionately meager compared with known risksto the human subjects involved .

3 . Penicillin therapy should have been made available tothe participants in this study not later than 1953 .

The Panel qualifies its conclusions with several positionstatements summarized as follows :

a. The judgments in 1973 about the conduct of theTuskegee Study in 1932 are made with the advantageof hindsight, acutely sharpened over some forty yearsconcerning an activity in a different age withdifferent social standards . Nevertheless onefundamental ethical rule is that a person should notbe subjected to avoidable risk of death or physicalharm unless he freely and intelligently consents .There was no evidence that such consent wasobtained from the participants in this study .

b . History has shown that certain people underpsychological, social or economic duress are particu-larly acquiescent. These are the young, the mentallyimpaired, the institutionalized, the poor and personsof racial minority and other disadvantaged groups .These are the people who may be selected for humanexperimentation and who, because of their station inlife, may not have an equal chance to withholdconsent .

c. The Tuskegee Syphilis Study, placed in the per-spective of its early years, is not an isolated event interms of the generally accepted conditions andpractices that prevailed in the 1930's .

d. The position of the Panel must not be construedto be a general repudiation of scientific research withhuman subjects . It is possible that a scientific study in1932 of untreated syphilis, properly conceived with aclear protocol and conducted with suitable subjectswho fully understood the implications of theirinvolvement, might have been justified in the pre-penicillin era because of the uncertain nature ofresults of treatment of late latent syphilis with thehighly toxic therapeutic agents then available .

REFERENCES

1 . Clark, T . The Control of Syphilis in Southern Rural Areas .Julius Rosenwald Fund, Chicago, 1932 . p . 27 .

2. Ibid . pp .6-36 .3 . Moore, Joseph Earle . Latent Syphilis Cooperative Clinical

Studies in the Treatment of Syphilis . Reprint No . 45 fromVenereal Disease Information, Vol . XIII, Nos. 8-12, 1932and Vol . XIV, No . 1, 1933 . pp .!-56 .

4 . Bruusgaard, E . The Fate of Syphilitics Who are not GivenSpecific Treatment. Archiv tur Dermatologie and Syphilis1929, 157, p . 309 .

5. Vonderlehr, R.A. et al. Untreated Syphilis in the MaleNegro . Venereal Disease Information 17 :260-265, 1936 .

6 . Heller, J .R. and Bruyere, P .T . : Untreated Syphilis in MaleNegro: 11 . Mortality During 12 Years of Observation .Venereal Disease Information 27 : 34-38, 1946 .

7. Shafer, J.K., Usilton, L.J ., and Gleason, G .A. UntreatedSyphilis in Male Negro : Prospective Study of Effect on LifeExpectancy. Public Health Reports 69:684-690, 1954 ;Milbank Memorial Fund Quarterly. 32:262-274, July 1954.

8. Caldwell, J .G ., Price, E.V ., Shroeter, A.L ., and Fletcher,G.F . Aortic Regurgitation in a Study of Aged Males withPrevious Syphilis . Presented in part at American VenerealDisease Association Annual Meeting, 22 June 1971 .

9. Feinstein, A . R . Clinical Judgment. Baltimore, William andWilkins Co ., 1967, pp . 45-48 .

10. Gaupin, C . E . The Treatment of Latent Syphilis . KentuckyMedical Journal 30: 74-77, February 1932 .

11 . Pfeiffer, A . Medical Aspects in the Prevention and Manage-ment of Late and Latent Syphilis . Psychiatric Quarterly 9 :185-193, April 1935 .

12. Greenbaum, S .C. The "Bismuth Approach" in the Treat-ment of Acute (Late) Syphilis . Journal of Chemotherapy13 : 5-8, April 1936 .

13 . Stokes, J.H., et al. The Action of Penicillin in Late Syphilis .JA.MA. 126 : 73-79, September 1944 .

14. Dexter, D .C. and Tucker, H .A . Penicillin Treatment ofBenign Late Gummatous Syphilis, Report of Twenty-oneCases . American Journal of Syphilis, Gonorrhea, andVenereal Disease 30: 211-226, May 1946 .

15. Committee on Medical Research : The Changing Characterof Commercial Penicillin with Suggestions as to the Use ofPenicillin in Syphilis. U.S . Health Service and Food andDrug Administration . J.A .M.A . 131 : 271-275, May 1946 .

16. Barnett, C .W. The Public Health Aspects of Late LatentSyphilis . Stanford Medical Bulletin 10 : 152-156, August1952 .

17. Reynolds, F .W. Treatment Failures Following the Use ofPenicillin in Late Syphilis . American Journal of Syphilis,Gonorrhea, and Venereal Disease 32: 233-242, May 1948 .

.o

1 3

18. McElligott, G.L.M. The Management of Late and LatentSyphilis . British Medical Journal 1 :829-830, April 1953 .

19. Bamett, C.W., Epstein, N .J ., Brewer, A .F . et al . Effect ofTreatment in Late Latent Syphilis . Arch Dermat Syph 69 :91-99, January 1954 .

20 . VD Fact Sheet. No . 10 . U.S. Public Health ServicePublication, December 1953, p . 20 .

21 . VD Fact Sheet. No. 17 . U.S . Public Health ServicePublication, December 1960, p . 19 .

22. Wenger, O .C. Untreated Syphilis in Negro Male . Hot SpringsSeminar, 9-18-50 (From CDC Files)

23. Usilton, L. et al. A Tentative Death Curve for AcquiredSyphilis in White and Colored Males in the United States .Venereal Disease Information 18: pp . 231-234, 1937 .

24. Rosahn, P .D. Autopsy Studies in Syphilis. Journal ofVenereal Disease Information 28 : Supplement No . 21, pp .32-39, 1949 .

25. Rivers, E ., Schuman, S ., Simpson, L., and Olansky, S .Twenty Years of Follow-up Experience in a Long-RangeMedical Study . Public Health Reports, 68 : (4), 391-395,April 1953 .

Respectfully Submitted,

Ronald H. BrownJean L: Harris, M .D .Seward Hiltner, Ph .D., D.D .Jeanne C. Sinkford, D.D .S ., Ph.D .Fred SpeakerBarney H . Weeks

Approval with Reservations :(See addendum for reservation statement)

Jay Katz, M .D .Vernal Cave, M .D .

Abstention :Broadus N. Butler, Ph .D . r

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YALE LAW SCHOOLNEW HAVEN, CONNECTICUT 06520

TO: THE ASSISTANT SECRETARY FORHEALTH AND SCIENTIFIC AFFAIRS

FROM: JAY KATZ, M.D .

TOPIC: RESERVATIONS ABOUT THE PANELREPORT ON CHARGE I

I should like to add the following findings andobservations to the majority opinion :

(1) There is ample evidence in the records availableto us that the consent to participation was not obtainedfrom the Tuskegee Syphilis Study subjects, but thatinstead they were exploited, manipulated, and deceived .They were treated not as human subjects but as objectsof research. The most fundamental reason for con-demning the Tuskegee Study at its inception andthroughout its continuation is not that all the subjectsshould have been treated, for some might not havewished to be treated, but lather that they were neverfairly consulted about the research project, its con-sequences for them, and the alternatives available tothem. Those who for reasons of intellectual incapacitycould not have been so consulted should not have beeninvited to participate in the study in the first place .

(2) It was already known before the TuskegeeSyphilis Study was begun, and reconfirmed by the studyitself, that persons with untreated syphilis have a higherdeath rate than those who have been treated . The lifeexpectancy of at least forty subjects in the study wasmarkedly decreased for lack of treatment .

(3) In addition, the untreated and the "inadver-tently" (using the word frequently employed by theinvestigators) but inadequately treated subjects sufferedmany complications which could have been amelioratedwith treatment . This fact was noted on occasion in thepublished reports of the Tuskegee Syphilis Study and aslate as 1971 . However the subjects were not apprised ofthis possibility .

(4) One of the senior investigators wrote in 1936that since "a considerable portion of the infected Negropopulation remained untreated during the entire courseof syphilis . . .an unusual opportunity (arose) to studythe untreated syphilitic patient from the beginning ofthe disease to the death of the infected person ."Throughout, the investigators seem to have confused thestudy with an "experiment in nature ." But syphilis wasnot a condition for which no beneficial treatment wasavailable, calling for experimentation to learn moreabout the condition in the hope of finding a remedy .The persistence of the syphilitic disease from which the

1 4

victims of the Tuskegee Study suffered resulted from theunwillingness or incapacity of society to mobilize thenecessary resources for treatment . The investigators, theUSPHS, and the private foundations who gave supportto this study should not have exploited this situation inthe fashion they did . Unless they could have guaranteedknowledgeable participation by the subjects, they allshould have disappeared from the research scene or elseutilized their limited research resources for therapeuticends. Instead, the investigators believed that the personsinvolved in the Tuskegee Study would never seek outtreatment ; a completely unwarranted assumption whichultimately led the investigators deliberately to obstructthe opportunity for treatment of a number of theparticipants .

(5) In theory if not in practice, it has long been "aprinciple of medical and surgical morality (never toperform) on man an experiment which might be harmfulto him to any extent, even though the result might behighly advantageous to science" (Claude Bernard 1865),at least without the knowledgeable consent of thesubject . This was one basis on which the Germanphysicians who had conducted medical experiments inconcentration camps were tried by the NurembergMilitary Tribunal for crimes against humanity .Testimony at their trial by official representatives of theAmerican Medical Association clearly suggested thatresearch like the Tuskegee Syphilis Study would havebeen intolerable in this country or anywhere in thecivilized world. Yet the Tuskegee study was continuedafter the Nuremberg findings and the Nuremberg Codehad been widely disseminated to the medical com-munity. Moreover, the study was not reviewed in 1966after the Surgeon General of the USPHS promulgated hisguidelines for the ethical conduct of research, eventhough this study was carried on within the purview ofhis department .

(6) The Tuskegee Syphilis Study finally was reviewedin 1969. A lengthier transcript of the proceedings, notquoted by the majority, reveals that one of the fivemembers of the reviewing committee repeatedlyemphasized that a moral obligation existed to providetreatment for the "patients." His plea remainedunheeded. Instead the Committee, which was in partconcerned with the possibility of adverse criticism,seemed to be reassured by the observation that "if weestablished good liaison with the local medical society,there would be no need to answer criticism ."

(7) The controversy over the effectiveness and thedangers of arsenic and heavy metal treatment in 1932and of penicillin treatment when it was introduced as amethod of therapy is beside the point. For the real issueis that the participants in this study were neverinformed of the availability of treatment because the

investigators were never in favor of such treatment .Throughout the study the responsibility rested heavilyon the shoulders of the investigators to make everyeffort to apprise the subjects of what could be done forthem if they so wished . In 1937 the then SurgeonGeneral of the USPHS wrote : "(f) or late syphilis noblanket prescription can be written . Each patient is a lawunto himself. For every syphilis patient, late and early, acareful physical examination is necessary before startingtreatment and should be repeated frequently during itscourse ." Even prior to that, in 1932, ranking USPHSphysicians stated in a series of articles that adequatetreatment "will afford a practical, if not completeguaranty of freedom from the development of any latelesions . . ."

In conclusion, I note sadly that the medical profes-sion, through its national association, its many individual

societies, and its journals, has on the whole not reactedto this study except by ignoring it . One lengthy editorialappeared in the October 1972 issue of the SouthernMedical Journal which exonerated the study andchastised the "irresponsible press" for bringing it topublic attention . When will we take seriously ourresponsibilities, particularly to the disadvantaged in ourmidst who so consistently throughout history have beenthe first to be selected for human research?

Respectfully submitted,

(sgd .) Jay Katz, M .D .

I

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d

REPORT ON CHARGE II

Transmittal Note from Chairman ofSubcommittee on Charge I I

This report on Charge II was prepared by the Subcom-mittee on Charge II (Ronald H . Brown, J.D ., Jean L .Harris, M.D., F.R .S.H ., Jay Katz, M .D., F.A.C .P ., FredSpeaker, J .D ., Jeanne C . Sinkford, D.D.S ., Ph.D .,Secretary, Vernal G . Cave, M.D., F .A.C .P ., Chairman) .

The provisional basis for this report which was the resultof the earliest deliberations the panel dealt with is nowamply substantiated by our documentations, conclu-sions, and recommendations under Charges I and III . Onbehalf of the entire subcommittee, the Chairmanexpresses deep thanks and appreciation for theirsplended cooperation to Dr . Robert C . Backus, Mr .Robert Rawles, Mr . James Morant, Mrs. JacquelineEagle, and Mrs . Bernice M. Lee .

1 6

LETTER OF TRANSMISSION

October 27, 1972

Merlin K. DuVal, M.D .Assistant Secretary for

Health and Scientific AffairsDepartment of Health, Education,

and WelfareWashington, D.C. 20201

Dear Dr. DuVal :

As Chairman of the Tuskegee Syphilis Study Ad HocAdvisory Panel, I enclose our first report to you, relatingonly to the second charge of the three assigned to thePanel. Although one member of the Panel was inhospital on the day this report was put into form fortransmission to you, her written suggestions concerningan earlier draft have been incorporated . Hence, thereport represents concurrence of the Panel as a whole .

You will note that our initial recommendations call forsome very early steps on your part . We as a Panel, alongwith the excellent staff that is assisting our work, standready to help you to implement the recommendations inany way .

It is our understanding, on the basis of the statementsyou made to us at our orientation meeting, that ourreports to you, including this initial one, will be madepublic only by you whether or not you decide to acceptand implement our recommendations .Since agreeing on the enclosed report, two-thirds of ourPanel have been able to engage in a first-hand investiga-tion for two days, in Macon County, Alabama . Nothingthat we have discovered through this recent field visithas afforded us cause to alter any part of the enclosedreport concerning the second charge . The first-handinvestigation, brief as it has been, has provided us withinformation and new understandings that - will prove ofgreat value in our subsequent work on charges 1 and 3 .

Sincerely,

(sgd.) Broadus N. Butler, Ph .D.ChairmanTuskegee Syphilis Study

Ad Hoc Advisory Panel

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INITIAL RECOMMENDATIONOF THE

TUSKEGEE SYPHILIS STUDY AD HOCADVISORY PANEL

The Charter of the Tuskegee Syphilis Study Ad HocAdvisory Panel, issued on August 28, 1972, mandatesadvice on three specific aspects of the study of untreatedsyphilis initiated by the Public Health Service in 1932 .Item two of the three charges requires the Panel to :

"Recommend whether the study should be con-tinued at this point in time, and if not, how itshould be terminated in a way consistent with therights and health needs of its remainingparticipants ."

Initially, the Panel has limited its deliberations andrecommendations exclusively to this charge, and therecommendations contained in this report are intendedto respond solely to this specific issue .

In determining our initial recommendations, thePanel has made inquiries which have led us to acceptcertain evidence outlined here . Though our research onthe background and conduct of the Tuskegee SyphilisStudy has not been completed, the Panel is satisfied thatin the light of its preliminary findings, which will befully documented at a later date, the recommendationsset forth below are fully justified .

BACKGROUND

Since 1932, under the leadership, direction andguidance of the United States Public Health Service,there has been a continuing study, centered in MaconCounty, Alabama, of the effect of untreated syphiliticinfection in approximately 400 Black male humanbeings previously infected with syphilis as subjects . Inthe pursuit of this study approximately 200 Black malehuman beings without syphilis were followed as con-trols . No convincing evidence has been presented to thisPanel that participants in this study were adequatelyinformed about the nature of the experiment, either atits inception or subsequently .

The United States Public Health Service from theonset of the study has maintained a continuous policy ofwithholding treatment for syphilis from the infectedsubjects . There was common medical knowledge, beforethis study, that untreated syphilitic infection producesdisability and premature mortality . To date, including itsearliest reports, this study has confirmed that untreatedsyphilitic infection produces disability and prematuremortality . Since the late 1940's numerous medical

1 8

authorities have recommended treatment for syphiliswith penicillin in all stages of the disease, including latelatent syphilis and tertiary syphilis .

A technical and medical advisory panel convened in1969 by the United States Public Health Service isreported to have recommended with some ambiguity,that the participants surviving at that time should not betreated. It is estimated that approximately 125 of theparticipants, including 50 of the controls, are still alive ;and the current health status of the participants in theTuskegee Study is not known .

RECOMMENDATIONS

I . Termination :

The study of untreated syphilis in Black males inMacon County, Alabama, now known as the "TuskegeeSyphilis Study," should be terminated immediately .With this most basic recommendation, the participantsinvolved in this study are to be given the care nowrequired to treat any disabilities resulting from theirparticipation . In furtherance of this goal we recommend :

A. That Select Specialists Group, composed ofcompetent doctors and other appropriatepersons, with experience in the problems arisingfrom this study, be appointed by the AssistantSecretary for Health and Scientific Affairs,DHEW, no later than fifteen days after theadoption of these recommendations .

B . That the members of the Select SpecialistsGroup have had no prior involvement in theTuskegee Syphilis Study .

C . That the Select Specialists Group be composedof, but not necessarily be limited to, a derma-tologist with experience in syphilology who willserve as Chairman, two internists (at least oneof whom shall be a cardiologist), a radiologist, aneurologist, an ophthalmologist, a psychiatrist,a doctor of dental surgery, and a social worker .

D. That the Select Specialists Group be solelycharged to apply its expert diagnostic andtherapeutic skills in order to safeguard the bestinterests of the participants and of others whomay have been infected as a result of thewithholding of treatment from the participants .

E . That the Select Specialists Group be vestedwith the full legally permissible medicalauthority, medical supervision and medicaljudgment with regard to the treatment orreferral of all of the surviving participants andothers within and outside Macon County whomay be identified, in cooperation with the

appropriate medical societies and HealthDepartments .

F . That the Public Health Service immediatelyinform all surviving participants of the natureof their participation in the study, and thedesire of the Public Health Service to assesstheir current health status .

G. That the members of the "Subcommittee onMedical Care" of the Tuskegee Syphilis StudyAd Hoc Advisory Panel be ex-officio membersof the Select Specialists Group to functionprimarily as liaison between the SelectSpecialists Group and the entire Panel .

H. That on completion of its charge, the SelectSpecialists Group submit a detailed reportabout its activities to the Tuskegee SyphilisStudy Ad Hoc Advisory Panel through itsChairman. This report shall include, but by nomeans be limited to, the reasons foradministering or withholding penicillin andother drug treatment for syphilis fromuntreated participants who are infected withsyphilis .

1 . That the highest priorities be given to thismission so that the charge to the SelectSpecialists Group shall be completed at theearliest possible date consistent with the bestinterests of the participants and the ethicalresponsibilities of the Department of Health,Education, and Welfare .

11 . Assessment, Treatment and Care

A. That arrangements be made with all speed forthe immediate health assessment, treatment andcare of all persons included in the study in asuitably adequate facility easily accessible tothe surviving participants. That whenever aparticipant expresses the wish to be cared for ortreated by physicians of his own choice, suchchoices be respected and given all necessarysupport .

B . That every effort be made to preserve con-fidentiality with respect to the identification ofany participant .

C . That the United States Public Health Service'sepidemiologists be mobilized, on a highestpriority basis, to assist in locating all survivingparticipants as well as others who may havebeen infected as a result of the withholding oftreatment from the participants .

19

III . Encouragement of Participation:

A. That adequate arrangements be provided formaintaining present standards of living duringthe evaluation and treatment periods in orderto minimize any economic barriers to thecooperation of the participants .

B . That at a minimum, any benefits which havebeen promised to the participants in the pastcontinue to remain in effect .

Respectfully submitted,

Broadus N . Butler, Ph .D.Ronald H. BrownVernal Cave, M.D .Jean L. Harris, M .D .Seward Hiltner, Ph.D., D.D .Jay Katz, M . D .Jeanne C . Sinkford, D.D .S ., Ph .D .Fred SpeakerBarney H . Weeks

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October 27, 1972

TO:

ASSISTANT SECRETARY . FOR HEALTHAND SCIENTIFIC AFFAIRS

FROM: JAY KATZ, M.D .

SUBJECT: ADDENDUM TO PANEL REPORT ONCHARGER

I entirely concur in the Panel's recommendations andin the reasons given therefor . However, one additionalpiece of evidence lends even greater conviction, if any isstill needed, to the decision to terminate the TuskegeeSyphilis Study . We have been informed that no scientificknowledge of any consequence would be derived fromits continuation. The Panel felt that recording this factmight create the impression that it was the major reasonfor terminating the study . I believe that its inclusionshould not, and would not, be so construed .

There are cogent reasons for not dismissing the issueof scientific merit . As long as society continues to favorthe pursuit of medical knowledge for the possiblebenefit of the patients participating in research or forthe benefit of future patients, a balancing of risks andbenefits is inevitable . We must acknowledge this realityin order to confront such questions as : Do we wish topreserve this balancing process and, if we do, how mightwe learn to minimize inevitable harm to, subjects andscience? We urgently need to establish an orderly processwhich will permit the assessment of the conflictingclaims inherent in decisions to initiate, continue orterminate research projects. Such an assessment mightproceed in four steps: (1) a relentless inquiry into theharmful consequences to the participants ; (2) anappraisal of the benefits which may accrue to science aswell as to society : (3) a balancing of the risks to theparticipants against the benefits to them and/or science ;and (4) an anticipatory rebuttal to the charge that eitherthe interests of the participants or of science have notbeen sufficiently considered . In the light of the findingthat no interests of science are surrendered byterminating the Tuskegee Syphilis Study, there isnothing to balance and nothing to rebut, and continu-ance of the study would for this reason alone beinadmissible .

I appreciate that had the conclusion been otherwise,the study would in all probability still have to beterminated because of the other findings set forth in thePanel's report, findings which will be further explored inour deliberations with respect to Charge One ("whetherthe- study was justified") . Moreover, I should note thatthe four factors, listed above, do not directly address

20

themselves to such other important considerations as :who should be selected for research, what disclosuresmust be made to participants in research, etc . This willsurely be considered in our response to Charge Three("whether existing (research) policies are adequate andeffective") . Finally, I also leave unconsidered for nowanother question which emerges from the finding of "noscientific merit": why was the study not terminated at atime prior to the appointment of this Panel? One of thebenefits of including a finding of scientific merit in everyassessment is that many more projects might beterminated sooner, because the reviewer would be hardpressed to make an affirmative finding on this issue .

Respectfully submitted,

(sgd.) Jay Katz, M .D .

REPORT ON CHARGE IIITO:

THE ASSISTANT SECRETARY FORHEALTH

FROM: TUSKEGEE SYPHILIS STUDY AD HOCADVISORY PANEL

TOPIC : FINAL REPORT ON CHARGE III

I . INTRODUCTION

In his third charge to the Tuskegee Syphilis Study AdHoc Advisory Panel, Dr. Merlin K . DuVal, the HEWAssistant Secretary for Health and Scientific Affairs, hasasked us to determine

whether existing policies to protect the rights ofpatients participating in health research conductedor supported by the Department of Health, Educa-tion, and Welfare are adequate and effective and torecommend improvements in these policies, ifneeded .

Our response to this charge, embodied in this report,should not be viewed simply as a reaction to a singleethically objectionable research project . For theTuskegee Syphilis Study, despite its widespreadpublicity was not an isolated phenomenon . We believethat the revelations from Macon County merely broughtto the surface once again the unresolved problems whichhave long plagued medical research activities . Indeed, wehasten to add that although we refer in this reportalmost exclusively to physicians and to biomedicalinvestigations, the issues we explore also arise in thecontext of non-medical investigations with humanbeings, conducted by psychologists, sociologists, educa-tors, lawyers and others . The scope of the DHEW Policyon Protection of Human Subjects, broadened in 1971 toencompass such research, attests to the increasingsignificance of non-medical investigations with humanbeings .

Our initial determination that the protection ofhuman research subjects is a current and widespreadproblem should not be surprising, especially in light ofthe recent Congressional hearings and bills focusing onthe regulation of experimentation . In the past decadethe press has publicized and debated a number ofexperiments which raised ethical questions : for example,the injection of cancer cells into aged patients at the

*This report was prepared by the Subcommittee on Charge III(Jay Katz, M .D ., chairman, Ronald H. Brown, J.D ., SewardHiltner, Ph .D. and Fred Speaker, J.D .) . The subcommitteechairman wishes to thank his research assistant Stephen H .Glickman, a third year law student at Yale University, for hisvaluable contributions to this report . Special thanks go also toDr. Robert C . Backus, Mrs . Bernice M . Lee and Ms . Jackie Eaglewho in many ways facilitated the work of the subcommittee .

21

Jewish Chronic Disease Hospital in Brooklyn, thedeliberate infection of mentally retarded children withhepatitis at Willowbrook, the development of hearttransplantation techniques, the enormous amount ofdrug research conducted in American prisons, thewhole-body irradiation treatment of cancer patients atthe University of Cincinnati, the advent and spread of"psychosurgery," and the Tuskegee Syphilis .Study itself .

With so many dramatic projects coming to theattention of the general public, more must lie beneaththe surface. Evidence for this too has been forthcoming .In 1966, Dr. Henry K . Beecher, the eminent DorrProfessor of Research in Anesthesia at the HarvardMedical School, charged in the prestigious New EnglandJournal of Medicine that "many of the patients (used inexperiments which Dr. Beecher investigated andreported) never had the risk satisfactorily explained tothem, and . . .further hundreds have not known that theywere the subjects of an experiment although graveconsequences have been suffered as the directresult . . ."' Dr . Beecher concluded that "unethical orquestionably ethical procedures are not uncommon ."2Quite recently this charge has been corroborated by thesociologist Bernard Barber and his associates, whointerviewed biomedical researchers about their ownresearch practices.3 Despite the expected tendency ofresearchers to minimize ethical problems in their ownwork, Barber et al. were able to conclude that "while thelarge majority of our samples of biomedical researchersseems to hold and live up to high ethical standards, asignificant minority may not ."4

The problem of ethical experimentation is theproduct of the unresolved conflict between two stronglyheld values : the dignity and integrity of the individual,and the freedom of scientific inquiry . Professionals ofmany disciplines, and researchers especially, exerciseunexamined discretion to intervene in the lives of theirsubjects for the sake of scientific progress . Althoughexposure to needless harm and neglect of the duty toobtain the subject's consent have generally been frownedupon in theory, the infliction of unnecessary harm andinfringements on informed consent are frequentlyaccepted, in practice, as the price to be paid for theadvancement of knowledge. How have investigatorscome to claim this sweeping prerogative? If the answerto this question is that "society" has authorized profes-sionals to choose between scientific progress and

1 . Beecher, "Ethics and Clinical Research," 274 New Eng . J .Med. 1354 (1966)2 . Ibid., p . 1355 .3 . Barber, Lally, Makarushka, and Sullivan, Research on HumanSubjects : Problems of Social Control in Medical Experimenta-tion (Russell Sage Foundation 1973) (hereinafter, Barber et al.)4 . Barber et al., supra, footnote 3, at 52 .

individual"society"prise? We a

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individual human dignity and welfare, should not"society" retain some control over the research enter-prise? We agree with philosopher Hans Jonas that

a slower progress in the conquest of disease wouldnot threaten society, grievous as it is to those whohave to deplore that their particular disease be notyet conquered, but that society would indeed bethreatened .by the erosion of those moral valueswhose loss, possibly caused by too ruthless apursuit of scientific progress, would make its mostdazzling triumphs not worth having . 5

22

We have, as will be seen, made far-reaching recom-mendations for change. We do not propose these changeslightly . But throughout, in accordance with ourmandate, our concern has not been just to define theethical issues, but also to examine the structures andpolicies thus far devised to deal with those issues . Inurging greater societal involvement in the researchenterprise, we believe that the goal of scientific progresscan be harmonized with the need to assure the protec-tion of human subjects .5 . Jonas, "Philosophical Reflections on Experimenting withHuman Subjects," 98 Daedalus 219, 245 (1969) .

II . SUMMARY OF CONCLUSIONS ANDRECOMMENDATIONS

A. Evaluation of Current DHEW Policiesfor the Protection of Human Research Subjects

1 . No uniform Departmental policy for the protectionof research subjects exists . Instead one policy governs"extramural" research - research supported by DHEWgrants or contracts to institutions outside the FederalGovernment and conducted by private researchers - andanother policy governs "intramural" research - researchconducted by personnel of the Public Health Service .Furthermore. Food and Drug Administration (FDA)regulations promulgated to protect subjects in drugresearch, whether or not supported by DHEW orconducted by the PHS, incorporate variations of theirown. The lack of uniformity in DHEW policies createsconfusion, and denies some subjects the protection theydeserve .

Moving to the next higher level, no uniform Federalpolicies exist for the protection of subjects inGovernment-sponsored research. Other agencies whollyseparate from DHEW - most notably, the Departmentof Defense - support or conduct human research .DHEW policies do not govern such research . Here too,the Federal Government's failure to develop a uniformpolicy has been detrimental to the welfare of researchsubjects .

2. Under current DHEW policies for the protection ofresearch subjects, regulation of research practices islargely left to the biomedical professions . Since theconduct of human experimentation raises importantissues of social policy, greater participation in decision-making by representatives of other professions and ofthe general public is required .

3. The present reliance by DREW on the institutionalreview committee as the primary mechanism for theprotection of research subjects was an importantadvance in the continuing effort to guarantee ethicalexperimentation. Prior peer review of research protocolsis a requirement which should be retained .

4. The existing review committee system suffers frombasic defects which seriously undermine the accomplish-ment of the task assigned to the committees :

a. The governing standards promulgated by DHEWwhich are intended to guide review committeedecisions in specific cases are vague and overlygeneral .

b. No provisions are made for the dissemination orpublication of review committee decisions . Their lowlevel of visibility hampers efforts to evaluate and

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learn from committee attempts to resolve thecomplex problems of human research.

c. Although the informed consent of the researchsubject is one of the most important requirements ofresearch ethics, DHEW policies for obtaining consentare poorly drafted and contain critical loopholes . As aresult, one crucial task of institutional review com-mittees - the implementation of the informedconsent requirement is commonly performedinadequately . In particular, consent is far too oftenobtained in form alone and not in substance .

d. DHEW policies do not give sufficient attention tothe protection of such special research subjects aschildren, prisoners and the mentally incompetent .The use of these subjects in human experimentationpresents grave dangers of abuse .

e . The obligation of institutional review committeesto conduct continuing review of research projectsafter their initial approval is undefined and as aconsequence often neglected .f. Inefficient utilization of institutional review com-mittees contributes to their ineffectiveness . Com-mittees are overburdened with a variety of separatefunctions, and could operate best if their tasks werenarrowly defined to encompass mainly the imple-mentation of research policies adequately formulatedby others .

g. Effective procedures for enforcing DHEW policies,when those policies are disregarded, have not beendevised .

5 . No policy for the compensation of research subjectsharmed as a consequence of their participation inresearch has been formulated, despite the fact that nomatter how careful investigators may be, unavoidableinjury to a few is the price society must pay for theprivilege of engaging in research which ultimatelybenefits the many . Remitting injured subjects to theuncertainties of the law court is not a solution .

B . Policy Recommendations1 . Congress should establish a permanent body with theauthority to regulate at least all Federally supportedresearch involving human subjects, whether it is con-ducted in intramural or extramural settings, orsponsored by DHEW or other government agencies, suchas the Department of Defense . Ideally, the authority ofthis body should extend to all research activities, eventhose not Federally supported . But such a proposal mayraise major jurisdictional problems . This body could becalled the National Human Investigation Board . TheBoard should be independent of DHEW, for we do not

t

t

believe that the agency which both conducts a great dealof research itself and supports much of the research thatis carried on elsewhere is a position to carry outdispassionately the functions we have in mind . Themembers of the Board should be appointed from diverseprofessional and scientific disciplines, and should includerepresentatives from the public at large .

2 . The primary responsibility of the National HumanInvestigation Board should be to formulate researchpolicies, in much greater detail and with much moreclarity than is presently the case . The Board mustpromulgate detailed procedures to govern the imple-mentation of its policies by institutional reviewcommittees . It must also promulgate procedures for thereview of research decisions and their consequences . Inparticular, this Board should establish procedures for thepublication of important institutional committee andBoard decisions. Publication of such decisions wouldpermit their intensive study both inside and outside themedical profession and would be a first step toward thecase-by-case development of policies governing humanexperimentation . We regard such a development,analogous to the experience of the common law, as thebest hope for ultimately providing workable standardsfor the regulation of the human experimentationprocess .

3 . The National Human Investigation Board shoulddevelop appeals procedures for the adjudication ofdisagreements between investigators and the institutionalreview committees.

4. The National Human Investigation Board should alsodevelop a "no fault" clinical research insurance plan to

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assure compensation for subjects harmed as a result oftheir participation in research . Institutions whichsponsor Federally supported research activities should berequired to participate in such a plan .5 . With the establishment of adequate policyformulation and review mechanisms, the structure andfunctions of the institutional review committees shouldbe altered to enhance the effectiveness of prior review.In place of the amorphous institutional reviewcommittee as it now exists, we propose the creation ofan Institutional Human Investigation Committee (IHIC)with two distinct subcommittees . The IHIC should bethe direct link between the institution and the NationalHuman Investigation Board, and should establish localregulations consistent with national policies . The IHICshould also assume an educational role in its institutions,informing participants in the research enterprise of theirrights and obligations. The implementation of researchpolicies should be left to the two subcommittees of theIHIC :

a. A Protocol Review Group (PRG) should beresponsible for the prior review of research protocols .The PRG should be composed mainly of competentbiomedical professionals .b. A Subject Advisory Group (SAG) should beresponsible for aiding subjects in their' decision-makingwhenever they request its services . Subject must bemade aware of the existence of the SAG . The primaryconcern of the SAG should be with procedures forobtaining consent, and with the quality of consentsobtained. The SAG should be composed of bothprofessionals and laymen .

III . DEVELOPMENT OF CURRENT DHEW POLICIES

A. Historical Background

Experimentation with human beings is not a modemphenomenon ; it dates back to the beginning of recordedhistory. However, until the advent of scientific medicine,"research" was largely conducted unsystematically inthe context of clinical practice which benefited, harmedor did nothing to untold patients . Indeed, harmfulconsequences most often accrued to countless patientswho were given treatments whose value had not beenestablished by carefully controlled clinicalinvestigations . 6 Since the individuals involved in"research" were generally also considered potentialrecipients of the knowledge gained, few questions wereraised about the propriety of these interventions byeither the medical or legal profession . As far as themedical profession was concerned, the systematic use ofhuman beings for research purposes, a trend which beganin the late nineteenth century and has accelerated eversince, did not lead until relatively recently to a sustainedexploration of the need to safeguard research subjects . Anotable exception was Claude Bernard who in 1865published his influential An Introduction to the Studyof Experimental Medicine, in which he not onlydemonstrated the need for experimentation on humansubjects but also began to formulate rules of ethicalconduct .

Similarly the law has had little to say about the rightsof human subjects in the research enterprise . Indeedprior to the nineteen-sixties, no specific federal or statestatutes regulated research institutions or investigators intheir use of human subjects for experimental purposes .Though beginning with the English case of Slater v.Baker and Stapleton 8 in 1767 and the American case ofCarpenter v. Blake 9 in 1871, courts were from time totime confronted with the claim of experimentation inmalpractice actions, the resulting opinions evincedconcern about "experimentation" but did not provideany meaningful legal guidelines for investigators tofollow . Perhaps the fact situations in these cases, whichoften raised other important issues besidesexperimentation, precluded judges from speaking outmore clearly on the legal limits to human research .Through the first third of the twentieth century, thegenerally accepted legal rule seemed to be that a

6 . See, e .g ., Modell, "Let Each New Patient Be a CompleteExperience," 174 J .A.M.A. 1717 (1960) .7 . Bernard, An Introduction to the Study of ExperimentalMedicine, H. C . Greene (Transl .) (Macmillan, 1927) .8 . 95 Eng . Rep . 860 (1767) .9 . 60 Barb . 488 (N.Y ., 1871) .10. See Curran, "Governmental Regulation of the Use ofHuman Subjects in Medical Research : The Approach of TwoFederal Agencies," 98 Daedalus 542, 543 (1969) .

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physician experimented "at his peril" if his patients wereharmed thereby .' 0 Eventually, the distinction betweenrash human experimentation and careful, scientific andethical experimental practice was acknowledged by thecourts. In 1935, the Supreme Court of Michigan statedin a malpractice case :

We recognize the fact that if the general practiceof medicine and surgery is to progress, there mustbe a certain amount of experimentation carriedon; but such experiments must be done with theknowledge and consent of the patient or thoseresponsible for him and must not vary tooradically from the accepted method ofprocedure . "

Although this dictum was a broad generalization, madein a therapeutic context, and was not directed atnontherapeutic investigations, it signalled theascendency of a more balanced judicial attitude towardmedical research involving human beings .

This posture was sorely tested by the revelations ofthe horrifying atrocities perpetrated under the Nazis byGerman physicians and scientists in the name of clinicalresearch.' 2 The disclosures at Nuremberg disturbed themedical community, and many physicians and researchscientists called for worldwide acceptance of ethicalstandards to assure the protection of subjects inbiomedical research . However, the impact of theirconcern was blunted by the cruelty of the concentrationcamp experiments which obscured the fundamental factthat similar problems of research ethics, though not ofthe same magnitude, had characterized the researchenterprise from its beginnings . Nonetheless, the trial ofthe Nazi physicians led the Military Tribunal to set forthten basic principles, the so-called Nuremberg Code, 13

which must be observed in human experimentation "inorder to satisfy moral, ethical, and legal concepts ." Thefollowing principles illustrate the nature of the Code :

1 . The voluntary consent of the human subject isabsolutely essential . . . .

2 . The experiment should be such as to yieldfruitful results for the good of society,unprocurable by other methods of study, andnot random and unnecessary experiments innature .

6. The degree of risk to be taken should never

11. Fortner v. Koch, 272 Mich . 273, 282 ; 261 N.W. 762, 765(1935) .12. See Trials of War Criminals Before the Nuremberg MilitaryTribunals. Volumes I and II, The Medical Case. Washington,D.C . : U .S. Government Printing Office (1948) . For excerptswhich indicate the nature of the offenses and the resultingjudgments, see Katz, Experimentation with Human Beings, pp .292-306 (Russell Sage Foundation, 1972) (Hereinafter Katz).13. Katz, supra footnote 12, at 305 .

exceed that determined by the humanitarianimportance of the problem to be solved by theexperiment .

The widely felt need to supplement and modify theprovisions of the Nuremberg Code led to the prolifera-tion of other "improved" codes of research ethics . TheWorld Medical Association's Helsinki Declaration(1964),14 the American Medical Association's EthicalGuidelines for Clinical Investigation (1966) 15 and thedraft code of the American Psychological Association(1972)16 are three which have received the mostattention .

The promulgation of such documents helped to focusattention on the ethical problems inherent in researchactivities involving human subjects . However, as thenumber of documents increased their limitation becomemore evident to concerned observers . As one of us haselsewhere remarked :

The proliferation of such codes testifies to thedifficulty of promulgating a set of rules which donot immediately raise more questions than theyanswer . By necessity these codes have to besuccinctly worded and, being devoid of com-mentary, their meaning is subject to a variety ofinterpretations. Moreover, since they generallyaspire to ideal practices, they invite judicious andinjudicious neglect . Consequently, as long as theyremain unelaborated tablets of exhortation, codeswill at best have limited usefulness in guiding thedaily behavior of investigators . 17

Furthermore, discrepancies between codes have helpedto sow confusion. Discussing the Helsinki Declarationand the A .M.A. Guidelines, Professors Katz and Capronobserved :

The significant discrepancies between these twodocuments highlight the need for mechanismswhich would permit their reconciliation . . . Unlikethe Helsinki Declaration, the AMA guidelinespropose that "(m)inors or mentally incompetentsubjects may be used as subjects only if (t)thenature of the investigation is such that mentallycompetent adults would not be competentsubjects." On the other hand, the Declaration ofHelsinki states, and the AMA guidelines do not,that "(a)t any time during the course of clinicalresearch the subject or his guardian should be free

14 . 271 N . Eng . J . Med . 473 (1964).15. American Medical Association, Opinions and Reports of theJudicial Council, pp . 9-11 (Chicago, 1969) .16. American Psychological Association, Ethical Principles inthe Conduct of Research with Human Participants (DraftDocument, 1972) .17. Katz, "The Education of the Physician-Investigator," 98Daedalus 480, 482-3 (1969) .

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to withdraw permission for research to becontinued ." No explanation is provided for thedifferences nor is any mechanism available toguide physician-investigators in adopting orrejecting part or all of either document, based onits disagreement with the other or for anyadditional reasons . 18

In retrospect, the promulgation of so many varyingcodes of ethics can be viewed as a tacit recognitionwithin the professions that self-regulation by investiga-tors could not be relied on to control research practices .When it was also realized that the codes themselves hadserious shortcomings, new and quite different proposalsfor ordering the research process began to emerge .Procedures were gradually developed to apply thegeneral principles contained in codes of research ethicsin the formal evaluation of individual research projectsby institutional review committees .

The National Institutes of Health (NIH) firstdeveloped such procedures in order to regulate clinicalresearch performed at its Clinical Center in Bethesda,Maryland. Since 1953, human research has not beenconducted there without prior approval of a reviewcommittee responsible for the protection of subjects .19

In 1966, Surgeon General William H . Stewart extendedthe requirement of prior review by "a committee of (theinvestigator's) institutional associates" to all "extra-mural" research supported by United States PublicHealth Service (PHS) grants and awards .20 This reviewwas to

assure an independent determination : (1) of therights and welfare of the individual or individualsinvolved, (2) of the appropriateness of themethods used to secure informed consent, and (3)of the risks and potential medical benefits of theinvestigation .21

Prior committee review was also instituted, in 1967, forall "intramural" research programs of the Public HealthService .22 The Tuskegee Syphilis Study, conducted byPHS investigators, was an intramural activity .

18. Katz and Capron, Social Factors Affecting the ModernTreatment of Catastrophic Diseases (Unpublished Manuscript,1973) (hereinafter, Katz and Capron).19. Sessoms, "Guiding Principles in Medical Research InvolvingHumans, National Institutes of Health," 32 Hospitals, Journal ofAmerican Hospital Association 44 (1958) .20. Memorandum of Surgeon General William H . Stewart to theHeads of Institutions Conducting Research with Public HealthGrants, (February 8, 1966) .21 . Ibid.22. DHEW - Public Health Service, Protection of the Individualas a Research Subject - Intramural Programs (May 1, 1969)(hereinafter Intramural Guidelines) .

In 1971, the Department of Health, Education, andWelfare formulated its policy for the protection ofhuman subjects 23 which superseded the Public HealthService extramural program guidelines . Institutionalcommittee review was retained as the central feature ofthe new DREW policy . The DREW regulations apply toall research supported by Departmental grants or con-tracts, regardless of whether the research is medical innature. However, the new regulations do not apply tointramural PHS activities, which are still governed byseparate and sometimes divergent PHS guidelines . Alsoin 1971, the Food and Drug Administration promul-gated additional regulations, 24 patterned on the DHEWframework, to govern the testing of "investigational newdrugs." And recently, in response to the TuskegeeSyphilis Study revelations, Senator Jacob Javits intro-duced a bill which would enact most of the currentDHEW requirements into law .25 Senator HubertHumphrey also responding to the Tuskegee Study,introduced another bill, quite different in conception .26

It would create within the executive branch anindependent board to establish guidelines for humanexperimentation, to review research practices and toenjoin the conduct of certain investigations .

Due to the Federal Government's prominent role infunding biomedical research, the PHS-DHEW regulationshave had a noticeable impact on the conduct of humanresearch in this country . Over 700 American researchinstitutions have established review committees in orderto satisfy DHEW or PHS requirements .27 Althoughthese committees are required to review only Federally-funded research, they often have extended their reviewto all research on human subjects conducted at theirinstitutions .28

B. Description of DHEW Policy 29

At present DHEW policies vest primary responsibilityfor the protection of research subjects in institutionalreview committees . These committees are charged withthe initial review of all project proposals and are alsoexpected to subject research activities to "continuingreview." Once a committee has approved a research23. DHEW Grants Administration Manual Chapter 1-40 (1971)(hereinafter Grants Administration Manual) . The Departmentpublishes The Institutional Guide to DHEW Policy on Protectionof Human Subjects (1971) (hereinafter Institutional Guide) tohelp institutions sponsoring research to implement DHEWpolicy .24. 36 Fed. Reg . 5037-38 (1971) .25. S. 3935, 92d Cong., 2d Sess . (1972) .26. S. 3951, 92d Cong., 2d Sess . (1972) .27. For a description of the s pread of institutional reviewcommittees. following the promulgation of the PHS guidelines,see Barber et al., supra, footnote 3, at 145-148 .28. Barber et al. estimate that 85% of the institutional reviewcommittees they surveyed review `all clinical research" con-ducted at their institutions, regardless of funding. Barber et al.,supra, footnote 3, at 149 .29. This description is based on the Intramural Guidelines,supra, footnote 23, and the Institutional Guide, supra, footnote23. Hereinafter, the policy of the Manual and the Guide will bereferred to as "DHEW" policy, while the policy of theIntramural Guidelines will be referred to as "PHS intramural"policy .

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protocol, its decision is reviewed again by the DHEWstudy section which considers the protocol for funding .When either group disapproves a protocol, that decisioncannot be appealed to the Department, and the protocolcannot be Federally funded . In contrast to the DHEWrequirements, PHS intramural policy does not requirecontinuing review . Instead, the burden is on the investi-gator to bring "significant proposed changes in protocoland emergent problems of investigation . . .to theattention of the review group involved ."30 Nor doesPHS intramural policy specify distinct stages of protocolreview .

DHEW requires institutional committees to review allaspects of "any activity" which might expose a subjectto the possibility of harm if the activity "goes beyondthe application of those established and acceptedmethods necessary to meet his needs ."3 1 Recognizingthat this jurisdictional standard leaves much to thediscretion of committees and investigators the Depart-ment concedes that "(a)cceptance is a matter of profes-sional response, and determination as to when a methodpasses from the experimental stage and becomes`established and accepted' is a matter of judgment ."32

Before the committee can approve an activity underreview, it must "determine that the rights and welfare ofthe subjects involved are adequately protected, that therisks to an individual are outweighed by the potentialbenefits to him or by the importance of the knowledgeto be gained, and that informed consent is to beobtained by methods that are adequate and appro-priate."33 Like the jurisdictional standard, these reviewstandards are phrased in general terms, although the"basic elements" of "informed consent" are set forth ingreater detail . 34 DHEW policy also requires each institu-tion to provide written assurance that it will abide byDHEW policy . The assurance must include "a statementof compliance with DHEW requirements for initial andcontinuing committee review of the supported activities ;a set of implementing guidelines, including identificationof the committee, and a description of its reviewprocedures."35 As part of the "implementing guide-lines," each institution is asked to adopt a "statement ofprinciples that will assist the institution in the discharge

34. See infra., pp. 31-32 .35 . Grants Administration Manual, supra, footnote 23,s 1-40-40 (A) .36. Grants Administration Manual, supra, footnote 23,f 1-40-40 (C) (2) (a) .37. Ibid. See also Institutional Guide, supra, footnote 23, at 5,footnote 2, and at 23 .

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30. Intramural Guidelines, supra, footnote 22, at 5 .31 . Grants Administration Manual, supra, footnote 23,it-40-10.32 . Institutional Guide, supra, footnote 23, at 3 .33. Grants Administration Manual, supra, footnote 23,® 1-40-20(A). The PHS Intramural Guidelines, supra, footnote22, contain essentially equivalent standards for review, at 4-5 .

of its responsibilities for protecting the rights andwelfare of subjects . ,36 These statements are typicallyderived from existing codes of ethics not much moreexplicit that the DHEW review standards themselves . 3 7

Unlike DHEW policy, the intramural guidelines of thePHS make specific, albeit limited, reference to "(s)tudiesinvolving children, the mentally ill or the mentallydefective .s38 Such studies "shall be carried out onlywhen there is no significant risk of physical or mentalharm to the subject or when direct benefit to the subjectis anticipated ."39 The intramural guidelines alsoexplicitly provide that "(s)tudies of individuals withlimited civil freedom shall also be subject to groupconsideration and approval ."40 Although the referencesto minors, incompetents, and prisoners do not imposeadditional substantive restrictions on research, they mayalert review committees and investigators to the specialproblems presented by research with such subjects .41

Since institutional review committees are entrustedwith such difficult decision-making responsibilities, theircomposition is a matter of Departmental concern :

The committee must be composed of sufficientmembers with varying backgrounds to assurecomplete and adequate review of projects andactivities commonly conducted by the institution .The committee's membership, maturity,experience, and expertise should be such as tojustify respect for its advice and counsel . Nomember of an institutional committee shall beinvolved in either the initial or continuing reviewof an activity in which he has a professionalresponsibility, except to provide informationrequested by the committee . In addition topossessing the professional competence to reviewspecific activities, the committee should be able todetermine acceptability of the proposal in terms ofinstitutional commitments and regulations, appli-cable law, standards of professional conduct andpractice, and community attitudes . The committeemay therefore need to include persons whoseprimary concerns lie in these areas rather than inthe conduct of research, development, and serviceprograms of the types supported by the DHEW.42

Beyond this, the Department does not specify anyparticular size or membership requirements, believinginstead that disparity in institutional situations demands

38 . Intramural Guidelines, supra, footnote 22, at 10 .39 . Ibid.40 . Ibid .41 . PHS intramural policy does impose stricter consent require-ments for experiments with such sub,~'ects . These consentrequirements are discussed infra, at~pp . 25 ff .42 . Grants Administration Manual, supra, footnote 23,11-40-40 (C) (2) (b) .

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flexibility. For the same reason the Department does notprovide any directions for the conduct of initial orcontinuing review . Instead, as already noted, institutionsare required to submit for Departmental approval adescription of the procedures their committees willfollow to implement review.

When DHEW funding is sought, a research proposalapproved by an institutional committee is reviewed againwithin the Department .43 A study section, composed ofscientists not connected with the proposal or itssponsoring institution, examines the proposal andtransmits its recommendation to the particular NationalAdvisory Council authorized to grant the requestedresearch funds. This Departmental review is notrestricted to a reconsideration of the "ethical sound-ness" of the proposed research . Instead, it encompassesall other factors which enter into any research funding .decision, such as the scientific rigor of the proposal, thescientific significance of the proposed project, and therelationship of budgetary estimates to the proposedstudy . As a result, the review of ethical issues at .thisstage cannot be as thorough as it is intended to be at theinstitutional level.

The adoption of this institutional review committeeapproach promised to be a significant advance towardthe goal of ethical human research . For the first time,codes of research ethics were to be applied in concretesituations by means of a definite procedure providing forindependent scrutiny of individual research proposals .Moreover, a decentralized, pluralistic approach,emphasizing decision-making at the institutional level,seemed to offer other advantages . The exploration ofproblems from different points of view could ultimatelylead to a fuller appreciation of the issues requiringresolution. Concern for the rights and welfare of subjectscould be more easily communicated to individual investi-gators. The review of research protocols could behandled in depth and yet with dispatch .

Despite these hopes, the present DHEW regulatoryframework can only be considered a qualified success .The continued existence of two varying sets of guide-lines to govern intramural and extramural humanresearch activities respectively serves no purpose andgenerates confusion. As to the content of the guidelines,although from a historial perspective institutional com-mittee review was a major improvement over priorpractices, many deficiencies, to which we now turn, haveprecluded successful supervision of human experimenta-tion for the protection of human subjects .

43 . Grants Administration Manual, supra, footnote 23,s S 1-40-20 (B) and 1-40-50 (B). See also NIH Manual § 4107"Grants Involving Human Subjects," s 4107 (G) (1972) .

IV. CRITIQUE OF DHEW POLICY

A. Vagueness of Standards

At bottom, the difficulties which face review com-mittees derive from the generality of the standardswhich are to guide their determinations in specific casesunder either the intramural or extramural policies . Toillustrate, if a review committee had evaluated theTuskegee Syphilis Study under current guidelines,questions calling for searching examination would havesurfaced .

(1) If the requirement of informed consent 44 is tobe taken seriously, should impoverished anduneducated Blacks from rural Alabama have beenselected as subjects in the first place? Or should aconcerted effort have been made to find subjectsfrom among the most educated within the populationat large, or at least to select from the given subgroupthose subjects most capable of giving "informedconsent"? Put more generally, what general principlesshould guide the selection of subjects? Thephilosopher Hans Jonas has given one answer to thisquestion: "(O)ne should look for (subjects) amongthe most highly motivated ; the most highly educated,and the least `captive' members of thecommunity ."45

(2) If "(t)he welfare of the individual is paramount(and) the subject must have available to him thefacilities and professional attention necessary for theprotection of his health and safety,"4fi what specialefforts should have been made by investigators toprovide medical treatment beyond the economicreach of the subjects before enlisting them in theTuskegee Study? Or should the institutional reviewcommittee have turned down the Tuskegee SyphilisStudy because no adequate treatment facilities wereavailable in Macon County?

(3) How should "continuing review" operate? Forexample, at what point in time, after penicillintreatment for syphilis became available, should thesubjects of the Tuskegee Syphilis Study have beenapprised of this new development? Since it generallytakes time before medical consensus is reached on thevalue j of a 11ew, medication and is reported in themedical literature, when should the subjects havebeen told that a drug was available which at leastsome competent physicians considered effectivetreatment?

44 . The requirement of informed consent is analyzed in greaterdetail infra, at pp.31 ff.45. Jonas, "Philosophical Reflections on Ex erimenting withHuman Subjects," 98 Daedalus 219, 235 (1969.46. Intramural Guidelines, supra, footnote 22, at 1 .

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(4) How should the risks inherent in this study havebeen weighed against the predicted advancement ofmedical knowledge? The rule that "the risks to anindividual . . .(must be) outweighed by the potentialbenefits to him or by the importance of theknowledge to be gained,"47 is perhaps the mostdifficult guideline for review committees toimplement . The seeming simplicity of this commandbelies its complexity. How are such tangibles as"risks," "benefits," and "importance of knowledge"to be measured and weighed? Can serious harm toresearch subjects ever be outweighed solely byadditions to the sum of human knowledge? 48 If so,what, kind of knowledge, in what circumstances,would outweigh what risks to subjects? Thedifficulties inherent in evaluating the scientific meritsof a particular study are, demonstrated by the ongoingdifferences of opinion among scientists of the PHS asto whether continuation of the Tuskegee SyphilisStudy can still be defended on the ground ofscientific merit . It is necessary for review committeesto scrutinize carefully the research design of everyproposed study if the requirement that risks bebalanced against benefits is to be taken seriously, forthe acquisition of knowledge depends so much on thesoundness of the research protocol .49 Does theinformed willingness of the subject to accept certainrisks have any bearing on the committee's balancingof risks against benefits? Finally, since the design ofthe Tuskegee Study could not completely exclude thepossibility that non-subjects might contract syphilisfrom untreated subjects, how should a review com-mittee have balanced risks to nonsubjects againstbenefits to society?50

(5) Review committees are also required to"determine that the rights and welfare of the subjectsinvolved are adequately protected.s51 What rightsdid the Tuskegee Study subjects possess? The tre-mendous confusion which exists in the area of patientsubjects' rights is in part the result of the traditionalbut largely unexamined prerogative of professionals

47. Grants Administration Manual, supra, footnote 23,• 1-40-20 (A) ; see also Intramural Guidelines, supra, footnote22, at 2, 4-5 .48. Although PHS policy does proscribe seriously risky experi-mentation which cannot benefit the subject, Intramural Guide-lines, supra, footnote 22 at 2, DHEW policy for extramuralresearch does not categorically prohibit such research . TheInstitutional Guide, supra, footnote 23, states at 6 : "If thepotential benefits are insubstantial, or are outweighed by risks,the committee may be justified in permitting the subjects toaccept these risks in the interests of humanity ."49. Intramural Guidelines, supra, footnote 22, at 1 .50. The Intramural Guidelines, supra, footnote 22, at 1, state:The health and safety of persons other than the subject, ifendangered by the research procedures, must be protected .DHEW policy neglects this problem .51 . Grants Administration Manual, supra, footnote 22,i 1-40-20 (A) ; see also Intramural Guidelines, supra, footnote22, at 1, 4-5 .

to intervene in their patients' behalf without fulldisclosure whenever it is supposed to be "in theirpatients' best interests ." The doctrine of "informedconsent" has had little impact on this longstandingprofessional practice . Since much medical research iscarried out in the context of "patient care the rightto make decisions for patients has more often thannot unwittingly been carried over into the researchdomain. The confusion about patient-subjects' rightsis bolstered by the scientist's felt obligation toadvance knowledge for the good of society, althoughsociety has inadequately defined the extent of thisobligation .

To illustrate the confusion about subject's rights :Can the subject claim the right to be indemnified forany harm he suffers as a result of the research,regardless of the investigator's fault and in spite onconsent? Is so, who is responsible for informing himthat an injury has occurred which is not the result ofthe natural progression of his illness? Do TuskegeeStudy subjects have a cause of action because theydid not receive suitable medical treatment? If so, whomay be liable-the individual investigators, the PHS,the Milbank Memorial Fund, the Tuskegee Institute?The intramural guidelines of the PHS and TheInstitutional Guide to DHEW Policy on Protection ofHuman Subjects also identify confidentiality as aright which must be protected .52 Does confi-dentiality extend only to the subject involved in thestudy or does it also include the group of which he isa part? If the latter, what are the limits of groupconfidentiality? The Tuskegee Syphilis Study, incommon with many other studies, singled out oneparticular group, and revealed much that was intimateand private about all its members . Where can reviewcommittees seek guidance in devising procedureswhich safeguard subjects' rights in general, and theirrights to confidentiality, privacy and respect, inparticular?53

(6) The jurisdiction of institutional review com-mittees encompasses "any activity which goes beyondthe application of those established and acceptedmethods necessary to meet. . (the subject's)needs. ,54 How are "established and accepted"methods to be ascertained? Among "established"treatments should distinctions be made betweenthose of "proven" and those of "dubious" value?What are the criteria for a "necessary" intervention?

52. Intramural Guidelines, supra, footnote 22, at 9 ; InstitutionalGuide, supra, footnote 23, at 6 .53. The Institutional Guide, ibid ., does make an effort tosuggest procedures for safeguarding confidentiality .54. Grants Administration Manual, supra, footnote 23,a 1-40-10 (B) ; see also Intramural Guidelines, supra, footnote 22,at 2-3, 7-8 .

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Since there is so much professional disagreement as towhen a procedure becomes "therapeutic," thequestion must be posed: "accepted" by whom? Wasthe withholding of arsenic and heavy metal treat-ments at the beginning of the Tuskegee Study a"therapeutic" intervention since the effectiveness ofsuch treatments was in doubt, particularly for latesyphilis? When did penicillin treatment become an"established and accepted method"? What degree ofcertainty is required of investigators and reviewcommittees? Certainly no clear line can be drawnbetween experimental and routine treatment since, ashas so frequently been asserted, "the therapy ofdisease is, and always will be, an experimental aspectof medicine ."55

The vagueness and generality of the governingstandards have disadvantaged all participants in theresearch decision-making process . For conscientiousreview committees, they have meant hard work and,insofar as the committees are overwhelmed by theenormity of their task, superficial examination ofprotocols. For subjects, the inevitable result has been todeprive them in some measure of the protection whichreview committees were supposed to provide . Forinvestigators, the pervasive uncertainty about what kindof human studies are now permissible has impeded theirresearch. And for society, fears about the protection ofits citizens in the research enterprise have not beenstilled . Especially because review committees work inisolation from one another and no mechanisms havebeen provided for disseminating the knowledge gainedfrom their individual experiences, each committee iscondemned to repeat the process of finding their ownanswers to all the questions we have raised . This is anoverwhelming, unnecessary and unproductive task forwhich they are not prepared and which we doubt theyare willing to assume .

What is needed, is an overall official body authorizedto formulate more detailed policies with respect toresearch on human beings . The need for such a policymaking body has in point of fact already been perceived,and other bodies, official and non-official, have partiallyand on an ad hoc basis attempted to fill the gap . Forexample, the FDA has promulgated comprehensive rulesfor the conduct of drug research, 56 although on manycrucial issues of subject protection it has simply copiedDHEW policy .57 Similarly, in the wake of organtransplantation, an ad Hoc Committee of the Harvard

55. Ivy, "The History and Ethics of the Use of Human Subjectsin Medical Experiments" 108 Science (July, 1948) . Barber et al.have recently documented the prevalence of professionaluncertainty over the definition of "research ." See Barber et al.,supra, footnote 3 at 150 .56. See 21 C .F.R . 0 ® 130.3, 130 .37 .57 . Ibid . ; see also 36 Fed. Reg . 5037 (1971) .

Medical School redefined the criteria of "death" in orderto facilitate the removal of needed organs .58 Moreover,the Division of Research Grants of NIH, 59 which atpresent supervises the implementation of DHEW policy,has occasionally transmitted memoranda to review com-mittees "concerning the interpretation and implementa-tion of (its) policy ."60 Recent memoranda focused onpotential hazards of screening programs for sickle celltrait, the definition of "human subject," and guidelinesfor fetal studies. These policy making activities need tobe consolidated, under the auspices of a broadlyrepresentative body, about which we shall have more tosay below. Such a body would not only provideguidance to review committees but would also enablethem to obtain advice whenever difficult problems arise .

B. Invisibility

The creation of institutional review committees couldhave led to increased visibility of decisions regarding theprotection of subjects . But since neither publication norfree access to their findings was specifically planned for,increased visibility has not been realized. A low level ofvisibility hampers efforts to evaluate and learn fromattempts to resolve the complex problems of humanresearch. Especially so long as guidelines for humanresearch remain so indefinite, high-visibility decision-making is an essential feature of a well-functioningregulatory framework . Moreover, since committee dis-approvals can block research, with no recourse to higherlevel review, invisibility may impede the acquisition ofvaluable knowledge .

The 1969 committee review of the Tuskegee SyphilisStudy illustrates the problems which a low level ofvisibility creates. Our knowledge of that proceedingcomes from an unofficial summary which constitutes theonly available report on that committee's deliberations .From this summary it is impossible to determine thefactors which the committee considered or the groundson which the committee based its decision to approve acontinuation of the study . This state of affairs is notatypical. Because institutional committee decisions arenot published, committee decision-making .Dperates at aprimitive level, uninformed by pertinent prior decisionsof other committees or by scholarly outside criticism. Amechanism for self-improvement over time is lacking .Professor Guido Calabresi has observed :

58. Ad Hoc Committee of the Harvard Medical School, "ADefinition of Irreversible Coma," 205 J .A.M.A. 337 (1968) .59. Grants Administration Manual, supra, footnote 23,s 1-40-50 (A) .60 . Memorandum of January 24, 1972, from Stephen P.Hatchett, Director, Division of Research Grants, NIH, DREW, toOfficers Responsible for Institutional Implementation of DHEWPolicy on Protection of Human Subjects .

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. . .The best way of broadening the imputs tothe committee-lies in another device: publicationof the cases decided by the committees. Such casescould well be anonymous (at least at first) . Theycould be collected and published in much the sameway that decisions of courts are collected . Thereports on any case could include, first a factualpart describing, among other things, theexperience of the experimenter, the antecedenttests in non-human subjects, the major risksperceived, the scientific gains perceived possible,the availability of subsequent controls to limit therisks, the origin and life expectancy of thesubjects, and the nature of the consent and themanner in whcih it was obtained ; and, second, ajurisprudential section containing the decision ofthe committee (whether favorable or unfavorable),together with the principal arguments made forand against the decision reached .

Such published cases would soon become thesubject of intense study both inside and outsidethe medical profession. Analyses in learnedjournals by lawyers, doctors, and historians ofscience would inevitably follow . These wouldundoubtedly re-argue the more important or path-breaking cases. If law cases are any guide, theanalyses would sometimes conclude that the caseswere wrongly decided, but frequently that theywere rightly decided, and perhaps more frequentlythat they were rightly decided but for the wrongreasons . To the extent that Law Reviews considerthemselves courts of last appeal beyond thehighest courts in the land, so would the learnedjournals in which this giurisprudenza would be dis-sected. From all this, a sense of what society atlarge deems proper in medical experimentsmight well arise . This sense would, in turn,guide the committees and make their decisionsmore sophisticated. The result would not only bebetter thought out decisions, but also a morecomplex system of controls, which, in effect, tookinto account much broader sources of informationas to societal values . . . . 61

In the Recommendation section of our report weincorporate Calabresi's suggestions in a comprehensiveframework for the regulation of human experimenta-tion .

C. Subject Consent

1 . The Definition of "Informed Consent"

Institutional review committees are' expected to

61 . Calabresi, "Reflections on Medical Experimentation inHumans," 98 Daedalus 387, 400-401 (1969) .

ascertain "that informed consent is. . . obtained bymethods that are adequate and appropriate ."62 TheDHEW Grants Administration Manual, in contrast to itstreatment of other important matters, defines "informedconsent" in some detail :

Informed consent is the agreement obtained from asubject, or from his authorized representative, to thesubject's participation in an activity .

The basic elements of informed consent are :1 . A fair explanation of the procedures to be

followed, including an identification of thosewhich are experimental ;

2. A description of the attendant discomforts andrisks ;

3 . A description of the benefits to be expected ;

4. A disclosure of appropriate alternative proceduresthat would be advantageous for the subject ;

5 . An offer to answer any inquiries concerning theprocedures ;

6. An instruction that the subject is free to withdrawhis consent and to discontinue participation in theproject or activity at any time 63

The PHS Intramural Guidelines also explicateinformed consent in some detail :

The individual must be free to choose whether ornot to be a subject in research. His participationshall be accepted only after he has received a fairexplanation of the procedures to be followed,benefits, and attendant hazards and discomforts,and, suited to his comprehension, the reasons forpursuing the study and its general objectives . Hemust be informed of his right to withdraw fromthe study at any time .64

For no apparent reason, two "basic elements" ofinformed consent identified in DHEW policy are ignoredby the PHS intramural policy . Nothing is said in theintramural policy statement about disclosure of alterna-tive procedures ("basic element" number four) orresponse to inquiries ("basic element" number five) .

Despite the commendably greater detail with whichDHEW policy on obtaining informed consent is setforth, major gaps do remain. For instance, the DHEWdirectives permit consent to be obtained from thesubject's "authorized representative" in lieu of thesubject himself. But the circumstances in which thirdparty consent may properly be substituted for theconsent of subjects are undefined . Committees are not

32

advised as to who can validly consent in place of thesubject or whether consent can be obtained fromanother person besides the subject only for certaininvestigations, such as those specifically designed tobenefit the subjects themselves. Thus, committees areleft to their own devices in fashioning rules about theparticipation in research of such subjects as the veryyoung or the very old, the mentally incompetent or theemotionally disturbed, the imprisoned or those other-wise under duress, or, as in the Tuskegee Study, thosewho are ill-prepared as a consequence or culturaldeprivation or inadequate education .

In contrast to the DHEW extramural guidelines, thePHS intramural research rules do address the problemsof substitute consent for special subjects in more detail :

Studies involving children, the mentally ill or thementally defective. should be carried out onlywhen there is no significant risk of physical ormental harm to the subject or when direct benefitto the subject is anticipated . . . . In general,written informed consent of the parent orguardian shall be required for all medical or dentalstudies with such subjects, except in studies of anobservational nature or in those conducted duringthe administration of accepted health care pro-cedures that do not require specific informedconsent in ordinary practice . Any exception shallbe carefully considered and fully documented .Written informed consent of parent or guardianmay be desirable in certain other studies withthese groups and shall be required if conditionswarrant . . . . Studies of individuals with limitedcivil freedom shall also be subject to groupconsideration and approval . Informed consent ofthe responsible institutional authority shall berequired in all cases . Written informed consent ofthe individual shall also be required except forstudies of an observational nature conductedduring the administration of accepted health careprocedures that do not require specific informedconsent in ordinary practice .65

The major difficulties with these provisions result fromthe exceptions to the general requirement of substituteconsent. "Studies of an observational nature" and"accepted health care procedures that do not requirespecific informed consent in ordinary practice" arephrases too vague to be meaningful . For example, wasthe Tuskegee Syphilis Study "of an observationalnature"? In what "other" kinds of studies mayinvestigators dispense with the consent of parent orguardian unless unspecified "conditions warrant" it?

64 . Intramural Guidelines, supra, footnote 22, at 1 .65 . Intramural Guidelines, supra, footnote 22, at 10-11 .

62 . Grants Administration Manual, supra, footnote 23,f 1-40-20 (A) .63 . Grants Administration Manual, supra, footnote 23,11-40-10 (C) .

Moreover, the PHS instructions ignore the issue of thecapacity of third parties to represent the interests ofspecial subjects adequately, and the subtle inducementswhich may persuade prisoners to consent .

Prisoners in particular are a group whose participationin research has long been controversial .66 Becauseprisoners are a captive group, the danger is great thattheir consent to participate in research will be obtainedby duress . Jessica Mitford has recently documentedsome of the abuses to which prisoner participants inexperimentation have been subjected, and shecomments :

The (Institutional) Guide expresses a "particu-lar concern" for "subjects in groups with limitedcivil freedom . These include prisoners . . . ." Havinguttered this praiseworthy sentiment, HEW hasapparently let the matter drop . Dr . D.T . Chalkley,chief of the Institutional Relations Branch,Division of Research Grants, and signer of theGuide, tells me that HEW does not even maintain alist of prisons in which HEW-financed researchprograms are in progress and has "no centralsource of information" on the scope of medicalexperiments on prisoners by drug companies . . . .

What efforts have been made by HEW toenforce its guidelines in HEW-financed medicalresearch behind prison walls? "We do give somegrants that involve prisoners. But there's noconvenient way of recovering the information asto whether our guidelines are being followed," saidDr. Chalkley. "That responsibility lies with theprincipal investigator . . . ." has HEW ever broughtany action to enforce its regulations in any prisonsanywhere? "None, to date .i fi7

Most new drug testing is initially conducted onprisoners, and is subject to FDA regulations, but theFDA also has no list of persons in which such research iscarried out . 6 8

We regard the failure of the DHEW policies to includecomprehensive guidelines for safeguarding prisoners,children, mental incompetents, and other specialsubjects in research, as a major shortcoming which mustbe rectified. Detailed policy must be formulatedspecifying the kinds of research which may be carriedout with special subjects of different types, theinducements which are permissible, the circumstances in

66 . See, e .g ., Lasagna, "Special Subjects in Human Experimenta-tion," 98 Daedalus 449 (1969) ; Katz, supra, note 12, pp .1018-1052 ; Mitford, "Experiments Behind Bars," The AtlanticMonthly 64 (January, 1973) .67. Mitford, "Experiments Behind Bars," supra, footnote 67, at67-68 .68. See Mitford, "Experiments Behind Bars," supra, footnote67, at 68 .

33

which third-party consent is necessary, the identity ofthose who can validly consent for the subject, additionalprecautions which must be taken for such subjects, andother matters .

2. Exceptions to the Consent Requirement

In its Institutional Guide to DHEW Policy on theProtection of Human Subjects, the Department setsforth the following additional exceptions to the require-ment of informed consent :

The review committee will determine if theconsent required, whether to be secured before thefact, in writing or orally, or after the factfollowing debriefing, or whether implicit involuntary participation in an adequately advertisedactivity, is appropriate in the light of the risks tothe subject, and the circumstances of the project .

Where an activity involves therapy, diagnosis, ormanagement and a professional/patient relation-ship exists, it is necessary "to recognize that eachpatient's mental and emotional condition isimportant . .and that in discussing the element ofrisk, a certain amount of discretion must beemployed consistent with full disclosure of factnecessary to any informed consent ."69

The first exception which permits obtaining consent"after the fact," is so general in scope and so extensivein the discretion it accords review committees that italmost staggers the imagination. What are "the cir-cumstances of the project" which could ever permit suchan invasion of subjects' rights to self-determination andprivacy? Is this exemption limited to investigations withnormal subjects employing placebos or to deceptionstudies so frequently employed by psychologists? In onesentence the requirement of prior 70 informed consent isseriously undermined .

Furthermore, another exception provides for adeparture from informed consent in situations in which"a professional/patient relationship exists ." Since mostmedical research is carried out in such settings, it canapply to almost all medical interventions . It is particu-larly in clinical settings that overreaching in obtainingconsent, however unwitting, is a constant danger . 71

Thus the unqualified provision that "a certain amount of

69 . Institutional Guide, supra, footnote 23 ; at 8 .70 . It is implicit that consent is normally to be obtained prior tothe subjects participation in research, although DHEW policynowhere so states.71 . See infra, pp. 40ff.

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discretion must be employed consistent with full dis-closure of fact" is particularly unsatisfactory .72

PHS intramural policy also contains loopholes in itsconsent provisions. First, the guidelines state that

An explanation so detailed as to bias his responseor otherwise to invalidate findings is not necessary

in those procedures that involve no risk of physicalharm to the subject .73

This qualification is apparently designed to minimizeinterference with behavioral and other studies commonto the social sciences. This guidelines elsewhere statethat

a major class of procedures in the social andbehavioral sciences does no more than observe orelicit information about the subject's status bymeans of tests, inventories, questionnaires orsurveys of personality or background . In - suchinstances, the ethical considerations of voluntaryparticipation, confidentiality, and propriety in useof the findings are the most generally relevantones. The procedures may in many instances notrequire the fully informed consent of the subjector even his knowledgeable participation .74

The. lack of concern in the quoted passages forpsychological-as opposed to physical-harm to subjectsis striking. Despite acknowledged ethical problems, theguidelines suggest that in "many instances" the"knowledgeable participation" of the subject may beunnecessary . Here again, the regulations fail to providemeaningful guidance to review committees .

3. The Quality of "Informed Consent"Another difficulty which seriously undermines the

implementation of informed consent has not been dealtwith at all in the DHEW policies . It has long beenrecognized that consent is far too often obtained in form

72 . Compare the more satisfactory provisions on informedconsent adopted by the FDA, 21 CFR s 130 .37, which requirethat consent be obtained "in all but exceptional cases ." This isdefined as follows :

(d) "Exceptional cases," as used in paragraph (b) ofthis section, which exceptions are to be strictly applied,are cases where it is not feasible to obtain the patient'sconsent or the consent of his representative, or where, asa matter of professional judgment exercised in the bestinterest of a particular patient under the investigator'scare, it would be contrary to that patient's welfare toobtain his consent . s r

(f) "Not feasible" is limited to cases where theinvestigator is not capable of obtaining consent because ofinability to communicate with the patient or his repre-sentative ; for example, where the patient is in a coma or isotherwise incapable of giving informed consent, hisrepresentative cannot be reached, and it is imperative toadminister the drug without delay .

(g) "Contrary to the best interests of such humanbeings" applies when the communication of informationto obtain consent would seriously affect the patient'sdisease status and the physician has exercised a profes-sional judgment that under the particular circumstancesof this patient's case, the patient's best interests wouldsuffer if consent were sought .

73 . Intramural Guidelines, supra, footnote 22, at 1-2 .74 . Intramural Guidelines, supra, footnote 22, at 9 .

34

alone, and not in substance. As the Department itselfadmits in its Institutional Guide (quoting Doctor HenryK. Beecher of Harvard Medical School) :

"The informed consent of the subject, whileoften a legal necessity is a goal toward which wemust strive, but hardly ever achieve except in thesimplest cases."75

For as Doctor Beecher has written elsewhere,

Lay subjects, sick or well, are not likely tounderstand the full implications of complicatedprocedures, even after careful explanation .76

Even with the best of intentions, investigators mayfail to "get through" to their subjects for a variety ofreasons. The subjects themselves may have greatdifficulty in understanding or little interest in knowingthe nuances of what the investigator tries to explain tothem. As Senator Hubert Humphrey recently lamentedin response to the Tuskegee Syphilis Study :

Who are the people who have been the subjectsof medical experiment? The clear and shockingimplications of the most recently revealedexperiments indicate that the powerless, the poor,the least educated, and members of minoritygroups are the likeliest human guinea pigs . . . .

It is those who cannot understand what is beingdone to them that constitute by far the largestnumbers among human experimentationsubjects .? 7

Moreover, the circumstances in which consent issought may foster or hinder an informed and voluntarydecision. The subject may be under stress or distractedby other pressing concerns . For example, he may be apatient, desperately hoping for successful treatment ofhis condition, whose judgment is distorted by thenatural tendency to grasp at any straw in reach . Thelikelihood of this result is magnified by the profounddependence which many patients develop on theirattending physicians, who are often responsible forobtaining consent . Indeed, however wrongly, the patientmay well fear that his refusal to consent to experimental

75 . Institutional Guide, supra, footnote 23, at 7 .76. Beecher, Research and the Individual (Little, Brown and Co .1970) .77. 118 Cong. Rec. S 14041 (Sept. 5, 1972). SenatorHumphrey's assertion is corroborated by the recent study ofresearch practices conducted by Barber et al. In the twoinstitutions they analyzed, they found that studies in which therisks were relatively high in proportion to therapeutic benefits tothe subjects were "almost twice as likely as more favorablestudies to be done using subjects more than three-fourths ofwhom (were) ward and/or clinical patients," as opposed toprivate and/or semi-private patients . Moreover, this pro portion isnot significantly altered when studies in which the risk exceedsall possible benefits, to the subjects or to medicine generally areexamined : "the `least favorable' studies (were) still almost twiceas likely as the more favorable to be done using three-fourths ormore ward or clinical patients ." Barber et al., supra, footnote 3at 55, 56.

treatment will anger his physician and deprive him ofadequate medical care .

Lastly, the investigator . himself may fail to describehis own research objectively, or unwittingly create subtlepressures on a subject to consent . To suggest this is notto deny the integrity of the researcher, but only toacknowledge the reality of investigators' bias towardtheir work . Their scientific curiosity and excitementmake it difficult for them to take a detached view of theresearch they wish to conduct with their subjects .

D . Continuing Review

Although extramural research projects supported byDHEW grants or contracts must be reviewed on acontinuing basis, intramural research activities of thePublic Health Service need not be reviewed again afterinitial committee approval . This omission for intramuralprograms of what the Department itself calls "anessential part of the review process" 78 explains the longneglect of the Tuskegee Study. Begun long beforecommittee review became a reality, the Study was notreviewed by any committee until 1969, three years afterSurgeon General Stewart had inaugurated the policy ofcommittee review. Moreover, the 1969 review wasundertaken at the behest of the principal investigatorsthemselves, and not as the result of the Public HealthService review policy . The Tuskegee Study was notreviewed again until this Panel was appointed . We havebeen unable to ascertain why intramural researchprograms are exempt from the continuing reviewrequirement .

Although DHEW extramural policy does require"continuing review," a better definition of the natureand extent of this obligation is needed . The presentindefinite regulations invite a perfunctory performanceof the continuing review function . Essentially theDepartment expects that the committees will

. . . adopt a variety of continuing reviewmechanisms. They may involve systematic reviewof projects at fixed . intervals, or at intervals set bythe committee commensurate with the project'srisk. Thus, a project involving an untried pro-cedure may initially require reconsideration aseach subject completes his involvement . A highlyroutine project may need no more than annualreview. Routine diagnostic service procedures,such as biopsy and autopsy, which contribute toresearch and demonstration activities generallyrequire no more than annual review . Spot checksmay be used to supplement scheduled reviews .

78. Institutional Guide, supra, footnote 23, at 8 .

35

Actual review may involve interviews with theresponsible staff, or review of written reports andsupporting documents and forms . . 79Institutional review committees ; already over-

burdened by the task of examining all new researchprojects, are thus also responsible for re-examining fromtime to time all ongoing research . If something has togive first, it tends to be this assignment . Pressed for time,the review committees assume that the initial review hassatisfactorily resolved all existing problems and that acursory review is sufficient .

E . Structure and Composition of InstitutionalCommittees

Institutional review committees are charged withcarrying out a number of distinct functions . They arerequired to formulate policies and regulations to guidethe conduct of research at their institutions,8 0 oftenunder the rubric of protocol review ; to communicatethese policies to investigators ; to administer the policiesthey have promulgated through the prior appraisal ofresearch proposals, the supervision of the attempt toobtain consent and the continuing review of approvedresearch activities ; to review the consequences of theirdecisions; and to keep informed of DHEW policychanges and suggestions in order to reformulate institu-tional policies and rules when necessary .

In recognition of the variety of tasks which have beendelegated to committees, DHEW policy stresses thecomposition of committee membership .

. . . In addition to possessing the professionalcompetence to review specific activities, the com-mittee should be able to determine acceptabilityof the proposal in terms of institutional com-mitments and regulations, applicable law,standards of professional conduct and practice,and community attitudes. The committee maytherefore need to include persons whose primaryconcerns lie in these areas rather than in theconduct of research, development, and serviceprograms of the types supported by DHEW(emphasis supplied) . 81

In carrying out their functions, the institutionalreview committees are thus also asked : "to determineacceptability of the proposal in terms of . . . applicable

79. Institutional Guide, supra, footnote 23, at 8-9 .80. Although the parent institutions are charged by DHEW withthe responsibility of formulating policies to guide institutionalreview committees, Grants Administration Manual, supra, foot-note 23 11-40-40, to our knowledge this task is generallydelegated to those committees. As we have previously described,the burden of formulating policy weighs heavily on localinstitutions because the DHEW policy is vague and incomplete.81 . Grants Administration Manual, supra, footnote 23,11-40-40 (C) (2) (b) .

law, standards of professional conduct and practice, andcommunity attitude ." By assigning these tasks to abroadened committee membership, DHEW recognizesthat decision-making in the human experimentationprocess cannot be left solely to professionals, butrequires the participation of informed and concernednon-scientists. who may be laymen, lawyers, clergymen,and appropriate others . However, the functions of thesenon-professional participants are not spelled out . Andthe assumption that they can make their most effectivecontribution at the administrative stage, when individualprotocols are reviewed, rather than at other stages of theprocess remains unexamined . The DHEW policiesattempt to consolidate all phases of researchregulation-formulation of detailed policies, administra-tion of research, and review of decisions andconsequences-in one committee structure . Asking eachreview committee to determine far-reaching policies byitself overburdens the review committee structure . Thepolicy issues which must be resolved with the assistanceof lay members are so complex that to require eachcommittee to work them out by itself is at bestinefficient and at worst self-defeating .

It would be more functional and efficient to leave theadministration of research, like the administration oftherapeutic interactions between physicians andpatients, primarily in the hands of the professionals . Ifreview committees were guided by comprehensivepolicies formulated by a broadly representative body,the review of individual protocols could focus ontechnical matters, such as degree of risk, likely benefits,research design, competence of investigators, safetyprecautions, and the like . This allocation of authoritywould help to reduce the widespread concern amongphysician-investigators about "meddlesome outsiders ."

F . Enforcement

The DHEW guidelines on enforcement are written inpermissive and general language :

The Division of Research Grants (DRG), NIH,will follow up reports by reviewers, evaluators,consultants, and staff of the DHEW indicatingconcern for the welfare of subjects involved inapproved and funded grants or contracts, and ofsubjects potentially involved in activities approvedbut not funded, and in disapproved proposals . Onthe basis of these reports and of other sources ofinformation, the DRG, NIH, may, in collaborationwith the operating agency concerned, correspondwith or visit institutions to discuss correction ofany apparent deficiencies in its implementation ofthe procedures described in its institutionalassurance .

36

If, in the judgment of the Secretary, aninstitution has failed in a material manner tocomply with the terms of this policy with respectto a particular DREW grant or contract, he mayrequire that it be terminated in the mannerprovided for in applicable grant or procurementregulations. The institution shall be promptlynotified of such finding and of the reason therefor .

If, in the judgment of the Secretary, aninstitution fails to discharge its responsibilities forthe protection of the rights and welfare of theindividuals in its care, whether or not DHEW fundsare involved, he may question whether the institu-tion and the individuals concerned should remaineligible to receive future DHEW funds for activitiesinvolving human subjects . The institution andindividuals concerned shall be promptly notifiedof this finding and of the reasons therefor . 82

These enforcement guidelines delegate sole responsi-bility for the detection of failures to comply to theDivision of Research Grants. But staff members of theDRG are probably the last persons to hear of anyinfractions once they have occurred, and then onlywhen, as in the Tuskegee Study, they are of majorproportions . Indeed, no procedures have been estab-lished to require institutional review committees toreport to DREW any evidence on noncompliance .Moreover, DHEW has made no efforts to definecategories of noncompliance 83 which should lead to theimposition of sanctions or to specify different kinds ofsanctions which should be imposed in particular cases .Finally, institutional review committees and DHEW arenot authorized to take disciplinary action, except for theSecretary's prerogative to terminate grants or make theinvestigator or his institution ineligible to receive futurefunds .

G . Compensation of Subjects

Existing DHEW policy provides no mechanism for thecompensation of subjects harmed as a consequence oftheir participation in research, in spite of the growingrecognition that no matter how careful investigators maybe, harm still will befall some subjects .84 Unavoidableinjury to a few is the "cost" of engaging in researchwhich ultimately benefits the many . But unless theinjured individuals can prove carelessness, failure to

82. Grants Administration Manual, supra, footnote 23,1 1-40-50 (E).83 . Because the requirement of "continuing review" has notbeen elaborated, committees themselves only haphazardly comeacross evidence of noncompliance .84 . See Ladimer, "Protection and Compensation for Injury inHuman Studies," In Experimentation With Human Subjects(Paul A. Freund, ed .) 247 . (George Braziller, 1970) (hereinafterLadimer) .

obtain informed consent, or actual malice, theirparticipation bars recovery for the harm done to them .Those subjects whose injury does result from negligenceare faced with t'ie usual difficulties and uncertaintiesinherent in a law suit . For his part, any investigator whois sued as a result of his research may find that hisordinary malpractice insurance does not cover medicalresearch.85 If it does not-and the question is as yetunsettled-the personal liability of the investigator canbe substantial . In addition, the economic vulnerability ofsubject and investigator adds to society's uneasinessabout human experimentation, and may deter somepersons from engaging in research activities .

H . Applicability of DHEW Policies

The DHEW guidelines quite appropriately wereformulated for research grants and contracts to befunded by the Department . While much research in thiscountry is supported by DHEW funds, a great deal ofresearch is also funded or conducted by other Federalagencies, such as the Department of Defense .86Additionally, many research activities receive no Federalsupport . Is there any justification for permitting lessstringent protective controls for human experimentationsupported by other governmental agencies, privatefoundations, or other private sources than for research

85 . See Ladimer, supra, footnote 84 at 251 .86. For documentation of the human research conducted by thearmed services, see the Legislative Reference Service's report"Medical Experimentation on Human Beings, March 1967,"placed in the Congressional Record by Senator Jacob Javits, 118Cong. Rec. S. 13789, 13793-95 (August 17, 1972) . The reportstat es

There is very little information available on thenumber and types of military persons who serve assubjects in research . Intuitively appraised, however, thenumber of topics and of human subjects must be large .

118 Cong . Rec . S . 13793 .

conducted or supported by DHEW?87 Since a majorrestructuring in existing policies is necessary, we believethat serious consideration should be given to developing,through Congressional action, rules and procedureswhich apply to the entire human research enterprisewithout reference to the source of funding . A tentativestep in this direction has already been taken by DHEW .Its enforcement section provides for the discontinuationof funds to any institution which has failed "todischarge its responsibilities for the protection of therights and welfare of the individuals in its care, whetheror not DHEW funds are involved . "88 If it is concluded,however, that such broad coverage is beyond the powerof Congress, then Congress should at least act to bring allfederally funded research within a comprehensive regula-tory framework .

When this is done, the existing anomaly in theapplicability of DHEW policies should be corrected . Werefer to the different policies described earlier whichgovern intramural and extramural research . We can findno justification for differential protection of subjects onthis basis . Moreover, the conduct of human research byDHEW employees and under the Department's aegislends additional support to our call for an independentGovernment body to oversee all research. For to expectDHEW to scrutinize and judge its own activities ascritically and strictly as it supervises outside researchprojects is arguably unrealistic and unnecessarily strainsinternal Departmental relationships .

87 . Barber et al., found that in 15% of the institutions theysurveyed some clinical research was not reviewed by aninstitutional committee. Moreover, 35% of these institutionswere medical schools, "the type of institutional setting mostproductive of biomedical investigations using human subjects ."They concluded that "a perhaps significant volume of humanresearch is still not subject to review by peer review com-mittees ." Barber et al., supra, footnote 3, at 149 .88 . Grants Administration Manual, supra, footnote 23,§ 1-40-50 (E) .

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V. RECOMMENDATIONS

A. Preface

Before turning to our specific recommendations wewould like to anticipate three possible criticisms of ourproposals. First, the argument may be advanced that anyregulation of human research is an unwarranted infringe-ment of the "freedom of inquiry ." But freedom ofinquiry is only one facet of freedom in general . Whenscientists use other human beings as subjects of experi-mentation and in so doing jeopardize their rights andwelfare, the scientists' freedom of inquiry clashes head-on with the right of every individual in our society topersonal autonomy. Therefore, society must retain theright to define and limit the human costs it is willing tobear in order to benefit from advances of knowledge .

Second, whenever it is suggested that representativesof society at large participate in decision-making ofsignificance to both science and society, concerns aboutthe intrusion of "outsiders" in the domain of profes-sionals are voiced. This position was forcefully expressedby Dr. Owen W. Wangensteen in a letter to SenatorWalter F . Mondale prior to congressional hearings in1968 on a proposed Commission to study the social andethical problems raised by biomedical advances .

Senator, I would urge you with all the strengthI can muster to leave this subject to the conscion-able people in the profession who are strugglingvaliantly to advance medicine. We are livingthrough an era in which the innovator is oftenunder suspicion, being second-guessed by self-appointed arbiters more versed in the art ofcriticism than in the subject under scrutiny . Weneed to take great care lest the wells of creativityand the spring of the mind of those who breakwith tradition are not manacled by well-intentioned but meddlesome intruders .

I would urge you to leave these matters in thehand of their proponents, the persons who areactually doing the work. They know more aboutall this than any of us possibly could . They havewrestled with the problem day and night, almostinvariably over many years . Theirs are not over-night judgments or convictions . In the academiccommunity in which I have worked and spent myentire professional life of almost 50 years, you willfind as warm, symphathetic human beings as are tobe found on this earth . . . .

It is important that we look back as well asforward. To have no concern for history istantamount to having a physician with totalamnesia. If we leave this matter alone, it will

38

simmer down. Discussion should not be restrained,but legislative action, never .89

We appreciate Dr . Wangensteen's fears, which have beenechoed by others . But not all intrusions by "outsiders"into medical decision-making are viewed by the profes-sion as unwarranted interferences with the practice ofmedicine . Authorized representatives of society have theright to circumscribe some activities of professionals andthis has been accepted ; for example, the discretion ofphysicians to commit patients against their will or toprescribe addictive drugs is limited . Thus, the pertinentquestions are : under what circumstances, to whatextent, and by what means should the activities of themedical professional be controlled?

We have already mentioned that the human researchdecision-making process can be divided into threefunctionally distinct stages : the formulation of researchpolicies, the administration of research, and the reviewof research decisions and their consequences . Theparticipation of "outsiders"-which is to say, of personsdeemed capable of representing the interests of societyin the proper conduct of research-is highly desirable inthe formulation and review stages . Such decisions as theallocation of resources for research, the extent ofhazardous experimentation, the degree of respect to beshown for the autonomy of research subjects, and theextent of the participation of children, prisoners,members of minority groups, and other captive ordisadvantaged persons in research, are of momentousconsequence to society as well as to science . Thesedecisions implicate general social policies and must notbe left to the sole discretion of scientists .

Nonetheless, we agree that the often expressed fear ofinterference by laymen with the immediate clinicalresearch decisions which physician-investigators mustmake has merit. However, we believe that the twopositions can be reconciled. Once satisfactory rules andprocedures for the protection of human subjects havebeen formulated and research practices are adequatelyreviewed by "insiders" and "outsiders," society shouldfeel safe in leaving the actual administration of researchand therapy to physician-investigators within therestraints imposed by peer review (through the alreadyestablished institutional review committees .)

Current DHEW policies fail to identify the differentstages in the regulation of research. Instead, institutionalreview committees are charged with formulating policies,administering policies, and evaluating the consequencesof their decisions. Taken together these tasks are tooburdensome for such committees . Moreover, because

89 Hearings on S . J. Res. 145 before the Subcommittee onGovernment Research of the Senate Committee on GovernmentOperations, 90th Cong., 2d Sess . 98-99 (1968) .

these committees must formulate policy and evaluatedecisions, the demand for outsiders to sit on them hasintensified, justifying the fear of interference in profes-sional day-to-day decision-making by persons not quali-fied to do so . Our recommendations seek to reverse thisdevelopment by confining the role of the institutionalcommittees largely to the implementation of policiesalready adequately formulated by others .

A third criticism may be leveled against oui recom-mendation that a National Human Investigation Boardbe established to oversee human experimentation. Somemay fear that this Board will promulgate such detailedrules and impose so many legal duties that progress inresearch and innovation in treatment will be seriouslyimpaired . The danger of cumbersome bureaucracy cannotbe lightly dismissed and every effort must be made toavert it .90 At the same time we doubt that society, ifproperly informed, would tolerate any serious impedi-ments to the acquisition of knowledge, for the pervasiveand compelling desire to benefit from advances inmedicine should counteract any tendency to stifleresearch .

A national Board to regulate human research isneeded for many reasons. One central group should beresponsible for formulating policy, instead of the manydifferent Federal agencies and the hundreds of individualreview committees which, as we have argued, cannot beexpected to assume this complex task . Moreover, "out-siders" who could represent and protect individual andsocietal values and interests could then be included inpolicy formulation and review, where they are mostneeded, without thereby hindering physician-investigators in their professional decision-making . Thenational Board would ' provide a forum in which thecompeting interests of science and society could bedebated openly before authoritative decisions are made .

B. National Human Investigation Board

A permanent Governmental agency, to be called theNational Human Investigation Board (NHIB), should beestablished to oversee at a minimum all Federally-supported research involving human subjects. The juris-diction of this Board should extend to all extramuraland intramural research sponsored by DHEW (includinghuman research currently governed by FDA regulations)as well as to research supported by Government agenciesother than DHEW, such as the Department of Defense .Ideally, the authority of this Board should also extend

90. Another commonly expressed fear is that detailed regula-tions may adversely affect the well-being of patient-subjectsbecause the physician-investigator's authority to intervenequickly, whenever his professional judgment dictates it, isunduly restricted . But discretionary authority must of course bedelegated to physician-investigators in the exercise of purelyprofessional judgments regarding their patient's health,

39

to all human research activities, even if not Federallysupported. However, despite its apparent merits, such asweeping proposal may raise insurmountable jurisdic-tional problems. We leave it to others to determinewhether Congressional authority to regulate researchmay encompass investigations not conducted or financedby the Federal Government .91

The primary function of the NHIB would be toformulate policies and procedures to govern researchwith human beings . For this reason the Board mustinclude, in addition to eminent medical and otherprofessional researchers, lay members who can representthe interests of society in the ethical conduct of researchwith human subjects. Such lay members should beselected for their ability to make disinterested judg-ments about research issues of societal concern . Becausemedical and other research professionals have beentrained to pursue other goals, they should not beexpected to shoulder the added burden of speaking forthe concerns of society .

Senator Hubert Humphrey has called for theestablishment of a National Human ExperimentationStandards Board which in some respects resembles theBoard we propose . His bill92 provides as follows :

Sec. 2. (a) There is hereby established, as anindependent agency in the executive branch, aNational Human Experimentation StandardsBoard (hereinafter referred to as the "Board") .

(b) The Board shall be composed of 5 membersto be appointed by the President by and with theadvice and consent of the Senate from amongindividuals who by virtue of their service, experi-ence, or education are especially qualified to serveon the Board . . . .

(3d) Members should be chosen from personswho are representative of the fields associated andconcerned with clinical investigations .

Sec. 5. (a) It shall be the function of the Boardto-

(1) establish guidelines for the involvement ofhuman beings in medical experiments which arefunded in whole or in part with Federal funds ;

(2) review all planned medical experiments thatinvolve human beings which are funded in whole

91 . Senator Jacob Davits has also recently introduced a bill, inresponse to the Tuskegee Study, for the protection of researchsubjects. S . 3935, 92d Cong ., 2d Sess. However, this proposedamendment to the Public Health Service Act is in essence simplya statutory enactment of current DHEW regulations . As we haveargued, more than this is needed for the protection of researchsubjects.92 . S . 3951, 92d Cong ., 2d Sess .

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or in part with Federal funds to determine if theguidelines established under paragraph (1) arebeing complied with ;

(3) obtain an injunction to prevent such experi-mentation in a case where such experiments arefound not to comply with established guidelines ;and

(4) prepare and submit an annual report to thePresident, for transmittal to the Congress recom-mending legislation, if required, and detailing theperformance of the Board during the precedingyear .

Senator Humphrey's bill assigns to his Board policymaking, administrative and review powers. We believethat some of these functions should not be delegatedentirely to the NHIB and that those functions which theNHIB should be given must be spelled out in greaterdetail. Senator Humphrey's bill also does not provide forthe continuation of the institutional review committeesystem . We believe that institutional review committeesshould be maintained, although in modified form . Wenow turn to a discussion of the functions of the NHIBand institutional committees in the formulation,administration and review of policies for humanresearch .

1 . Formulation of Policy

The National Human Investigation Board mustestablish guidelines for the conduct of research withhuman beings with respect to such matters as :

a. Selection of Subjects-The Board must formulatecriteria for the selection of subjects . It will have toreexamine the contemporary research practice of choos-ing subjects from the less educated, disadvantaged, orcaptive groups within society . In doing so, the Board willhave to confront many questions. For example, shouldevery effort be made, consistent with research objec-tives, to obtain a subject sample which represents across-section of the population at large? Or shouldsubjects first be selected from among the best educatedbefore turning to the less educated, since the former aremore capable of giving "informed consent"? How shouldthe recruitment of subjects be effectuated to implementwhatever rules for their selection are adopted? Underwhat circumstances should non-comprehending subjectssuch as children or severely mentally disturbedindividuals, or captive subjects such as prisoners or otherinstitutionalized persons, be barred from participating inresearch?

b . Ambit of Informed Consent-The Board must notonly formulate the overall criteria of informed consentbut must also specify the circumstances in which the

40

consent requirement can be modified, and to whatextent, in order to accomplish important researchobjectives. In doing so, the Board will have to findanswers to such policy questions as : Under whatcircumstances can what benefits to individuals or societyjustify modifications 'in the informed consentrequirement? Should certain groups or potential subjectsbe excluded from participating in research or high-riskinvestigations be proscribed unless informed consent canbe obtained? When is third party consent permissible,and what safeguards should be introduced whenever theconsent of a third party is invoked? The Board may haveto promulgate separate guidelines for the conduct ofinvestigations which are predicated on the absence ofinformed consent, such as placebo, double blind, decep-tion and secret observation studies . The latter twoprocedures are employed by sociologists and psycholo-gists on such an extensive and repetitive scale, andconstitute such a significant exception to the generalrequirement of informed consent, that serious considera-tion should be given to restricting their use .

This may be an appropriate place to introduce a noteof caution. The policies we have in mind cannot beformulated overnight or without serious study of theproblems inherent in this field. An example from theliterature on informed consent illustrates this point . Ithas traditionally been assumed that the consent require-ments should be more stringent in research with"healthy" volunteers than with patients. This assump-tion ought to be reexamined. Perhaps, as AlexanderCapron has written :

. . . higher requirements for informed consentshould be imposed in therapy than in investiga-tion, particularly when an element of honestexperimentation is joined with the therapy . The"normal volunteer" solicited for an experiment isin a good position to consider the physical,psychological and monetary risks and benefits tohim in consenting to participate. How muchharder that is for the patient to whom anexperimental technique is offered during a courseof treatment. The man proposing the experimentis one to whom the patient may be deeplyindebted (emotionally as well as financially) forpast care and on whom he is probably dependentfor his future well-being ; the procedure may beoffered, despite its unknown qualities, becausemore conventional modalities have proved ineffec-tive .9 3

Finally, more attention must be given to the nature

93 . Capron, "The Law of Genetic Therapy," in The NewGenetics and the Future of Man, M . Hamilton, ed . (EerdmansPub . Co ., 1972) .

and quality of the interactions between investigator andsubject if the ensuing consent is to be truly informedand voluntary. In this connection, consideration shouldalso be given to make an adviser available to a subjectwhenever he thinks that his decision to participate ornot might benefit from disinterested advice .94 Theauthority and obligations of such advisers must becarefully defined and, as we have said repeatedly, withregard to policy formulation, cannot be left to eachindividual research committee to work out .

c. Definition of `Research "-To clarify the jurisdic-tion of the Board and of the institutional reviewcommittees, distinctions must be made between"research" activities and"accepted and established pro-cedure." We have pointed out already that the border-line between research and therapy is difficult to draw .Physician investigators have often wittingly or unwit-tingly added to the obfuscation by calling some investi-gations "therapy ." in order to escape the obligationswhich the research designation entails . Such practicesdiminish the protection afforded subjects, and alsoundermine the scientific validity of the results of suchinvestigations, because they were not established incarefully controlled clinical trails .

d . Application of Risk-Benefit Criteria-We havealready suggested that the risk-benefit equation is one ofthe most difficult guidelines to implement . To evaluaterisk taking, distinctions must be made between researchdesigned to benefit its participants and those which maybenefit society at large . With respect to societal benefits,answers will have to be found to such crucial questionsas : Do even minimal risks from participation require anintensive scrutiny of the benefits to be derived from thestudy or should "minimal" risks, however defined, beexempted from this burdensome requirement? Howoften can risky experiments be repeated for the sake ofverification, if results have already been reported in theliterature? Must certain groups, such as children andmentally defective subjects, be excluded from all riskystudies that are not designed to benefit them? When therisks and benefits of therapeutic measures are unknown,as in all first clinical trials of a new drug, should the testsbe randomized with a limited number of patients inorder to ascertain a scientifically valid estimate ofeffectiveness? In research with so-called normal volun-teers or other subjects who are able to give a satisfactoryconsent, can greater risks to be taken than a weighing ofrisks against benefits would in general permit? Shoulddying patients who are willing to participate in riskyexperiments be exempted from the rule that- no experi-ments are to be conducted which might hasten death?

94 . We elaborate upon this recommendation infra, pp . 44 ff.

41

e . Promulgation of a Compensation Scheme-Aninsurance plan should be devised and implemented forthe compensation of subjects harmed as a consequenceof their participation in research activities . Though manyschemes for compensating subject deserve considera-tion, we mention one which we believe has substantialmerit: "no fault" clinical research insurance paid for byeach institution sponsoring research . Subjects would becompensated for any injurious consequences of theirparticipation in research whether or not caused by thefault of the investigator . This plan would provide fullprotection for subjects and relieve investigators of thethreat of liability . As to cost, one of the principalpromoters of research insurance, Irving Ladimer, hasasserted that :

. . . it is unlikely that the costs will be great,probably a small fraction of customary malpracticepremiums. First, there are few compensable occur-rences within responsible research institutions,where most of the studies are conducted . Second,the assumption of medical care, most likely at thesponsor's premises, will reduce such costs . Third,the adoption of such a system should tend toimprove prior protection, controls, and researchdesign; this is expecially true for studies approvedby research review committees . Fourth, the spiritand philosophy of this form, which should be fullyexplained in advance in discussions with partici-pants, should serve to diminish rather than induceany questionable claims .9 5

The cost of the insurance would probably varydirectly with institutional safety records and thus mightprovide an additional impetus to careful considerationof research proposals . Guido Calabresi has called atten-tion to this possiblity :

. . . Requiring compensation of injured subjectscauses the full cost of research in humans to beplaced on the research center . Accordingly,approval by the center of a particular experimentwill require conscious consideration not only ofthe possible payoff (either in market or scientificterms), but also of the risks, converted to money,that the project entails . This may not deter manyexperiments, but it may cause those involved inthe most risky or least useful ones to considercarefully whether the experiment is worth it,whether it is best done by those who propose todo it, and whether there is an alternative, andsafer, way of obtaining approximately the sameresults . It may well be that all these considerationsare already firmly in the minds of the experi-

95 . Ladimer, supra, footnote 84, at 259 .

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menters. If so, nothing is changed by requiringcompensation. But if researchers-like automakers, coal mine owners and the rest ofmankind-tend to consider costs and benefits a bitmore carefully when money is involved, a usefuladded control device will have been imposed.96

If "no fault" research insurance, or any othermechanism, is adopted as a device for compensatingsubjects, regulations will have to be established foradjudicating disputes over such matters as causation-whether the worsened condition of the subject wascaused by the research in which he participated orwhether it was merely the inevitable outcome of thesubject's particular illness-or the amount of compensa-tion. Similarly, the NHIB will have to work out proce-dures for implementing whatever compensation schemeis adopted .

f. Promulgation of Sanctions-Senator Humphrey'sbill authorized his Board "to obtain an injunction toprevent . . .experimentation in a case where . . .experi-ments are found not to comply with established guide-lines." Though the promulgation of sanctions raisesmany sensitive issues, more is needed than has beenprovided in Senator Humphrey's bill . Other sanctionstailored to specific violations of the policies governingresearch are required. For example, an investigator'sfailure to submit a protocol for review, his departurefrom an approved research protocol or a review commit-tee's failure to follow its established procedures might insome circumstances justify suspension of further Federalfunding of the investigator or the sponsoring institution .

It is beyond the scope of this report to detail theoffenses which should lead to the invocation ofsanctions, the particular penalties which should beimposed, or the procedures which must be followed tosatisfy due process requirements . We also leave open thequestion of who-the National Human InvestigationBoard or Congress-should promulgate the regulationswhich will govern the imposition of sanctions.

g. Delegation ofAuthority to Administer and Reviewthe Research Process-The National Human InvestigationBoard must also promulgate rules and procedures for theadministration and review of the human researchprocess. We now turn to these issues under theirappropriate headings .

2. Administration of Researcha . Institutional Human Investigation Committees

Once adequate research policies have been formulatedby a broadly representative body, "outsiders" should

96 . Calabresi, "Reflections on Medical Experimentation inHumans," 98 Daedalus 387, 398 (1969).

42

intervene as little as possible in the administration ofthose policies. For when research policies are put intoeffect, limitations imposed by colleagues are bettertolerated by investigators than restrictions imposed byoutsiders. The administration of research should there-fore be performed principally by researchers' profes-sional peers sitting on institutional review committees .Thus we seek to reverse the trend97 toward outsidermembership on institutional review committees andoutsider interference with day-to-day professionaldecision-making . In our proposed restructuring ofinstitutional review committees, we have sought torestrict the participation or outsiders to those areas wherethey have the most to contribute .

Senator Humphrey's bill does not specify the statusof the institutional review committees which are nowrequired by DHEW. The advantages of institutionalcommittees are numerous, and we propose that they beretained, though with redefined functions . Among otherthings, administration at the institutional level simplifiesthe task of prior review of research protocols ; permitscloser scrutiny of research activities ; encourages investi-gator involvement in and respect for the problems ofethical research ; enables different institutions to dealwith complex new problems from different vantagepoints, and facilitates responsiveness to difficulties in theresearch process as they arise . Instead of eliminatinginstitutional committees, they should be restructured toenable them to perform their functions better than theynow do .

We recommend the creation of a structured institu-tional body, to be called the Institutional HumanInvestigation Committee (IHIC), in place of the existingunspecialized institutional review committee . Eachinstitution which is subject to the jurisdiction of theNHIB would be required to provide written assurance tothe NHIB that it had appointed an IHIC . This would besimilar to current practice which requires institutions tonegotiate assurances with the NIH's Division of ResearchGrants .98 As outlined below, each IHIC would beresponsible for the conduct of research in its institution,and would be required to file with the NHIB its plans forcarrying out the responsibility . Thus the NHIB wouldpass on the suitability of the IHIC membership, localpolicies, and administrative procedures, and NHIB

97 . Current DHEW regulations suggest, and FDA regulationsrequire, that outsiders be members of institutional reviewcommittees. See Grants Administration Manual, supra, footnote23, s 1-40-40 (C) (2) (b) ; 21 CFR § 130.3 ; 36 Fed. Reg . 5037,5038 (March 17, 1971) .98 . See Grants Administration Manual, supra, footnote 23,s 1-40-40 (A) :

The assurance shall embody a statement of compliancewith DHEW requirements for initial and continuingcommittee review of the supported activities ; a set ofimplementing guidelines, including identification of thecommittee ; and a description of its review procedures. . .

approval would be required before Federally fundedresearch99 could be conducted at the institution .10 0

IHIC members should be appointed by their institu-tions to serve for a period of years, so as to accumulateexpertise in the problems of human experimentation .The membership should represent a cross-section of thedisciplines involved in research at the institution . Itought also to include a few "outsiders." who can make avaluable contribution to the supervision of the consentprocess, as described below .

The main functions of each IHIC would be : toestablish local policies, consistent with the uniformnational guidelines promulgated by the NHIB, which areresponsive to the individualized needs of the institution,to bring to the attention of the NHIB any proceduralmodifications deemed necessary for effective func-tioning ; to inform local participants in the researchenterprise of their rights and obligations ; and to establishtwo subcommittees to carry out its administrativefunctions-a Protocol Review Group and a SubjectAdvisory Group . Although the membership of the sub-committees should be drawn largely from the IHIC,these subcommittees could also include others associatedwith the institution . Our recommendations regarding thetwo subcommittees are modeled on a similar proposalrecently advanced by Jay Katz and Alexander Capron ina somewhat different context, and in what follows wequote from the draft document they have prepared .

b . Protocol Review Groups

The heart of IHIC's will be their ProtocolReview Groups (PRG) which will be responsiblefor approving, disapproving or offering suggestionsfor modification in protocols for experimental andtherapeutic interventions which come within thepolicies on risk and consent formulated earlier inthe process . The PRG's task is to apply the rulesand policies already set down, but this should notbe a matter of "clockwork" or mere routine .Realistically, it is unlikely that even if policyformulation proceeded with much more rigor (aswe urge) it will result in directive that settle allissues faced by the PRG's . This does not suggest,however, that Protocol Review Groups set policiesthemselves, though these rules may give themsome discretion in light of local institutional

99 . Or any research - see supra, p . 39 .100. It should be noted that, as in present DHEW policy,different requirements might be established for institutions"having a significant number of concurrent" research projectsand for institutions sponsoring only one, or a limited number, ofsuch projects . See Grants Administration Manual, supra, foot-note 23, § 1-40-40 (B), (C), and (D). The description of the IHICpresented in our report hereinafter is for an institution with anumber of research activities .

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conditions and so as to permit experimentationwith a variety of alternative policies which are stillconsistent with the general directives . This sort offlexibility is vital if the PRG's are to operateeffectively and secure the services of thoughtful,devoted members .

Membership in the Protocol Review Groupshould consist primarily of professionals withcompetence in biomedicine . This reflects thecommittee's function, which is to scrutinizeprotocols in light of the policy guidelines anddirectives, to evaluate whether the procedureshould be undertaken, and to give advice to thephysicians and scientists involved. In mostinstances these group members will be members ofthe university or research center's staff andfaculty, but when the presence of more than oneinstitution in a locality permits- it, the cross-fertilization of having some people from onecenter serve on another's PRG would probably beadvisable. Such an arrangement would provide"outsiders" in the sense of people's free of thepersonal ties and biases of the institution's ownemployees, while maintaining the biomedicalexpertise that should characterize "insiders ."' 01

c. Subject Advisory Groups

Katz and Capron also propose "the establishment ofSubject Advisory Groups (SAG) to aid patient-subjectsin decision-making."10 2 We do not lightly suggest thecreation of another subgroup within the IHIC, since wehave no desire to overburden the process with excessivebureaucracy . But, as we have emphasized, presentprocedures for obtaining consent are concerned withform to the neglect of substance . If informed andvoluntary subject consent is to become a reality inhuman experimentation, efforts must focus on improv-ing the quality of the communications between investi-gator and subject . We therefore endorse the Katz andCapron proposal that an adviser be made available tocounsel any prospective subject who thinks his' decisionto participate or not might benefit from disinterestedadvice .

Not all patient-subjects may wish to seek outrepresentatives of the Subject Advisory Group, forsome may be satisfied with the informationobtained from physician investigators . Butpatient-subjects should be well apprised of theavailability of these representatives prior to theirparticipation in projects which have to be sub-

101 . Katz and Capron, supra, footnote 18 .102 . Ibid .

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The SAG should also aid investigators in developingfair methods of obtaining consent, and in avoidinginadvertent bias or coercion when seeking consent . Itought to go without saying that

. . . (c)reating an opportunity for someone inaddition to physician-investigators to talk withpatient-subjects does not suggest a lack of trust inthe investigators' integrity, rather it recognizes thereality that investigators cannot help but plead,however unconsciously, their interests in theresearch and therefore must find it difficult fullyto safeguard the interests of their subjects .104

Because the work of the SAG would be restricted toissues relating to consent, laymen could make a signifi-cant contribution in this subcommittee . They, morethan professionals, would appreciate the difficultiesprospective subjects might have when faced with aninvitation to participate in research . And potentialsubjects might be less overawed in interactions with theirpeers, than in interactions with physicians .

d. Appeals

From time to time disagreements will arise betweeninvestigators and the Protocol Review Groups . Noopportunity for appeal from an adverse institutionalreview committee ruling exists at present, and com-mittees can cut investigators off from Federal fundingwithout possibility of reconsideration . This may notonly hinder the acquisition of knowledge ; it may alsoundermine the legitimacy of peer review . Barber et al.have written :

We have heard researchers object to peer review asthey know or understand it because they believethat research proposals having real potential formedical scientific advances, or even "pioneeringbreakthroughs," frequently either are not or willnot be approved by those who sit on institutionalreview committees. The reasons for these rejec-tions they are especially concerned about do notinvolve the ethical defectiveness of the proposals .

103. Ibid.104 . Ibid.

44

Rather they include local institutional politics andconflicts as well as resistance to innovations justbecause they depart from accustomed ways ofscientific thinking and proceeding . . . (T)o forestallrejections of this kind, the biomedical communitymay have to go beyond the establishment of localappeal procedures by institutions . Perhaps what isnecessary is the establishment of a hierarchy of"courts of appeal" thoughout the nation, culmi-nating, as a final resort, in a "supreme court"composed of eminent peers including both"insiders" and "outsiders" with respect to anyfield. Such a system might be the best safeguardavailable against the object of these concerns-unjustified hindrance of medical progress by thepeer review process . 105

Procedures should be established for appeals to theNational Human Investigation Board .106 After a hearingof the controversy, the NHIB should be empowered tosustain or overrule the judgment of the Protocol ReviewGroup .

Since the NHIB has a role to play in the administra-tion of research, it must employ expert staff to evaluateresearch protocols and to prepare detailed findings . Thisstaff would take over the reviewing function currentlyhandled by DHEW study groups . However, it is beyondthe scope of this report to set forth all the specificfunctions which the NHIB should assume . In particular,we have refrained from deciding how many of theprotocols approved by the PRG's should be reviewedagain by the NHIB . Though a certain number will haveto be examined in order to provide the NHIB withsufficient information to carry out its most importantfunction-policy formulation, it may not be necessaryto review all protocols a second time . This would be atime-consuming task .

3. Review of Decisions and Consequences

The NHIB must create mechanisms for the overallreview of the human experimentation process in order toassess the continuing efficacy of its own policies and ofthe institutional peer group review. Thus, the Board hasto keep itself informed about ongoing research practices,and a number of already esisting resources wouldfacilities this task : scientific journals which publishresearch studies, legal cases in which conflicting claimsabout research have been brought before courts, news-paper accounts (such as the initial reports of the

105 . Barber et aL, supra, footnote 3, at 156-157 . (footnoteomitted) .106 . IHIC's might also find it appropriate to establish an internalappeals procedure . This would be more convenient than, andwould sometimes obviate the need for, appeals to the nationallevel .

Tuskegee Syphilis Study), reports from InstitutionalHuman Investigation Committees, etc .' 07

The NHIB must also establish rules and proceduresfor the direct review by IHIC's and by NHIB staffmembers of ongoing previously approved researchprojects. The current requirement of systematic review0f all projects at fixed intervals is burdensome andinefficient and encourages perfunctory review . Insteadof requiring continuing review of all research projects ona routine basis, it would reduce the burden on IHIC's andmaximize the effectiveness of continuing review ifinvestigators were asked to report immediately anycontemplated or necessary deviations from approvedresearch protocols, all inconveniences and injuriessuffered by any subjects which has not been anticipatedin the original protocol, or any medical advances whichmight benefit subjects and which has not beenanticipated in the original protocol . Moreover, periodic"spot checks" of selected interventions which are nowdiscretionary should be made a requirement. It isapparent that some approved research projects arecarried out improperly . For example, in a recent studyinvolving subjects subsequent to their participation in amedical research project which had been approved by aninstitutional review committee, an interviewer foundthat,

(m)ost of these subjects learned of the existence ofthe study during the interviews done for myresearch. Second, many more subjects (the exactnumber awaits further analysis), while aware ofthe research, has significant gaps in their under-standing of the project and consented on a moreor less uninformed basis . These included womenwho had no knowledge of whether there werealternatives to participation, women who did notknow of the double-blind nature of the study (itwas not part of the research design to withholdthis information), and women who were not awareof the fetal monitoring procedures and extra bloodsamples required by the research . Others were notaware beforehand that their consent to have thebaby observed would be sought by a separateresearcher .' 0 8

107. The NHIB might consider inviting others - for example,editors of scientific journals - to submit for review studieswhich raise ethical questions . Editorial boards should welcomesuch an opportunity, particularly in the light of the recentdebate about the publication of articles based on "unethical"research . Some commentators have favored non-publication,while others have felt that "(s)uch an editorial policy wouldmaintain the low visibility of unethical experimentation andpreclude not only review but also careful and constant appraisalof the conflicting values inherent in experimentation ." (Katz,"Human Experimentation," 275 New Eng . J . of Med . 790(1966)) Journal censorship creates difficult problems . Ifeditorial boards could be assured that violations of "ethical"practice would be dealt with by an authorized body, they mightprefer to call them to the attention of the NHIB and judgeacceptability of articles on the basis of scientific merits .

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Spot checks would determine the extent of noncompli-ance with existing procedures . Should the checks revealwidespread noncompliance, then remedial steps could betaken, such as better education of physician-investigatorsabout their responsibilities, more careful evaluation ofprotocols, or routine monitoring of all research activitiesfor a period of time .

The NHIB should also invite the IHIC's to submittheir most difficult decisions for an evaluation . Signifi-cant cases, inducing the original PRG rulings and thesubsequent NHIB opinions, should be published to givedirection to the deliberation of local committees, toprovide material for scholarly analysis, and to foster andsustain public awareness of the issues raised by humanexperimentation . Indeed, all important decisionsrendered at the local or national level should bepublished and preserved in easily accessible form . Thesecases would serve as precedents for future opinions .Thus publication would be a first step toward thecase-by-case development of sound policies for humanexperimentation . We regard such a development,analogous to the growth of the common law, as the besthope for ultimately providing workable standards for theregulation of the human experimentation process .

Finally, we emphasize again that the review ofresearch decisions and their consequences requires theparticipation of persons representing a wide variety ofsocietal interest and should not be limited to membersof the biomedical professions . It is at the policy-formula-tion and review stages of the human experimentationprocess that "outsiders" have an important role to playby championing individual and societal rights andinterests . Professionals have been trained to pursue othergoals and should not be expected, even if they could, toshoulder the added burden of speaking for the concernsof society .

C. Education

Our last recommendation pertains to the education ofinvestigators, particularly when they are still students,for the responsible practice of human research in ademocratic society. Recently, Senator Jacob Javitsintroduced a bill' 09 in the Senate which addresses itselfto this problem . The bill

would authorize special project grants for medicalschools to develop and operate programs whichprovide increased emphasis on the ethical, social,moral, and legal implications of advances inbiomedical research and technology .

108. Gray, "Some Vagaries of Consent," a preliminary report(1971) on data collected for the author's doctoral thesis,reproduced in Katz, supra, footnote 12, at 660 .109 . S. 974, 93d Cong ., lst'Sess.

The bill . . . provides the opportunity for ourNation's medical schools to develop the appro-priate program curriculums regarding ethical,moral, and social issues to meet the need-theprotection of human subjects at risk in medicalresearch and improved understanding of the con-sequences and implications for the individual andsociety of the advances in biomedical science-andthrough their own initiative and leadership con-struct and appropriate continuing professionalinstitutional activity to safeguard human subjectsin research .' 10

Senator Javits referred to the findings of ProfessorBernard Barber et a l., and to document further the needfor such an educational effort, we quote briefly anotherpassage from their study :

It is clear from our date that medical schoolsare presently giving very little serious attention tothese matters in their curriculum. Of the 307physicians interviewed, only 13% reported thatthey had had a seminar, a lecture or part of acourse devoted to the issues involved in the use ofhuman subjects in biomedical research, and onlyone researcher said that he had had a completecourse dealing with these issues . Thirteen per centof the respondents said that the issues of researchethics came up when as students they did practiceprocedures on one another, and 24% said that theybecame aware of the issues of balancing risk orsuffering against potential benefits when doingexperimental work with animals . Thirty-four percent remembered discussions with instructors or

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other students of the ethical issues involved inspecific research project which they had readabout or learned of in class . But 57% of thephysicians interviewed reported none of theseexperiences, even those peripheral to work withhumans, such as those involving animal experi-mentation .' 1 1

It has sometimes been asserted that the humansubject in experimentation is best safeguarded "by thepresence of an intelligent, informed, conscientious,compassionate, responsible investigator ."' 12 Whatevermerit underlies such a contention, sufficient attentionhas not been paid by educators in all professionalschools to exploring the responsibilities of the profes-sional toward his patients, clients, or research subjects.Without training, even a "conscientious" investigator ispoorly prepared to deal knowledgeably or systematicallywith these problems.

Though in recent years there has been an upsurge inefforts to expose students to the issues raised byprofessional responsibility, considerably more thoughtand support must be given to this work . Professionalschools must recruit faculty members who are interestedin pursuing the complex problems created by humanresearch in particular and contemporary professionalpractices in general. The task is not limited to educatingstudents but must ultimately include a re-examination ofthe entire scope of professional decision-making .

110. 110 Cong . Rec. S 3114 (Feb . 22, 1973)111 . Barber et al., supra, footnote 3, at 101 ;112. Beecher, "Ethics and Clinical Research," 274 New Eng . J .Med. 1354, 1360 (1966) .

VI . CONCLUSION

Human experimentation reflects the recurrentsocietal dilemma of reconciling respect for human rightsand individual dignity with the felt needs of society tooverrule individual autonomy for the common good .Throughout this report we have expressed our concernfor the lack of attention which has been given to theprotection of the rights and welfare of human subjects inresearch. Society can no longer afford to leave thebalancing of individual rights against scientific progressto the scientific community alone . The revelations of theTuskegee Syphilis Study . once again dramatically con-firmed this conclusion .

We offer our far-reaching proposals in the hope thatthe decision-making process for human research willbecome more open and more effectively regulated . Wehave amply documented the need for implementing thismost basic recommendation . Precise rules and efficientprocedures, however, are not by themselves proofagainst a repetition of Tuskegee . For, however well

7S-?5

*U.S . G .P .O . : 1973- 747-022/5334, Region No .4

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designed the system of regulation, the danger of tokenadherence to ethical standards and evasion in the guiseof flexibility will persist . Ultimately, the spirit in whichan aware society undertakes to use human beings forresearch ends will determine the protection which thosehuman beings will receive . Therefore, we have urgedthroughout a greater participation by society in thedecisions which affect so many human lives .

Respectfully submitted,

Ronald H. BrownVernal Cave, M.D .Jean L. Harris, M .D .Seward Hiltner, Ph.D., D .D .Jay Katz, M .D .Jeanne C . Sinkford, D .D.S ., PhD.Fred SpeakerBarney H. Weeks

Abstention :Broadus N. Butler, Ph .D .

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