Historical Background on HSR and the NIH

The argument in this report is that structural conflicts of mission between OPRR and the NIH engender con-flicts of interest for OPRR’s staff and NIH officials. How does this report use the term “concon-flicts 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.”¹³Erde 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 “motives 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.”¹⁴The 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 prede-cessor 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.¹⁵As 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,¹⁶to 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 institu-tional 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,¹⁷the 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

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? Jones¹⁸describes the mid-1960s confrontation of PHS and CDC officials about the Tuskegee study by Peter Buxton, a PHS venereal disease interviewer and investigator. These officials¹⁹could 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.²⁰Second, 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.²¹In 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.²²The 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.²³The 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 IRBs²⁴stated:

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 regulations²⁵were 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

A) … [requirement of prior IRB review of all applications to the Secretary for financial assistance to conduct research… ]

B) 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 out-ward 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 1965.²⁹It did not occur to them to require prior group review intramu-rally 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.”³¹A Clinical Research Committee (CRC) was organized as a subcommittee of the Medical Board of the Clinical Center. The CRC was designed as an “expert body” 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.³²The official review

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.³⁴Under congressional pressure, the 1974 regulations were hurriedly constructed.

Little attention was devoted to bringing the intramural research programs under the regulations, because intra-mural 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 pro-tected 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.³⁵The areas of sharpest conflict were over a) complaints from patients and family members about lack of informed consent, b) the obligation to seek informed assent of children to research or major medical procedures, c) disclosure of psychologically sensitive information to patients, d) changing protocol strategy in midcourse without Subpanel permission, e) conflicts of interest in Subpanel review of protocols of Scientific and Clinical Directors of the Institutes, f) testing normal volunteers for psychopathology, and g) 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 pro-gram 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