Accountability in Research, Vol. 7, pp. 283-292Reprints available directly from the publisherPhotocopying permitted by license only

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Is National, Independent OversightNeeded for the Protection of HumanSubjects?Alexander Morgan Capron

University Professor of Law and Medicine,Co-Director, Pacific Center for Health Policy and Ethics,University of Southern California, Los Angeles, CA 90089-0071

Science—which in this century has transformed our world andallowed us to probe everything from the heart of the atom to distantplanets—proceeds not merely from theory but from experimenta-tion. And when the object of science is to understand human beings,eventually humans become the experimental animal of necessity.Regrettably, this century has also taught that in the name of science,men and women—acting predominantly from a genuine desire toadvance knowledge and, more particularly to develop means ofpreventing and curing disease, of lengthening life and relieving itsburdens—have subjected one another to great harm and grievouswrongs.

The focus of this conference is on an area of research that has beenmarked by special problems, and it is tempting to think that it illus-trates the need of vulnerable populations for special protections. Yetin the annals of research with human beings, the category of vul-nerability seems almost limitless. Even putting aside the atrocitiescommitted by the Nazi doctors on their concentration camp victims,the groups who have been harmed and wronged appear all-encom-passing: pregnant women, children, students, farmers, prisoners,members of the public at large, and above all else, patients sufferingfrom every sort of illness. Some have been knowing and willing col-laborators in research; many others were more akin to victims.

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The human costs of research have not gone unnoted but have pro-voked criticism, commentary, and action. While the judgment handeddown by the American tribunal at Nuremberg five decades ago wasnot immediately translated into explicit expectations for Americanresearchers, by the mid-1960s federal officials had laid out the basicframework that still governs research with human subjects. Theiractions seem to have been spurred partly by concerns for the welfareof human subjects such as those articulated by a number of academics(including physicians such as Henry Beecher and Jay Katz, philo-sophers like Hans Jonas, lawyers such as Paul Freund and Bill Curran,to mention only a few of the pioneers) and partly by a desire to stayahead of those who would seize upon instances of harm or abuse asreasons to impose outside controls over the scientific enterprise.

The framework first constructed some 35 years ago has evolved insignificant ways, but its core has been relatively constant, consistingof five features: (1) diffused authority among the federal agenciesinvolved as sponsors of research or as regulators of the products ofresearch, (2) delegated responsibility from these federal agencies tothe institutions that carry on research, largely without anythingmore than "paper oversight" of the adequacy of the institutions'execution of their duties, (3) largely individualized decisionmaking(one might even say ad hoc), based upon the limited guidance giveninstitutional review boards about how to carry out their functions,the absence of any means of "appeal" or indeed any formal, regu-larized method of developing "interpretations" based on case-experience, and the absence of any means of ensuring that the samecommittee reaches consistent decisions about similar protocolsmuch less that committees at different institutions are deciding con-sistently, (4) utilization of a "peer-review" format, in which not solelythe scientific but also the ethical adequacy of research protocols isjudged by a researcher's scientific colleagues, with what is typicallyonly a modest involvement of persons with more independent per-spectives (either not affiliated with the research institution or atleast not from biomedical research), and (5) the limitation of federalrules that results from their origin as contractual conditionsattached to federal support (and later to the need of certain researchsponsors to secure federal action, principally, approval of a newdrug or device by the Food and Drug Administration). I believe thatthese features all need to be seriously examined because, despite theevolution that has taken place regarding all of them, they effectivelyconstrain the effectiveness of our present structure for protecting

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research subjects. The thesis of this paper is that the time has comefor a paradigm shift, not simply evolutionary adjustments of thedetails of the regulations but a new way of developing, promulgating,monitoring, and revising the regulations. To effect a new paradigm,we need to consolidate authority in this field in a new, independentfederal office, linked to but not controlled by research-sponsors.

Perhaps the simplest way to organize these remarks is to focus onwhat the National Bioethics Advisory Commission—which wasestablished by Executive Order in October 1995 and appointed byPresident Clinton the following summer, and which held its firstmeeting just over two years ago—is up to regarding relocating thefederal human subjects regulatory functions. I will begin by illus-trating the need for change by describing the Commission's responseto the last of the five factors I just set forth.

AN ILLUSTRATION: EXPANDING THE REACH OF HUMAN SUBJECTREGULATIONS

Early in its work, in discussing problems with the present regula-tions, the Commission focused on the fact that the federal rules areonly binding for research that is supported by, or whose productsneed approval by, a federal agency. At the time, Senator John Glennwas preparing a bill that would extend the central protections pro-vided by the present regulations to all persons including thoseenrolled in privately sponsored studies. The Commission agreed thateveryone enrolled in research in this country should be affordedthe basic protections of independent review and informed, vol-untary consent. While still at work on how best to achieve such aresult, the Commission formally approved this position in principlein the Spring of 1997 and incorporated it into the report on CloningHuman Beings which we sent to the President on June 9,1997.1

1 Recognizing that the ban on federal support for all forms of embryo research wouldmean that any attempt to apply to humans techniques like those that produced thefamous sheep Dolly would take place in the private sector, we recommended a broadmoratorium. But we also concluded that in the absence of a moratorium, anyresearch trials of human cloning should be "governed by the twin protections ofindependent review and informed consent, consistent with existing norms of humansubjects protection". CLONING HUMAN BEINGS: REPORT AND RECOMMENDATIONS OF THENATIONAL BIOETHICS ADVISORY COMMISSION, Rockville, Maryland (June, 1997), at p. iv.

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I supported this aspect of our report on human cloning, but itseemed to me that in order to mount a convincing case for the largerproposition, we needed a good deal of empirical support to estab-lish that the present system of federal oversight of research actuallyprovides effective protection for human subjects. After all, it is notenough to know that problems have arisen for subjects in privatelysponsored research—a conclusion for which there is substantialanecdotal support. Rather, we need to be able to show that fewerproblems have arisen in research conducted according to the dic-tates of the federal rules.

Yet, as the front page of the May 14,1997 New York Times report-ed, the ability of the federal government's Division of Animal Careto account for "every cat, dog, hamster, guinea pig, chimpanzee,rabbit or farm animal used in a laboratory experiment [for the last31 years] as well as any adverse effects that each animal suffered"stands in stark contrast to the absence of "comparable figures forpeople" who serve as research subjects.2 While Gary B. Ellis, dir-ector of the Office for Protection from Research Risks (OPRR) atNIH took the opportunity of the Times article to highlight that anindeterminate amount of "unchecked human experimentation [is]taking place" in the private sector beyond the reach of the federalhuman-subjects rules, an underlying theme in the article was thatOPRR could not supply data on research falling within its pur-view.

Yet, as I pointed out to the Commission in a memo shortlythereafter, the New York Times article was hardly "news." Thegovernment has known about (and apparently tolerated) thisproblem for many years. In fact, the President's Commission forthe Study of Ethical Problems in Medicine and Biomedical andBehavioral Research drew attention to the need to remedy thisproblem in 1981. In its First Biennial Report on federal policies forthe protection of research subjects, the President's Commissionrecommended that

All Federal departments and agencies that conduct or support researchwith human subjects should require principal investigators to submit, aspart of their annual reports to the IRB and the funding agency, information

2 Sheryl Gay Stolberg, '"Unchecked' Research on People Raises Concern on MedicalEthics," NY Times, 14 May 1997, at A1.

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regarding the number of subjects who participated in each research projectas well as the nature and frequency of adverse effects.3

This recommendation was prompted by the finding, which hadbeen made when the Commission was preparing its earlier reporton Compensating for Research Injuries, "that data on the number ofhuman subjects who participate in Federally funded research arenot routinely and systematically compiled. Data regarding theincidence and severity of injuries that occur in such research are alsonot collected."4 IRB reporting standards, derived from the thenexisting Department of Health and Human Services (HHS) regula-tions, contributed to this lack of information.5

The absence of information on the number of research projectsconducted in various categories (such as exempt, minimal risk, etc.)and the total number of subjects is particularly troubling for two rea-sons. First, as of 1981 the Director of OPRR reported that IRBs hadinterpreted the HHS regulation "to require reporting only adverseeffects not anticipated by the investigator and thus not reflected inthe research proposal and consent documents at the time of the ini-tial review."6 By simply expanding the catalogue of risks in advance,the President's Commission pointed out, researchers could greatly"reduce their obligation to report harm to subjects, even when someof the risks are so improbable that their manifestation would, incommon sense terms, be 'unanticipated.'" Because of this practice, itwas no surprise that under these standards, "only two adverse effectsassociated with HHS-supported research were apparently reportedto OPRR by either IRBs or investigators from 1975 to 1980."7

The experience of the President's Commission is instructive onanother score, namely, the slowness with which the federal bureau-cracy effects change. The central recommendation that the Commissionalso made in the 1981 report—that all departments adopt a "com-mon rule" for subject protection—took a decade to be implemented.The recommendation to collect data on the types of experiments

3 President's Commission for the Study of Ethical Problems in Medicine and Biomed-ical and Behavioral Research, PROTECTING HUMAN SUBJECTS: THE ADEQUACY ANDUNIFORMITY OF FEDERAL RULES AND THEIR IMPLEMENTATION, U.S. Government Print-ing Office, Washington, D.C. (1981) at p. 73.4 Id.5 45 CFR § 46.6(d), 39 Federal Register 18914, 18918 (May 30, 1974).6 Protecting HUMAN SUBJECTS, supra note 2, at 50.7 Id.

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and number of subjects still had not been addressed when the Pres-ident's Commission published its second (and final) Biennial Reporton research protections in March 1983, just as it was closingits doors. Indeed, as the President's Commission noted then, thehope it had expressed in 1981 that the reporting of adverse effectswould be improved—based on ongoing efforts in the VeteransAdministration—were dashed, as "definitional problems were sopervasive that the data collected during the first year of [the VA's]reporting requirement were not useful."8 The President's Commis-sion also noted that the FDA did not have a master list of Institu-tional Review Boards (IRBs), making it impossible to even selectIRBs for routine systematic inspection, much less record the numberof human subjects supposedly monitored by each IRB.9

This brief historical review should suggest the barriers that existto extending the federal regulations to all research studies—not theleast the huge delays that arise in trying to get agency agreement tomodify the Common Rule. This reality—which I mentioned as thesystem's first factor—has been repeatedly emphasized in NBAC'sdeliberations. If we want to get something done, we'd better try foran "interpretation" of the terms of the Common Rule or for a separ-ate "subpart," because it would take years to get the Common Rulemodified since decisionmaking power is diffused among the nearlytwo dozen federal departments or agencies that conduct or fundresearch with human beings.

PROBLEMS WITH DELEGATION, PEER REVIEW,AND AD HOC DECISIONMAKING

Having mentioned the first and last of the five factors, I turn now tothe middle three as they relate to the topic at hand. The second fac-tor—the delegation of responsibility for ensuring regulatory com-pliance to the institutions that are carrying on the research—mayhave been well intentioned when adopted but it is rife with conflictsof interest. This delegation not only makes it hard for OPRR and its

8 President's Commission for the Study of Ethical Problems in Medicine and Biomed-ical and Behavioral Research, IMPLEMENTING HUMAN RESEARCH REGULATIONS: THEADEQUACY ANP UNIFORMITY OF FEDERAL RULES AND OF THEIR IMPLEMENTATION, U.S.Government Printing Office: Washington, D.C. (1983) at p. 23.9 Id. at 57.

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counterparts in other federal agencies to know what is going on butalso reinforces the third factor: the ad hoc nature of decisions aboutprotocols, which are made with only minimal guidance from thefederal regulators and without any formal structure either for high-er review of individual institution's decisions or for sharing (andbuilding on) deliberations at other institutions.10 Finally, the formatfor protocol review by Institutional Review Boards (as prescribed bythe 1974 National Research Act) grew out of the peer-review processused for in-house research at the NTH. Despite the presence of somenon-affiliated members (whose number but not proportion is speci-fied in the Common Rule), IRBs not only have all the deficienciesidentified in the recent Inspector General's report—including toomuch work and too few resources—but conflicts of interest basednot only on the inevitable personal and professional ties betweenthe IRB and the researchers whose protocols are up for evaluationbut also on the interest most IRB members have in their institution'ssuccess in garnering research dollars.

While some of these problems would probably inhere in any sys-tem, the failure to address them and to seek solutions for those thatwould be most easily soluble—such as having adequate data onresearch participation and injuries, aiming for greater communica-tion to and among IRBs, providing means to make their decisionsmore consistent and visible, and introducing more objectivity andindependence into the review process—this failure is noteworthy initself. And it is here that the strands come together, for—as I arguedto my fellow Commissioners at our June 1997 meeting—this failureresults not merely from the diffusion of authority among the federalagencies that sponsor research but from the very assignment ofresponsibility to research sponsors in the first place. In light ofexperience with other federal agencies—such as the Atomic EnergyCommission—it is hardly surprising that those charged with

10 Under § 491 of the Health Research Extension Act of 1985, which updates provi-sions first enacted in the National Research Act of 1974 (including the requirementsof prior IRB review and approval of protocols), the Secretary of HHS is required tohave a "program . . . under which requests for clarification and guidance with respectsto the ethical issues raised in connection with . . . research involving human subjectsare responded to promptly and appropriately." OPRR has not used this provision toestablish a system of "appellate jurisprudence" or even publication of decisionsabout difficult or controversial protocols, which would foster a more nuanced anddetailed understanding of the meaning and application of the Common Rule. OPRRhas, from time to time, sponsored educational programs nationally and regionally.

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promoting a field do not make the best guardians against problemsand abuses. With this in mind, NBAC voted to undertake a study ofthe desirability and feasibility of moving the regulatory functionsnow played by OPRR (and its counterparts) out of the agencies thatconduct or sponsor research and into a less conflicted setting.

THE NBAC STUDY AND A PROPOSAL FOR CHANCE

As an aid to this study, we commissioned three papers: two by bio-ethicists with substantial experience at the NIH and one providingan outside analysis (namely from an academic administrator who isvery knowledgeable about the regulation of human subjects research).The first two papers were intended to take opposing views on thequestion of whether the oversight function should be moved, so it isall the more significant that Charles McCarthy, the long-time dir-ector of OPRR, and John Fletcher, who was the first in-house ethicistfor the NIH Clinical Center, largely agreed on their diagnosis of theproblem and differed only in how far away from NIH they thoughtthe oversight function needed to be moved. Indeed, the tale thatMcCarthy tells from an insider's perspective about just how resist-ant NIH has been to the whole process—to the point of being non-compliant with the very rules that were being applied to the outsideinvestigators it was funding—makes clear that concerns about con-flicts of interest are not mere academic speculation. Furthermore,even when OPRR can cleverly overcome the handicaps inherent inits organizational placement (within the NIH directorate), it facesother bureaucratic weaknesses, such as trying to carry out regulatoryfunctions in an institution (NIH) that sees itself as non-regulatory,or attempting to get cooperation (much less compliance) from othersubunits of its own department (Health and Human Services) thatresist recognizing its authority.

McCarthy and Fletcher differ principally as to where this author-ity ought to be lodged if not with OPRR. McCarthy recommendscreating an Office of Research Ethics (ORE)11 who would have gov-ernment-wide jurisdiction but answer directly to the HHS Secretary,

11 In addition to a Human Subjects Protection Division, ORE would also have divi-sions dealing with laboratory animals and with scientific integrity; my discussionfocuses solely on the first, which McCarthy divides into two branches, Education andCompliance.

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whereas Fletcher would create an independent agency. The argu-ment in favor of the first view is that the human subjects officewould be better protected from bureaucratic and Congressionalinterference if it were under the wing of a powerful Cabinet secret-ary; on the other hand, placing the office in a single department—albeit the one with the largest human subjects research budget—islikely to cause problems when the office needs to get involved withresearch sponsored by other departments or agencies. Moreover,while McCarthy would ensure that the head of the human subjectsdivision would have a separate budget and reporting authority, theoffice would still be a part of HHS, and should the office's activitiesoffend NIH, CDC, or other research sponsors, the HHS secretarymight, understandably, be inclined to give their concerns great weight.

The advantages of Fletcher's recommendation to establish aNational Office of Human Subjects Research (NOHSR) are that itwould give more visibility to human subjects protection and ensurethat the agency was independent of the federal agencies that sponsorresearch. The disadvantages are primarily political: that in an era of"smaller government," Congress would be unwilling to create anew agency and that such an agency once created would be vulner-able to pressure (such as threats of being discontinued if its actionsdiscomfitted a research institution in the district of a powerful Rep-resentative or Senator). This is a risk that exists for all independentagencies. Some protection could be expected to result from the exist-ence of a board of commissioners (drawn from outside government)who would serve as the policymaking council for NOHSR; suchindividuals could defend the Office in the sort of public fashion thatis more difficult for federal employees.

Plainly, such a government-wide Office could overcome the prob-lems of diffuse responsibility (with the attendant difficulties of mak-ing changes in regulations in a timely fashion), and it would also bebetter positioned to draw together the process of interpreting theregulations and developing means to allow a sort of "common law"to help local review boards in applying the Common Rule. I believethat by avoiding conflicts of interest within the federal government,the Office would also be better positioned to find solutions to theconflicts that inhere in the use of the institution- and peer-based IRBprocess. Finally, the creation of such an Office does not mean thatresearch sponsors would abolish their own human subjects protectionoffices (such as OPRR), which would continue to apply the uniformrules to the intra- and extramural research sponsored or conducted

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by their agency, just as each department now has its own ethicsoffice, which operates under the umbrella of the government-wideethics office. By serving this function of providing on-going inde-pendent oversight, NOHSR would not only check the work of theagency offices (just as the National Transportation Safety Boardchecks the work of the FAA) but could also support and buttress theagency offices in their internal struggles with the agencies in whichthey are lodged, which may understandably sometimes regard themas irritants.12

I hope that the National Bioethics Advisory Commission will, inthe coming year, officially endorse the idea of a new government-wide office on human subjects research, for all the reasons I havesurveyed here.

12 On 8 July 1999 (after this article was in press) HHS Secretary Donna E. Shalalaaccepted the recommendation made to her on 3 June 1999 by the Advisory Commit-tee to the Director, NIH, based on the report of the Office for Protection of ResearchRisks Review Panel, that OPRR be relocated in the Office of the Secretary. She alsoaccepted the committee's recommendation that an independent advisory committeebe established to provide scientific and ethical guidance to OPRR in its oversight role.Secretary Shalala also directed that the position of OPRR director be upgrade toSenior Executive Service level and that the resource needs of the office be reviewed aspart of the relocation. See HHS Fact Sheet, protecting Research Subjects, U.S. Depart-ment of Health and Human Services, July 8, 1999.