Location of the Office for Protection from Research Risks Within the National Institutes of Health: Problems of Status and Independent Authority

Author(s): John C. Fletcher, University of Virginia

Introduction
Moral and Political Reflection on the U.S. System to Protect Human Subjects
Location of OPRR: Impact on its Mission
Lessons from Other Regulatory Agencies
Recommendations
Attachment 1
Attachment 2
Footnotes

Introduction

Task and Methods. The task is to examine the location of the Office for Protection from Research Risks (OPRR) within the National Institutes of Health (NIH) and its effects on the mission of the Office. Recommendations will accompany the findings.

The issue of location is conceptually related to OPRR's mandate, the institutional histories of OPRR and the NIH with regard to human subjects research (HSR), and the general performance of the U.S. system for protection of human subjects of research (HSoR).1 These themes will be addressed in the report, although the discussion will mainly address the location issue.

In addition to literature on the strengths and weaknesses of other federal regulatory agencies, the author reviewed the history and present mandate of two federal bodies with similar missions and past problems of conflicts of institutional interests: 1) the Office of Government Ethics (OGE) and 2) the Nuclear Regulatory Commission (NRC).

Interviews

  • September 4, 1997 (telephone) Charles R. McCarthy, former Director, OPRR
  • September 11, 1997 (on-site, 10:00 A.M. - 3:00 P.M.) Gary B. Ellis, Director, OPRR J. Thomas Puglisi, Human Subject Protections, OPRR
  • September 25, 1997 (telephone) Alexander M. Capron, Professor of Law, University of Southern California
  • September 30, 1997 (telephone) James P. O'Sullivan, Associate General Counsel, U.S. Office of Government Ethics
  • September 30, 1997 (telephone) J. Samuel Walker, Historian, Nuclear Regulatory Commission
  • October 3, 1997 (telephone) Richard A. Merrill, Professor of Law, University of Virginia
  • October 5, 1997 (telephone) Jay Katz, Professor Emeritus, Yale University
  • October 17, 1997 (telephone) Robyn Y. Nishimi, Ph.D., Director, Presidential Advisory Committee on Gulf War Veterans' Illnesses
  • October 20, 1997 (telephone) Mary Ann Dufresne, Staff Aide to Sen. Glenn
  • October 22, 1997 (on-site, 10:00 A.M. - 12:00 P.M.) Gary B. Ellis, Director, OPRR F. William Dommel, Director of Education, OPRR
  • October 27, 1997 (telephone) Richard Riseberg, Chief Counsel, Public Health Service
  • November 10, 1997 (telephone) James H. Jones, Professor of History, University of Houston

Executive Summary and Major Findings

A. On the Location of OPRR in Government

1) OPRR's location within the NIH is a structural conflict of missions and incompatibility of functions. This structural conflict gives rise to several troubling and persistent problems, including conflicts of interest, for the professional staff of OPRR and the NIH officials who administer OPRR.

The report's arguments are based on these points and findings:

  • OPRR's mission is to uphold the primacy of the rights and welfare of HSoR. This mission is enveloped within the NIH's scientific mission and its powerful interests in funding and conducting research. This conflict of missions weakens OPRR's authority and stature and engenders conflicts of interest.
  • The most compelling evidence of conflict of interest is that OPRR is far more effective and authoritative in regulating grantee institutions than Department of Health and Human Service (DHHS) agencies.
  • The NIH is in the implausible position of regulating itself. Internally, the NIH leadership suffers from institutional blindness to the structural problem and the issue of conflict of interest. Externally, the NIH suffers a credibility problem. Others, such as the General Accounting Office (GAO), the Human Research Ethics Group, and this observer, clearly see a conflict of missions that lead to conflicts of interest. The NIH leadership neither acknowledges nor moves to remedy the situation. In that the NIH is an agency of the DHHS and part of the Executive Branch of government, the White House and DHHS have the ultimate responsibility for the problems that weaken OPRR and its mission in HSR.
  • An inappropriate location for OPRR imposes burdens that weaken the entire system, e.g., reduced status and lack of respect, political pressure from the NIH requiring problematic compromises, and inordinate time and effort to correct noncompliance and other significant problems.
  • OPRR's present location is entirely inappropriate for any future system of universal protection of human subjects as envisioned by Senator Glenn and other sponsors of federal legislation, the Advisory Committee on Human Radiation Experiments (ACHRE), the Human Research Ethics Group, or the National Bioethics Advisory Commission (NBAC) itself.2
  • The history of two other national agencies offers relevant analogies and remedies: the NRC and the OGE.

B. The U.S. System of Protection of HSoR Has Significant but Remediable Problems

  • 1. Federal legal protections exist only for HSR that is a) conducted or supported by any of 17 Federal Departments or Agencies that adhere to the Common Rule or b) regulated by the Food and Drug Administration (FDA). A substantial volume of HSR occurs beyond the perimeter of those protections;
  • 2. Sanctions are inadequate for violations of federal regulations to protect HSoR;
  • 3. No permanent national forum exists for informed debate, continuing interpretation, and application of ethical principles and rules for HSR, consideration of problematic cases, or formulation of policies to meet new needs;
  • 4. OPRR, the federal office for oversight of human subject Assurances representing approximately 5,000 domestic and foreign institutions and for consultation with 17 Federal Departments or Agencies that conduct or sponsor HSR, is now severely undersized and compromised in effectiveness, given the magnitude of its oversight of HSR activities within its current authority. If there were universal protection of HsoR, the current OPRR would be totally inadequate to the task.

Recommended Remedies:

For A.1, B.3, and 4: Elevated status, independent location, and adequate funding for a successor to OPRR: the National Office of Human Subjects Research (NOHSR) along with a National Advisory Committee for Human Subjects Research (NACHSR).

For B.1 and 2: Federal legislation that confers the protections of informed consent and Institutional Review Board (IRB) review for all HSoR, with appropriate sanctions for violators.

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Moral and Political Reflection on the U.S. System to Protect Human Subjects

A. Moral Reflections

1. How Vigorously Should Society Protect HSoR?

Answers to this question depend on ethical perspectives on the status of research. Given society's major goals and interests, is there a defensible moral imperative to conduct biomedical research and human experimentation? Is there a moral obligation - arising from the needs of society and the social contract with its members - for biomedical scientists to conduct research and for persons who are sick or well to participate in it? Does society have ìrightsî in human experimentation that it should claim to procure knowledge to save lives and reduce the incidence of disease? McDermott argued for a strong version of such a position in the 1960s.3 If his argument prevails, then the reasons for society to protect HSoR are weaker than reasons that flow from a different moral argument.

Jonas saw no moral duty to conduct research and especially HSR. Contrary to McDermott and other scientists who argued for the moral priority of society's need for knowledge to struggle against death and sickness, Jonas defended the dignity of the individual over the advance of knowledge. He wrote that social progress through medical progress is an 'optional goal, not an unconditional commitment.'4 His words capture the moral sense that, in my view, deserves the stronger loyalty in this debate. Jonas wrote: 'Let us also remember that a slower progress in the conquest of disease would not threaten society, grievous as it is to those who have to deplore that their particular disease be not yet conquered, but that society would indeed be threatened by the erosion of those moral values whose loss, possibly caused by too ruthless a pursuit of scientific progress, would make its most dazzling triumphs not worth having.'5 Higher loyalty to the dignity and welfare of HSoR ought (almost always) to prevail over loyalty to the cause of science and the needs of society for knowledge, relief of suffering, and cure and prevention of disease. The origin of this loyalty is respect for persons and their capacity for expressions of altruism and sacrifice - the ideal (although rarely the actual) moral source of participation in research. As Jonas pointed out, society has no special claim or command over the altruism and sacrificial gifts of subjects of research, especially those who are sick. Conscription for research is unethical in any society. The ìyesî to participate in research is one that only the individual or a legally authorized representative has the authentic moral capacity to give, despite all of the other real influences on subjects - motivation, including financial inducements and physicians - recommendations.

The caveat of ìalmost alwaysî above recognizes those periods in social life when morally justified wars and national emergencies can lead to troubling degrees of relaxation of normal moral boundaries for the sake of survival. Even on these extraordinary occasions, however, there should be no involuntary experimentation on members of the armed services, prisoners of war, or otherwise incarcerated research subjects. At such times, some degree of secrecy about specific research projects may be required to protect the national interest. Even in this special context, all HSR in secret or protected projects should still have the twin protections of prior review and informed consent.

U.S. law and regulations on HSR fall far short of the moral ideal, in that legal protections are extended only to subjects who participate in certain federally funded or regulated projects. Universalizing the scope of legal protection, as has now been done by the 21 member countries of the Council of Europe,6 is now a moral imperative for the U.S. Congress. A large and unknown number of human subjects are at risk in research projects funded through the private sector. The nations belonging to the Council of Europe have implemented the first truly international legal protection of all human subjects.

Higher loyalty to the welfare of HSoR does not mean that no loyalty at all is owed to science's quest for truth or to the needs of society to reduce and prevent disease. There is an important right of scientists to seek knowledge that can be infringed rarely and with a compelling public interest as the test. This right is constitutionally grounded in the right of 'free speech.'7 There is at least a nonbinding civic obligation (but not a stringent moral duty) for members of modern and democratic societies to support scientific investigation and to participate if able in research conducted within prevailing ethical and legal norms. This civic duty arises from the value of science to democracy and from a shared commitment to resolve significant social and scientific disputes by evidence rather than ideology.

Rather than a sharp 'either-or' division of loyalty that places all moral weight on protection of HSoR and none on any other related cause or claim, it is practical to recognize a hierarchy of loyalties in research activities. Loyalties are owed, in this order, to 1) protection of HSoR, 2) protection of scientific and academic freedom, 3) commitment to meeting society's needs for biomedical knowledge, and 4) concern for the welfare of particular research institutions and investigators. Such a hierarchy of loyalties underlies the author's views and recommendations of this report. The societal obligation to protect HSoR is higher than the other three, but it is also morally justifiable to be loyal to the other claimants when doing so does not override and unjustifiably infringe loyalty to protecting HSoR.

The guiding moral premise of this report is that Congress originally created the mandate that was delegated to OPRR out of fidelity to higher loyalty to the protection of HSoR. However belated this recognition by Congress in 1974, it is the moral core of OPRR's mission. Further reasons to protect human subjects arise from three realities of HSR: 1) HSR is mainly for the benefit of society and the medical sciences, 2) HSoR are vulnerable - they frequently volunteer with motives driven by a 'therapeutic misconception'8 that research will benefit them as well as trust in their physicians who refer or recruit them, and 3) the motivation of physicians who are also investigators studying their own patients is extremely complex and vulnerable to internal and external influences that can run counter to the welfare of the subjects - e.g., competition for scarce funding, career advancement, and financial inducements to enter patients into studies.9

B. Political Reflections

1. The Mandate of OPRR

Congress amended the Public Health Service Act (July 12, 1974) with Public Law 93-438, the National Research Act. This law directed the Secretary, DHEW, to 1) promulgate regulations regarding IRB review and institutional Assurances, 2) establish a program of ethical guidance, and 3) establish a process for responding to violations of the rights of HSoR. The second item was handled by OPRR's predecessor, the NIH Institutional Relations Branch, and was formally delegated by the Secretary to OPRR. OPRR is thus the DHHS-wide authoritative voice on clarification and guidance on ethical issues. The first and third items have always been done exclusively by OPRR.

2. The U.S. System of Protection of HSoR

Turning attention to the U.S. system of protection of HSoR and to OPRR's place within it, a very mixed picture of strengths and weaknesses emerges. Justified pride is due in that the United States was the first nation to extend legal protection for HSoR in federally funded research. A vast and very diverse network of IRBs, estimated at between 3,000 and 5,000, has evolved. These IRBs serve as the nation's primary resource for the protection of HSoR by examining the ethical aspects of a project before it begins. A morally valid process of informed consent to the particular research project is the second major resource to protect HSoR.

IRBs and their authority have gradually been accepted by clinical investigators with rare exceptions. However, the nation's IRBs have well-known problems, such as poor relationships to their local communities, inadequate education and training for members, inadequate scientific expertise, misallocation of effort to assure scrutiny of studies carrying greatest risk, poor quality control of reviewer performance, poor performance in continuing review, and little first-hand exposure to the context of clinical investigation and specific studies.10 These problems need attention within cooperative efforts between the local and federal partners in the enterprise. In my view, significant improvements will not occur without a national strategy, adequate funding incentives, and a strengthened successor to the OPRR, which is charged by Congress with the role of education and IRB welfare. Small staff and other pressures greatly limit OPRR's role and effectiveness in IRB education and oversight as compared to its role with Assurances and compliance.

Nishimi's testimony11 captures the history of the U.S. system of protection of HSoR. She explains that the approach that the federal government employs to protect HSoR is intentionally decentralized and diffused. The structure of the current system has changed very little from the approach set out by the 1966 Public Health Service (PHS) guidelines. Local review has been the centerpiece of protection, based on the belief that a local group of relatively disinterested individuals is most desirable because they are in the best position to know the prevailing values and ethics of the community and proposed subject population. At the NIH from 1966 - 1969, the author witnessed the earliest stage of the PHS regulation of HSR. The NIH leadership believed that local review coupled with a very modest NIH-based oversight mechanism would suffice. In 1982, the author interviewed Dr. James Shannon, former Director, NIH, and other NIH and PHS officials about the main features of the Surgeon General's policy and their memories of the need for it.12 Dr. Shannon stated, ìNone of us wanted a bureau of ethics in Bethesda. Local prior group review was the linchpin of the policy.î Despite the wish of Dr. Shannon and others, the OPRR, if not a bureau of ethics, is the sole official voice and continuing presence within government with a priority of protecting HSoR. The OPRR is inadequate, for several reasons, to do this task within its current mandate. Problems arising from location contribute to this condition. The NIH exercises a dual role to promote and regulate HSR. Although the NIH's problem is far less dangerous, there is a historical analogy in the Atomic Energy Commission's (AECs) failure from 1951 - 1973 to hold together both the promotion of nuclear energy and regulation of its uses. DHHS and Congress should face and resolve a persistent conflict of missions and interests between the NIH and OPRR.

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Location of OPRR: Impact on its Mission

A. Historical Background on HSR and the NIH

The argument in this report is that structural conflicts of mission between OPRR and the NIH engender conflicts of interest for OPRR's staff and NIH officials. How does this report use the term 'conflicts of interest?' In his discussion of this topic in the context of health care, Erde first describes an 'artificially narrow account' of a conflict of interest, i.e., 'conflicts of interest occur when and only [when] a [physician] strays or is tempted to stray from...role mandated duties for the sake of...economic benefit.'13 Erde goes on to discuss a much broader range of causes (e.g., motives, situations, and structures) that may or may not influence conflicts of interests. This report seeks an understanding of conflicts of interest informed by Erde's broader discussion, e.g., in this situation - for regulators (at OPRR) and for funders and sponsors of HSR (at the NIH) - conflicts of interests are either ìmotives that [regulators or funders/sponsors] have and/or situations in which we could reasonably think...[their] responsibilities to observe, judge, and act according to the moral requirements of their role are or will be compromised to an unacceptable degree.î14 The next several parts of the report provide historical background and data to support the argument.

1. Historical Background

A brief historical background should preface a discussion of OPRR's location. The history of NIH's role in the protection of HSoR can be evaluated from different standpoints. Viewed from within the NIH, there is much in which to take pride. From 1953, a form of prior group review at the Clinical Center, NIH, was an early predecessor of IRBs. The NIH leadership responded in the early to mid-1960s to social and media criticism of a lack of protection of HSoR and to the legal risks to clinical researchers.15 As described below, the NIH's intramural leaders continued to improve a very effective research review system from 1966 to the present. The NIH also helped to staff and support the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974 - 78), whose work developed consensus and a foundation for a systematic ethical perspective and body of ethical guidance on HSR. The work of the Commission, especially on research with children, had immediate effects within the intramural program. The NIH also funded and housed the OPRR to the present time.

From outside the NIH and the PHS, critical questions can be raised about the HSR record of the nation's major funder and sponsor of biomedical research. One finds at different periods examples of 'institutional blindness' to HSR issues,16 to congruence of public accountability between the NIH's intramural and extramural programs, and to the OPRR's legitimate authority. The first two examples are preludes to a condition of institutional blindness to the conflict of interests issue embedded in OPRR's location within the NIH.

a. Early History of NIH-PHS and HSR: How Could the Tuskegee Study Have Endured So Long?

The founders of the NIH's intramural program, which began when the Clinical Center opened in 1953, were very conscious of their moral responsibilities in HSR. Accordingly, they created and continued to improve forms of prior group review suited to the requirements of the intramural program. These efforts from 1953 - 1977 are described below. In this period, there was a greater degree of protection for normal volunteers and patients in research carrying higher risk than for patients in research with lower risks or who were being followed and studied in experimental conditions. The ethos of these years was also grounded in deep commitments to scientific freedom and flexibility for researchers to follow the implications of their discoveries with particular patients. It is important to remember that, in this period, there was no systematic body of ethical principles and guidance for HSR. As in the wider research community,17 the norms of the NIH culture permitted wide latitude with regard to informed consent and did not require prior group review of each research project with patients or of a single experiment involving one or a few patients.

In the 1950s and 1960s, the NIH was a relatively new agency where streams from two research cultures and one research bureaucracy met, but with apparently little creative or critical interaction. The first was an older pre-WWII research culture marked by a few general moral norms and an overriding degree of ethical relativism. It was this culture that created and supported the PHS-Centers for Disease Control (CDC) Tuskegee syphilis study from 1932 - 1972. The second was a post-WWII and post-Nuremberg research culture. It was marked by high commitment to the best science, to informed consent (tinctured heavily with flexibility and the therapeutic privilege), and to new forms of prior peer review of proposed research. The founders of the intramural program were largely members of this second culture. A third stream, a research bureaucracy with written ethical requirements on HSR, grew up around the NIH's extramural grants and contracts program in the 1960s. The 1966 and 1971 PHS-NIH policies requiring local IRBs and prior group review were required of grantees and contractors in this program.

A question deserving of more historical research arises as to whether the principals in these three arenas seriously discussed ethical issues among themselves. If they did so, it was without much perspective on the implications that strong commitments to post-Nuremberg research ethics within the intramural program had for the extramural program or for earlier research (e.g., Tuskegee syphilis study) being conducted by PHS and CDC physicians. If one hypothesizes great social distance between these three arenas, and such could be demonstrated, it would help greatly to explain subsequent events.

How else could the most dramatic example of institutional blindness to HSR issues in the history of the PHS-CDC be explained? Jones18 describes the mid-1960s confrontation of PHS and CDC officials about the Tuskegee study by Peter Buxton, a PHS venereal disease interviewer and investigator. These officials19 could find no ethical reasons to criticize or halt a longstanding (1932 - 1972) Tuskegee study of untreated syphilis, even after the discovery of penicillin. The depth of blindness and resistance to Buxton's moral claims can also be measured by two factors. First, awareness of the civil rights movement should have focused PHS's concern on the fact that all the subjects were black and totally uninformed.20 Second, it is also striking that the officials' resistance to Buxton's criticisms occurred at exactly the same time that the PHS-NIH was requiring prior group review of HSR in response to other famous cases, scandals, and Dr. Henry Beecher's historic article.21 In fact, the PHS-NIH requirement of local prior review grew directly out of a decade of experience in the NIH intramural program. Did the right hand (PHS-CDC) know what the left hand (NIH-extramural/intramural) was doing? More historical research is needed to answer this question and to explain the reasons for such profound silence about the implications of post-Nuremberg ethics, as practiced at the intramural NIH, for evaluation of the Tuskegee study.

b. Applying Federal HSR Regulations to NIH's Intramural Program

A second but less dramatic example of institutional blindness is a ten-year (1971 - 1981) period in which federal regulations incongruently applied to extramural grantees and contractors but not to the intramural research program. In government generally prior to this period, there was institutional blindness and a slow learning process as to the need for reforms in HSR ethics.22 The learning process within the PHS and the NIH was provoked by crises that sparked reforms and resulted in more NIH commitment to bioethics.

In 1966, PHS promulgated a Surgeon General's policy requiring local prior group review of all grant applications to PHS to involve human subjects.23 The 1966 policy was revised in 1971 ('the Yellow Book') to require IRBs to have outside members who were nonscientists. However, this policy did not apply to the NIH's intramural research at the Clinical Center. The policy was translated into federal regulations in 1974. Notably, the 1974 federal regulations requiring IRBs24 stated:

46.1 Applicability

a. The regulations in this part are applicable to all Department of Health, Education, and Welfare grants and contracts supporting research, development, and related activities in which HSoR are involved.

The regulations did not apply to NIH's intramural program until the 1981 revised regulations25 were published, but with a loophole to provide flexibility:

46.101 To what do these regulations apply?

(a) Except as provided in (b) of this section (i.e., categories of exempted research), this subpart applies to all HSR conducted by the Department of Health and Human Services and funded in whole or in part by a Department grant, contract, cooperative agreement or fellowship.

(1)This includes research conducted by Department employees, except each Principal Operating Component head may adopt such nonsubstantive, procedural modifications as may be appropriate from an administrative standpoint.

In 1991, Subpart A of the regulations was extended by the Common Rule to apply to all HSR conducted, supported, or otherwise subject to regulation by any Federal Department or Agency.26

In 1993, Congress finally closed the gap by specifically requiring all research conducted by the NIH be subject to IRB review:27

Section 492A (a) Review as Precondition to Research
  1. '[requirement of prior IRB review of all applications to the Secretary for financial assistance to conduct research']
  2. In the case of research that is subject to review under procedures established by the Secretary for the protection of human subjects in clinical research conducted by the National Institutes of Health, the Secretary may not authorize the conduct of the research, unless the research has, pursuant to such procedures, been recommended for approval.

What explains this long period of incongruence and differences of public accountability to federal regulation? Three factors influenced this delay. The first factor was that the source of leadership for reform of research ethics in the mid-1960s as well as the substance of that reform arose from within the NIH and was promulgated outward for grantees and contractors. NIH officials, especially Dr. James Shannon, led the response to widespread evidence of abuses of HSoR and fashioned the requirement of local prior group review as U.S. public policy.28 Dr. Shannon and the Surgeon General, Dr. Luther Terry, presented the arguments for this policy to the National Advisory Health Council in September 1965.29 It did not occur to them to require prior group review intramurally because it was already being done. Later, directors of the NIH and leaders of the intramural program in the period 1971 - 1981 probably did not believe that the regulations should apply to them because they were already highly self-regulated and believed that they were doing what the regulations required. In truth, a great deal had been done.30

1) Protection of HSoR Within the NIH Intramural Program

When the Clinical Center opened in 1953, a document had been prepared, based on extensive discussion, requiring 'group consideration' of clinical research procedures that 'deviated from acceptable medical practice or involved unusual hazard.'31 A Clinical Research Committee (CRC) was organized as a subcommittee of the Medical Board of the Clinical Center. The CRC was designed as an ìexpert bodyî to deliberate scientific and ethical questions in research proposals that were referred to it. Between 1953 and 1966 three types of research were required to be referred to the CRC: research with patients involving unusual hazard (1953), research with normal volunteers (1954), and purely investigational (nontherapeutic) research with patients (1961). The director of the NIH exercised second-level review of normal volunteer studies. Also, from 1953, internal Clinical Center staff who volunteered for research had to meet written consent requirements.

Prior to 1966, NIH intramural leaders changed policy and procedures to ensure more protection of HSoR. In 1964, an ad hoc committee was appointed by Dr. Jack Masur, Director of the Clinical Center. The group was charged with the evaluation of practices in group review and informed consent since the 1953 document. Led by Dr. Nathaniel Berlin, the National Cancer Institute (NCI), the committee did a major study of the existing system and interviewed each clinical director and many senior investigators. Its recommendations were adopted in July 1966, and prevailed until further revisions were made in 1976 and 1977.

The specific change was to require review bodies (CRCs) within each institute. These bodies were charged to review patient research that fell outside the boundaries of accepted practice. The institute CRC or clinical director could refer a controversial project to the medical board's CRC. Written informed consent was required only of normal volunteers. Patient consent could be given verbally with a note in the chart by the responsible physician. All normal volunteer studies remained under the aegis of the medical board's CRC.

Federal regulations of 1974 led to a response from the intramural program and more changes in 1975 - 1977. All patient and normal volunteer studies were centralized in a two-level system of review.32 The official review bodies in each institute were renamed Institute Review Subpanels,33 and their membership enlarged to include a richer mix of scientists and nonscientists from outside government. The author served as an outside member on a Subpanel at the NCI from 1975 - 1977. After 1977, I was responsible for helping NIH intramural officials to complete the process of shaping the Subpanels.

The drafters of the 1974 regulations were NIH officials whose attention was aimed at reducing research risks in the extramural program.34 Under congressional pressure, the 1974 regulations were hurriedly constructed. Little attention was devoted to bringing the intramural research programs under the regulations, because intramural research was not covered in the 1971 policy that served as a model for the regulations. These officials were also confident that the intramural program was reasonably well regulated.

Pressure for congruence of applicability of the regulations began to mount in the mid-1970s due to OPRR's mandate and influences of the work of the National Commission on the intramural program. The revised 1981 regulations created congruence (with a loophole), and the intramural program's Assurance was negotiated and approved by OPRR in 1981.

2) Protection of the NIH Intramural Program

A second factor influencing a degree of institutional blindness to the incongruence was the prominent and protected environment of the NIH intramural program in this period. One must assume efforts by NIH's directors to protect scientific freedom and flexibility in the intramural program, as well as their belief that its internal practices of peer review were sound. Flexibility and freedom from restrictions on research were prized values. Many research ideas were born by experimentation and observation in a single patient. Regimentation of almost any kind was considered an anathema.

The first three years of the author's service in the intramural program (1977 - 1987) were marked by challenges to a long tradition of freedom from external oversight and treasured flexibility in research practices.35 The areas of sharpest conflict were over

  1. complaints from patients and family members about lack of informed consent,
  2. the obligation to seek informed assent of children to research or major medical procedures,
  3. disclosure of psychologically sensitive information to patients,
  4. changing protocol strategy in midcourse without Subpanel permission,
  5. conflicts of interest in Subpanel review of protocols of Scientific and Clinical Directors of the Institutes,
  6. testing normal volunteers for psychopathology,
  7. and complaints of pressure on normal volunteers to complete studies.

At this time, there were internal struggles between advocates of NIH's past and advocates for change. Many intramural officials felt strong pulls from both sides. The former argued for a type of 'ethics exceptionalism' allied with the strong research culture. NIH scientists and officials with careers spanning the 1960s and 1970s tended to view their roles and mission as exceptional. They also viewed subjects' participation in clinical research largely as beneficent, in part due to the quality of medical care received. Also contributing to this view was the fact that the costs of research and patient care were borne by the federal government, including patient and family travel costs and housing. Advocates for change appealed to the larger claims of social movements, of values that informed legal issues in medicine, and of bioethics as a discipline. The work of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research (1980 - 1983) made a strong case for these claims bearing on the practice of medicine. The work of the President's Commission had effects in the intramural program. The same officials who wrote the 1974 regulations had been strongly influenced by the work of the National Commission and the President's Commission. They saw the imperative for congruence of public accountability between the two programs and effected it in 1981.

3) Social Distance Between Extramural and Intramural

A third factor was the social distance between intramural and extramural programs described above. Each program had different leadership who rarely talked with one another. Neither wanted to be governed by the other. Failure of intramural leaders to communicate with extramural leaders was a significant reason, among others, why the protection of HSoR was not extended to the intramural program.36

B. Problems and Conflicts Linked to OPRR's Location

1. OPRR's Authority and (NIH's) Institutional Blindness to Conflicts of Mission and Interests

OPRR's authority to require Assurances derives from the 1974 Act, which formalized the practice of obtaining written Assurances from DHHS-funded research institutions of their commitment to the ethical conduct of research. Before the 1974 Act, NIH had already developed such Assurance documents with many research universities, which were reviewed by OPRR. Even today, approval of an Assurance does not involve a site visit but reviews of paperwork and telephone discussions.

OPRR's Assurances are of several types. MPAs pledge compliance for all federally funded projects as well as a voluntary pledge regarding compliance in the context of privately funded research. Renewals are for a five-year period. OPRR currently has 448 MPAs with 756 entities. At non-MPA institutions, a Single-Project Assurance agreement must be negotiated with OPRR for each individual study. OPRR must negotiate each of these agreements as well as approve the consent document. OPRR today is holding approximately 3,000 active Single-Project Assurances. There are also cooperative project Assurances for large multiple site studies. Today, OPRR has more than 1,500 active cooperative project Assurances.

The NIH is an MPA holder with the OPRR. OPRR is the authority for assessing the NIH's compliance with federal regulations to protect human subjects. There have been longstanding concerns about the independence of OPRR and its ability to oversee the NIH itself, especially the NIH's intramural program. The GAO report to Senator Glenn cited above pointed to ìa potential weaknessÖbecause NIH is both the regulator of human subjects protection issues as well as an institution conducting its own human subjects research. The Director of NIH, therefore, has responsibility for both the success of NIH's intramural research program and for the enforcement of human subjects protection regulations by OPRR.î37 The GAO report was also critical of the fact that it took the NIH five years to respond to compliance violations in the intramural program as noted by OPRR in 1991.

A recent report of the Human Ethics Research Group of the University of Pennsylvania recommended that ìthe placement and role of the (OPRR) in the regulatory system should be reassessed.î The report stated:

The primary mission of the federal regulations is to protect research subjects. One important obstacle to reform in this area is structural: The agency charged with enforcing and interpreting the regulations, the OPRR, is part of a larger bureaucracy that is also its major client and one of the nation's leading sources of research funding, the NIH. As a matter of principle, the agency should not be located within the structure of any government funder, and its charter should specify that it is independent. Obviously, the agency would have to continue to be accountable to the professional and lay constituencies which its serves, and a suitable reporting structure would have to be devised.38

Dr. Harold Varmus, NIH Director, denied any conflict of missions or institutional interests. He wrote in response to the GAO report, ìIn fact, the OPRR oversees and interacts with the NIH just as with any extramural institution.î39 Dr. Varmus argued that there was no weakening of OPRR's independent oversight and authority, because 'the lines of authority of the NIH Deputy Director for Intramural Research and the OPRR Director do not cross within NIH.' He also attributed the five-year span to resolve the violations to 'the complexity of fully implementing the corrective actions rather than a function of weakness in the OPRR's ability to enforce human protection regulations within the NIH organizational structure.' Dr. Varmus did not discuss the nature of the 'complexity' or address the proposition that the NIH was demonstrating by its behavior the basic conflict of institutional interests. His answer to GAO's critique was essentially that it was resolved internally as a matter of lines of authority. The GAO report rightly reiterated before closing, 'We disagree with NIH's conclusion and believe that a potential weakness exists in OPRR's ability to enforce human subject protection regulations within NIH.'40

Representative Shays (R-Conn) questioned Dr. Varmus at a recent (May 8, 1997) hearing of a House subcommittee on the conflict of interest issue in regard to the location of OPRR at the NIH. Dr. Varmus responded, as reported in The Blue Sheet:

It is important to remember that the office (OPRR) does not have any vested interest in seeing the research go forwardÖ.The research is being funded by CDC or the institutes, each of which has its own authorization and its own appropriation and it is the institutes that are responsible for funding the studies, so there really isn't any conflict of interest.41

If Dr. Varmus was correctly quoted, this answer evades the basic question of conflict of missions and interests between OPRR and NIH by focusing on funding as the causative factor of conflicts of interest. The fundamental question is whether OPRR is less than effective, due to pressure from conflicts of interests, by being located at the NIH. In my view, the GAO's term 'potential weakness' as applied to OPRR's ability to enforce the regulations within the NIH is more accurately termed a 'past, present, and persistent weakness' due to location in a powerful parent organization that, in effect, looks down on OPRR, rather than respecting its authority and moving quickly to correct violations.

On behalf of human subjects, OPRR as the enforcer of federal regulations can use requirements for IRB review and informed consent to reduce excessive risks. However, when it comes to confronting powerful political and bureaucratic interests, OPRR's power on behalf of human subjects is greatly limited by its location and identity as an office of the NIH. OPRR does not, as a matter of fact, have effective and independent oversight over NIH's intramural or extramural programs, nor the research programs of other DHHS agencies, e.g., the CDC or the FDA, on the relatively rare occasions when it conducts or sponsors research. The records and documents that I have examined, while confidential in many details, strongly support this finding.

The tools that OPRR has developed in order to gain compliance from other institutions are:

  1. fear of loss of funding,
  2. respect for OPRR (the office/the authority),
  3. respect for the primacy of human subjects protection,
  4. and fear of bad publicity.

The first tool is utterly useless in PHS agencies, since funding for the agencies is assured and self-administered. The second tool is greatly diminished in PHS agencies, because they perceive OPRR as a small and weak office within the NIH. Respect for the primacy of HSoR protection is missing to an often startling degree in PHS agencies, as evident in recent documents which I have examined. Taken all together, OPRR lacks the political capital to

  1. impose serious measures
  2. and to move an agency quickly towards correction of problems, especially when CDC or NIH performance regarding compliance is a subject of scrutiny.

Specific Examples:

The following are specific examples of problems posed by OPRR's location:

  1. Burdened policy and rule-making process. Proposed changes in rules or regulations must be vetted by officials at a minimum of 11 sign-off points within the NIH bureaucracy, even before moving out to PHS and DHHS levels.42 Each one of these levels of bureaucracy has its own vested interests in funding of science, in a scientific mission, or in an aspect of NIH-related activity. The process of consideration of rules and policy changes regarding protection of human subjects is subjected to multiple sets of vested interests in an institution that is supposed to be regulated by OPRR.
  2. Resources. OPRR's resources (i.e., funding and staff) have remained static for years, despite growth through the 1980s and 1990s in appropriations and a concomitant increase in volume of proposals for biomedical and behavioral research sponsored by the NIH. OPRR is currently funded at $2 million with 22 staff members who devote some or all of their time to HSoR protection and another eight staff members devoted to animal welfare. That figure includes two volunteers and a consultant who have been recruited to the workforce. Congress itself, not the agency that would have to divert funds that it might wish to expend for other purposes, is the proper body to assess the funding and staffing needs of a national agency for oversight of human subjects.
  3. Climate and morale. The performance of OPRR employees and promotions and awards are assessed by officials in an agency responsible for a scientific mission that houses OPRR. Although the performance of any OPRR director and his or her small staff may be outstanding, considered within the circumstances and pressures within which they work, the decisionmaking climate and morale are too dependent on concern about consequences within the NIH itself for the OPRR.

  4. Lack of respect for OPRR's authority. OPRR is specifically located within NIH's Office of Extramural Research. In an interview43, the Office's Deputy Director, Mr. Geoff Grant, described 'various compliance requirements governing human subjects, animal welfare, and conflict of interest' as a 'robbery' that is 'distracting to research.' Dr. Ellis asked him if he had been quoted accurately in the article, and he verified that the quote was indeed accurate.

    Another example of lack of respect emerges by comparing the time required for the NIH to make changes regarding compliance with the performance of other institutions. GAO identified 17 instances (including NIH itself) from 1990 - 1995 in which OPRR imposed a restriction on an institution's authority to conduct HSR. GAO found those restrictions were lifted by OPRR in most cases after 12 to 18 months, when appropriate institutional corrective actions were taken. The NIH needed five years to implement corrective actions after being cited by OPRR in 1991 for compliance violations.

    Analysis of time domains of OPRR's governance of HSoR protections in another DHHS agency (documents are marked 'confidential') is similarly telling. The agency reported to OPRR, and OPRR independently identified a number of instances in which the agency failed to ensure that performance site institutions (in the dozens) conducting agency-supported research held an applicable OPRR-approved Assurance of compliance with the human subjects regulations. OPRR advised agency officials of these findings during the closing session of an August 1993 site visit. Twenty-one months later (September 25, 1995), OPRR reported that '...agency officials have informed OPRR that awards management procedures were recently modified to ensure that all institutions participating in human subjects research supported by the agency hold applicable OPRR-approved Assurances.' However, the truth is that the agency is still working to provide information and documentation to OPRR that will permit Assurance for all of the agency's human subjects research. Four years have elapsed and the problems are still not solved. The numbers involved are very large.

    Responses as sluggish as those seen in DHHS agencies are unknown among other institutions assured by OPRR. The protracted time periods consumed by DHHS research agencies to bring ongoing human subjects research into compliance with (what for these agencies are longstanding) regulations for protection of human subjects demonstrate that OPRR is not effecting proper HSoR protections from its position within the NIH. In the larger framework of government, DHHS and the Office of the President bear the ultimate responsibility for this problem and for initiatives regarding solutions.

  5. Misunderstanding the scope of the Assurance. A final example is related to the OPRR-approved Assurance of Compliance held by the NIH. This example illustrates the NIH's lack of understanding of, and/or lack of respect for, the authority of OPRR and, together with the comparatively sluggish response to citations, refutes Dr. Varmus' assertion that ìthe OPRR oversees and interacts with the NIH just as with any extramural institution.'

    The July 1, 1992, Assurance is 'applicable to all research activities that, in whole or part, involve human subjects ifÖthe research is conducted or supported by or under the direction of any employee of the NIH in connection with his/her institutional duties, regardless of the site of the activity....' On February 9, 1994, the NIH official signing the Assurance informed OPRR that 'NIH has amended the Applicability section of its Multiple Project Assurance [MPA] with the following rewrite:'

    applicable if 'the research is conducted or supported by the Intramural Research Program (IRP) of the NIH by or under the direction of any employee of the NIH, regardless of the site of the activity'

    NIH stated the change reflected 'a more precise statement of the fact that the NIH MPA does not apply to all NIH employees or research activities, but only to those individuals, either intramural or extramural, whose research is conducted or supported by the IRP in connection with their institutional duties.' In response (February 14, 1994), OPRR acknowledged receipt of the 'proposed' (OPRR's pointed characterization of NIH's February 9, 1994, memorandum) amendment to NIH's OPRR-approved MPA. OPRR reminded NIH that the terms of the NIH MPA approved by OPRR in July 1992 'remain in effect.' OPRR stated that it 'looks forward...to negotiating any changes' in the MPA that NIH may elect to pursue. More to the point, OPRR stated: 'Before OPRR can consider approving the proposed amendment, it will be necessary for NIH to clarify and define with as much specificity as possible the full dimensions of the 'Intramural Research Program.'' NIH did not respond to OPRR. The revision pursued by the NIH signatory official would have, inexplicably, left the human subjects in research conducted by some number of NIH employees (i.e., those not supported by the IRP) without the institutional protections conferred by an Assurance.

    Some three years later (April 21, 1997), OPRR found that the electronic text of the July 1992 NIH MPA existing on the NIH website differed from the OPRR-approved MPA in an important way. The 'Applicability' had been altered to omit the language in effect (i.e., applicability to research undertaken by '...any employee of the NIH.') and bore the new language sought by NIH in its February 9, 1994, correspondence to OPRR. Within two days after OPRR called this deviation to NIH's attention, the actual 'Applicability' language currently in force appeared on the NIH website.

In concluding this part, the report has provided examples of the effects of conflicts of interests that arise from a basic conflict of missions between the OPRR and the NIH. The latter's mission is to promote, fund, and to conduct biomedical research. The NIH's housing the OPRR is an arrangement that may have been acceptable in the past but does not fit the current scope and mission of OPRR in the 1990s and beyond. The basic mission of OPRR as regulator is organized around the primacy of the rights and welfare of human subjects. Like human subjects themselves, the OPRR's mission is confronted by and too often subjugated to a powerful and complex set of countervailing interests: a) scientific and funding interests and b) political and bureaucratic interests. The best remedies for the aforementioned problems of conflicts of mission and conflicts of interests are independent oversight and unfettered lines of authority.

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Lessons from Other Regulatory Agencies

One does not need to look far to find similar histories in two other federal agencies. A clear parallel exists in the creation of the NRC from the AEC in 1974. The AEC came under massive public and congressional criticism for trying at once to promote nuclear power and regulate its uses. Similar incompatibility of functions led to an imperative to move the OGE out of the Office of Personnel Management in 1989. Some of the problems of adequate staffing and freedom of action that burden OPRR's effectiveness were resolved by creating new agencies. Both agencies today are independent and adequately funded for their tasks.44 There is a striking contrast between the OGE's and the OPRR's resources for education. OPRR has no staff dedicated solely to education of IRBs, although Congress mandated this role. In 1992, OGE had five staff dedicated to education of ethics practitioners and trainers.

Both agencies have capabilities that would strengthen OPRR or its successor. They can propose and finalize regulations in the Code of Federal Regulations; visit and/or audit their clientele; promulgate guidance and educational materials for consumption by their clientele; and independently govern pertinent activity within another Federal Department or Agency.

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Recommendations

Despite a political climate that mitigates against the direction of these recommendations, the time has come to elevate the OPRR and create an adequate agency with an independent location. Initiatives from the DHHS and the Office of the President would greatly strengthen the plausibility of such solutions. An initiative from the White House is appropriate, inasmuch as OPRR's successor should be separate from the DHHS agencies that it oversees (NIH, CDC, FDA, and others) and have authority in relation to the 17 other Federal Departments or Agencies that conduct HSR according to the Common Rule. OPRR is a consultant to these agencies, but has no direct authority over them. Also, if the direction of universal protection of human subjects is legally and ethically sound, all human subjects of research in privately funded projects and their sponsors will require representation and oversight. That there are many examples and complaints regarding exploitation of ìmost vulnerableî research subjects beyond the scope of existing legal protections has been documented by Dr. Ellis in a communication to NBAC.45 If Congress legislates to guarantee legal protection of all research subjects and impose sanctions for violations of federal policies and rules for HSR, broadening the authority of a successor to OPRR to regulate all HSR activities would be a logical step. An agency with such authority would quickly move from negotiating Assurances with research sponsors to a simple requirement for annual registration. Registration would involve research sponsors providing information on the twin protections of HSoR: informed consent and IRB review. Registration would also yield more data about the actual incidence and magnitude of HSR in the United States. This information is not currently available.

Recommendation 1:

That the NBAC endorse the creation by Congress of a successor to OPRR: the National Office of Human Subjects Research (NOHSR). The NOHSR will have all of the present functions of OPRR with respect to DHHS and its Agencies. Additional authority should be given to NOHSR over all Federal Departments or Agencies conducting or funding HSR, as well as over privately funded HSR. The NOHSR should be headed by a single Director46 to be nominated by the President, subject to the advice and consent of the U.S. Senate. The NOHSR should be accountable to Congress and funded by congressional appropriation. A location within the Executive Branch is a logical step, similar to the OGE, but it should be an independent agency accountable to Congress and reporting to the President. The NOHSR's initial resources would require a staff of 45 to 50 individuals and a funding level of $6 million to $7 million.47 The report strongly recommends moving OPRR outside the PHS as a permanent solution to the conflict of missions and conflict of interest problems. If creating a new independent agency may be problematic for Congress at this time, an interim solution would be to relocate OPRR alongside or within an existing and effective independent agency, e.g., the OGE. Other partial solutions would be intolerable. For example, some consider reinventing OPRR by investing its mission and mandate in the Human Subjects Research Subcommittee of the Committee on Health, Safety, and Food, National Science and Technology Council. The Subcommittee was originally chartered to write the Common Rule and continues to meet six times annually as a discussion group of issues facing the 17 Departments covered by the Rule. This body has no staff and no funds. Locating OPRR within this weak entity makes no practical or political sense.

Part of this recommendation is to require that only Subpart A of DHHS regulation' the Common Rule' apply to new research sponsors and private sector institutions. The other subparts of DHHS regulations are dated and require scrutiny.

Recommendation 2:

Congress should also create a National Advisory Committee for Human Subjects Research (NACHSR) through the Federal Advisory Committee Act. NACHSR's role is to be the main source of advice and guidance on HSR policy and ethical issues to the NOHSR and to the nation. The NACHSR (11 to 13 members) will serve as a permanent forum for debate and resolution of issues referred to it by the nation's IRBs, new ethical issues arising in HSR, problematic cases, and ongoing interpretation and application of ethical principles and rules governing HSR. The NACHSR would answer longstanding appeals by Katz and others48 for such a body. These appeals for such a permanent body extend back to the report of the Ad Hoc Advisory Panel that examined the Tuskegee Syphilis Study (1973).49 The NACHSR should have terms of office not to exceed three years, with one-third of members able to succeed themselves one time; it should meet quarterly and on special request of the Director, NOHSR, and its chairperson could succeed him or herself for one second term.

Twenty-seven other nations have established standing national bodies commissioned to work on bioethical issues.50 Seventeen nations have national bodies with specific missions to work on HSR policy and guidance to IRBs. These nations are listed in Attachment 2. The United States should not only create such a permanent advisory body alongside the NOHSR but should lead the rest of the world in strengthening the governmental voice of HSR protections, elevating its status, and providing an independent and less problematic location for it.

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Attachment 1

Chart of Sign-Off Points Within NIH

Secretary of Health and Human Services (45 CFR Part 46)

  • Director, NIH Institute, Center, and Division Directors
  • Deputy Director for Management, NIH
  • Associate Director for Administration, NIH
  • Director, Office of Management Assessment
  • Director, Office of Management Support
  • Regulations Officer, Division of Management Support
  • Associate Director for Science Policy and Technology Transfer Institute, Center, and Division Directors

Office of the DHHS General Counsel, NIH Branch

  • Associate Director for Legislative Policy and Analysis Institute, Center, and Division Directors
  • Deputy Director for Intramural Research, NIH Institute, Center, and Division Directors
  • Deputy Director for Extramural Research, NIH Institute, Center, and Division Directors

Director, Office for Protection from Research Risks

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Attachment 2

Other Nations with Standing National Commissions or Agencies with Oversight for HSR Policy and Practices:

  • Argentina - National Bioethics Commission (1992) - secretarial.
  • Canada - National Council on Bioethics in Human Research (1989) - Established by the Medical Research Council, National Health and Welfare Canada, and Royal College of Physicians and Surgeons. Defines guidelines, advises IRBs, and promotes public and professional education in research ethics.
  • Denmark - Central Scientific-Ethical Committee (CSEC) (1978) - Given statutory authority in 1992. Acts on disputed proposals and in cases where a matter of principle needs to be decided.
  • Danish Council of Ethics - Broader mandate and disagrees with CSEC on issues of preserving brain tissue for research and teaching and on definition of death. Parliament told them to cooperate.
  • Finland - Finnish National Research Ethics Committee (1991) - A permanent advisory body of the government. Makes proposals, gives expert statements, promotes research ethics (has no teeth).
  • France - French National Consultative Ethics Committee on Life and Medical Sciences (1983) - Created by the President (Mitterand) to advise the government on issues of bioethics. French Parliament uses its work to make law. Has a small staff.
  • Hungary - Scientific and Research Ethics Committee (1987) - Established by the Hungarian Scientific Research Council. Parent forum overseeing HSR; coordinates regional research ethics committees, publishes guidance.
  • Israel - Supreme Helsinki Committee - Convened by the Director General of the Ministry of Health when research in sensitive areas is proposed.
  • Italy - National Committee on Bioethics (1990) - Created by the President of the Council of Ministers. Provides advice to Parliament (meets in closed sessions, no staff).
  • Mexico - National Bioethics Commission (1992) - Reports to the Ministry of Health.
  • Netherlands - Commission on Health Ethics and Health Law (1977) - Sponsored by the Health Council, this commission transmits findings to the government of the work of subcommittees organized by the Health Council. In 1989, Minister of Health created Dutch Interim Central Committee on Ethical Aspects of Medical Research. This national advisory commission on research ethics directly advises local medical ethics boards, not the government; recommendations are nonbinding.
  • New Zealand - Health Research Council Ethics Committee (1990) - Advises the Health Research Council on ethical issues in research.
  • Norway - Parliament created three bodies: 1) National Committee for Medical Research (already there but non-statutory), 2) for social sciences, and 3) for science and technology (1989).
  • Phillipines - National Ethics Committee and IRBs (1987) - Created by Phillipine Council for Health Research and Development.
  • Poland - Ethics Review Committee in Biomedical Research (1977) - Created by Ministry of Health; Commission for Supervising Research on Human Subjects (1982) - Created by Ministry of Health and Social Welfare; and Commission for Research Ethics (1991).
  • Russia - Russian National Committee on Bioethics (1992).
  • Sweden - Medical Research Council houses a central committee that oversees local research ethics committees concerned with individual research projects. National Council on Medical Ethics - (1985) - Links science, public, and Parliament.
  • U.K. - Several bodies, including the Nuffield Council on Bioethics (1991) - A private group that acts as though it was government appointed. Establishes working groups and has an executive secretary and two staff members. No oversight of local research ethics committees.

Source: U.S. Congress, Office of Technology Assessment. Biomedical Ethics in U.S. Public Policy Background Paper, OTA-BP-BBS-105. Washington, DC: U.S. Government Printing Office, June 1993.

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Footnotes

  • 1The abbreviations HSoR will be used for 'human subjects of research' (focus on the human beings who are research subjects) and HSR for 'human subjects research' (focus on the activities of research involving human subjects).
  • 2 At its May 17, 1997, meeting, the NBAC voted unanimously for this statement: 'No person in the United States should be enrolled in research without the twin protections of informed consent by an authorized person and independent review of the risks and benefits of the research.'
  • 3 McDermott, W., Opening Comments. The Changing Mores of Biomedical Research. A Colloquium on Ethical Dilemmas from Medical Advances, Ann Int Med 67 (Supp.7, No. 3-Part II):39 - 42, 1967. 'the hard core of our moral dilemmas will not yield to the approaches of 'Declarations' (i.e., Helsinki) or 'Regulations' (i.e., the FDA's 1967 human subjects regulations); for as things stand today such statements must completely ignore the fact that society, too, has rights in human experimentation' (p. 42).
  • 4 Jonas, H., Philosophical Reflections on Human Experimentation, Daedalus 98:245, 1969.
  • 5 Ibid.
  • 6 Dommel, F.W., Alexander, D., The Convention on Human Rights and Biomedicine of the Council of Europe, Kennedy Institute of Ethics Journal 7(3):259 - 276, 1997.
  • 7 Robertson, J.A., The Scientist's Right to Research: A Constitutional Analysis, Southern California Law Review 51:1203 - 1279, 1977.
  • 8 This term was coined by Paul Appelbaum, and the widespread power of its influence was ascertained in the Subject Interview Study of the Advisory Committee on Human Radiation Experiments, in which 1,882 patients receiving medical care in 16 outpatient facilities of private and public hospitals were surveyed.
  • 9 'Drug manufacturers offer clinician-investigators financial inducements to enter patients into studies, typically $2000 to $5000 per patient. By contrast when a patient is entered into a NIH-sponsored study, the clinician-investigator receives capitation of approximately $1000 per patient to cover the costs of the physician-investigator's time, the data manager's salary, and additional expenses (secretarial, photocopying, etc.) incurred in participating in the study.' Shimm, D.S., Spece, R.G., DiGregario, M.B., Conflicts of Interest in Relationships Between Physicians and the Pharmaceutical Industry, in Spece, Shimm, and Buchanan (eds.), Conflicts of Interest in Clinical Practice and Research, New York: Oxford University Press, 1996, 323.
  • 10 These problems are described in three recent reports: U.S. General Accounting Office, Scientific Research, Continued Vigilance Critical to Protecting Human Subjects, 1996. GAO/EHS-96-72; Advisory Committee on Human Radiation Experiments, Research Ethics and the Medical Profession, JAMA 276:403 - 409, 1996; and Moreno, J.D., Caplan, A.L., Wolpe, P.R., and the Members of the Project on Informed Consent, Human Research Ethics Group, 'Updating Protections for Human Subjects Involved in Research', JAMA, 1998 280(22):1951 - 1958.
  • 11 Nishimi, R.Y., Testimony for the House Committee on Government Operations, The Federal Role in Protecting Human Research Subjects, 103rd Congress, 2nd Session, September 28, 1994: 158 - 160.
  • 12 The occasion for the interviews was to prepare papers for presentation at the 125th anniversary of the Norwegian Academy of Sciences and for subsequent publication; i.e., Fletcher J.C., The Evolution of the Ethics of Informed Consent. In Research Ethics, Berg K., Tranfy K.E.(eds.), Alan R. Liss, Inc., New York, 1983, 1877 - 228; Boverman M., Fletcher J.C., The Evolution of the Role of an Applied Bioethicist in a Research Hospital. In Research Ethics, Berg K., Tranÿy K.E. (eds.), Alan R. Liss, Inc., New York, 1983, 131 - 158.
  • 13 Erde, E.L., Conflicts of Interest: A Conceptual Overview, in Spece, Shimm, and Buchanan (eds.), Conflicts of Interest in Clinical Practice and Research, New York: Oxford University Press, 1996, 13.
  • 14 Adapted from Erde, see note 13, p. 33.
  • 15 The impact on the NIH of a case involving Dr. Chester Southam's research at the Jewish Hospital for Chronic Diseases in Brooklyn, New York, had, in the author's view, the most telling and persuasive influence leading to change. Dr. Southam's license to practice medicine in New York was suspended for one year, and then he was placed on probation. For accounts of this case in historical context, see Langer E., Human Experimentations: New York Affirms Patients' Rights. Science 151:663 - 665, 1966; Fletcher J.C., The Evolution of the Ethics of Informed Consent. In Research Ethics, Berg K., Tranfy K.E. (eds.), Alan R. Liss, Inc., New York, 1983, 187 - 228.
  • 16 The term ìinstitutional blindnessî refers to the end-state of excessive loyalty to the welfare of an institution and one's role within it. The stronger and more uncritical the loyalty to an institution and role, the more impaired are independence of observation, judgment, and action with respect to prevention or moderation of conflicts of interest. Some professions are much better prepared and trained than others to detect and prevent conflicts of interests. Physicians and biomedical researchers do not receive the same degree of education and training about such issues as attorneys and behavioral scientists. For example, 'because physicians are not trained to look for conflicts of interest, they often find themselves enmeshed in them without recognizing the problem.' Spece R.G., Shimm D.S., Buchanan A.E., Conflicts of Interest in Clinical Practice and Research, New York: Oxford University Press, 1996, preface.
  • 17 See the ACHRE report cited in note 10 for description of the norms of the wider research community, at 404 - 405.
  • 18 Jones, J.H., Bad Blood, 2nd ed., New York: Free Press, 1993, 191 - 196.
  • 19 What was the involvement of the NIH, if any, in the Tuskegee study? The pre-1950s NIH was involved in analyzing spinal fluid and autopsy tissues from the subjects. Jones, see note 18, 124, 136. It is likely that no NIH physician-investigator or official was directly involved in the study itself or in its defense against Buxton's challenges. (James Jones, personal communication, November 10, 1997). Dr. John Heller was a junior officer in the PHS Division of Venereal Diseases who was actively involved in the study. Following his retirement as President of Sloan Kettering Hospital, he was in residence at the National Library of Medicine. In an interview with James Jones in 1977, Dr. Heller described his experience in meetings led by Dr. Raymond Vonderlehr, with the medical societies and boards of health of four Alabama counties in 1933: '...no one questioned whether the experiment was ethical; no one even came close to doing so. 'I don't recall any philosophical discussions at all,' declared Dr. Heller. What emerged from his comments was the image of a profession whose members had closed ranks behind a study they were told had real merit. The experiment obviously had struck their sense of scientific curiosity, and it did not occur to anyone to suggest that it should not be conducted.' Jones, see note 18, p. 144.
  • 20 Although Peter Buxtun, a PHS employee, challenged the ethics of the Tuskegee study from within DHEW as early as November, 1966, PHS officials did little to heed his criticism. The Tuskegee story was broken by the Associated Press on July 25, 1972, in a report by Jean Heller. Cf. Jones, J.H., Bad Blood, 2nd ed., New York: Free Press, 1993, 188 - 205. The author conducted numerous interviews and 10 focus groups with scientists and clinical investigators at the NIH from 1966 to 1968 in preparation for a Ph.D. dissertation on the ethics of medical research. No one brought up the Tuskegee study. The author was unaware of it until the news story.
  • 21 Beecher, H.K., Ethics and Clinical Research, N Engl J Med 74:1354 - 60, 1966. The occasion for the interviews was to prepare papers for presentation at the 125th anniversary of the Norwegian Academy of Sciences and for subsequent publication, i.e., Fletcher, J.C., The Evolution of the Ethics of Informed Consent. In Research Ethics, Berg K., Tranfy K.E. (eds.), Alan R. Liss, Inc., New York, 1983.
  • 22 In an earlier interview, Charles R. McCarthy, former director of the OPRR, commented: 'It seems to me thatÖfor the most part government was passive, a few farsighted individuals such as Shannon and Stewart in the Executive Branch, and Ted Kennedy in the Congress, initiated procedures that have matured into a remarkable system. These few individuals were both learners and teachers, but the government as a whole was at best a sleepy, distracted pupil, awakened periodically by a scandal, but otherwise content to 'get by' without having to recite' (personal communication, May 14, 1993).
  • 23 Surgeon General, PHS, DHEW, Investigations Involving Human Subjects, Including Clinical Research: Requirements for Review to Ensure the Rights and Welfare of Individuals, PPO 129, Revised Policy, July 1, 1966.
  • 24 DHEW, 45 Protection of Human Subjects 46, Federal Register, Vol. 39, No. 105, Part II, 46.1(a) (b), 1974.
  • 25 Federal Register, Vol. 46, No. 16, January 26, 1981.
  • 26 45 CFR 46.101(a), 56, Federal Register 28003, June 18, 1991.
  • 27 The National Institutes of Health Revitalization Act of 1993, Public Law 103-43, June 10, 1993, Section 492A.
  • 28 This story is well told in Faden, R.R., and Beauchamp, T. L., A History and Theory of Informed Consent, New York: Oxford University Press, 1986, 206 - 215.
  • 29 Ibid., 208.
  • 30 A fuller history of HSR protection and the evolution of prior group review in the NIH intramural program is found in Boverman M., Fletcher, J.C., the Evolution of the Role of an Applied Bioethicist in a Research Hospital. In Research Ethics, Berg K., Tranfy K.E. (eds.), Alan R. Liss, Inc., New York 1983, 131 - 158.
  • 31 NIH. 1958. Group Consideration of Clinical Research Procedures Deviating from Accepted Medical Practice or Involving Unusual Hazard. (Memorandum, approved by the Director, NIH, 1953); Sessions, S.M., What Hospitals Should Know About Investigational Drugs, Guiding Principles in Medical Research Involving Humans, Hospitals 32:44 - 64.
  • 32 Lipsett, M.B., Fletcher, J.C., Secundy, M., Research Review at NIH, Hastings Center Report 9:18 - 27, 1979.
  • 33 These programs were called 'Subpanels' to overcome the difficulty of having each chartered under the Federal Advisory Committee Act, because each had one or more outside members.
  • 34 The members of the drafting committee were Charles Lowe, Jane Fullerton, and Charles McCarthy (Charles McCarthy, personal communication, November 11, 1997).
  • 35 See note 30.
  • 36 McCarthy, C.R. (personal communication, November 11, 1997).
  • 37 U.S. General Accounting Office, Scientific Research, Continued Vigilance Critical to Protecting Human Subjects, 1996. GAO/EHS-96-72, 20.
  • 38 Project on Informed Consent of the Human Research Ethics Group. Updating Protections for Human Research Subjects, submitted for publication, 1997.
  • 39 Letter, Harold Varmus to Sarah F. Jaggar, February 15, 1996 (see GAO report, 33).
  • 40 Note 37, at 25.
  • 41 Research Administration, OPRR Location Questioned by Rep. Shays at Hearing, The Blue Sheet 40(20):2, May 14, 1997.
  • 42 See Attachment 1 for a chart showing sign-off points within the NIH bureaucracy. Proposals for changing federal regulations that arise from NBAC's deliberation on HSR, e.g., regarding studies involving cognitively impaired subjects, would in the near future necessarily be introduced through OPRR and be subject to the same vetting and sign-off process depicted in Attachment 1. Many of the entities in Attachment 1 have strong vested interests in the subject matter.
  • 43 The NIH Record, June 18, 1996, 4.
  • 44 U.S. Office of Government Ethics, Second Biennial Report to Congress, March, 1992; Walker, J.S., A Short History of Nuclear Regulation, January 1993 (NUREG/BR-1075).
  • 45 Letter, Gary B. Ellis to James F. Childress, April 10, 1997.
  • 46 The preference for agencies headed by a single administrator over a commission form of agency has been generally favored for some time by scholars in the administration sciences and based on research sponsored by the Committee on Government Operations. See 95th Congress, 1st Session. Study on Federal Regulation. Vol. 1. The Regulatory appointment Process, January, 1977.
  • 47 Ellis, Gary B. (personal communication, October 18, 1997).
  • 48 Katz, J., Do We Need Another Advisory Commission on Human Experimentation? Hastings Center Report 25(1):29 - 31, 1995.
  • 49 U.S. Department of Health, Education and Welfare, Final Report of the Tuskegee Syphilis Study Ad Hoc Advisory Panel, 1973, U.S. GPO: 1973-747-022/5334, Region No. 4.
  • 50 See Nishimi testimony, note 11.

John C. Fletcher, University of Virginia

Cite this page: "Location of the Office for Protection from Research Risks Within the National Institutes of Health: Problems of Status and Independent Authority" Online Ethics Center for Engineering 6/14/2006 National Academy of Engineering Accessed: Thursday, February 09, 2012 <www.onlineethics.org/Topics/RespResearch/ResResources/nbacindex/nbachindex/hfletcher.aspx>