The site visits will provide material for a report focusing on the possible processes through which information could regularly be developed by the Federal agencies that sponsor human research about the implementation of their regulations. The report is not envisioned as a critique of IRBS in general or of the specific IRBs visited in particular. Rather, the project is intended to illuminate what can be learned through a process of peer-based site visits and what problems exist with this approach. If the method is successful it might also replace the multiplicitous inspections now performed by Federal entities other than HHS which support research and by the FDA.3

Guidebook for IRBS

In 1974, in enacting the National Research Act, Congress directed (then) HEW to provide "a program ... for clarification and guidance with respect to ethical issues raised in connection with biomedical and behavioral research involving human subjects."4 Very little has been developed thus far, yet is is clear that researchers and IRB members desire help both in understanding the policies and principles that underlie the regulations governing research with human subjects, and in identifying the issues to which one should be sensitive in designing or reviewing research proposals. The Commission has embarked on a project, in collaboration with NIH and FDA, to develop a guidebook for IRBs. A contract was negotiated with a Boston-based organization well-known for sponsoring educational conferences for IRBs throughout the country, to prepare portions of the guidebook under the direction of senior staff of the Commission. Other portions of the book are being developed by NIH/FDA staff.

A draft of the guidebook is under preparation and will be distributed to the Commissioners for review early in 1982. Comments and suggestions from the Commissioners will be incorporated in a final version which should be completed by April 1982.

3 Some hope for success with the peer site visit approach can be derived from the observation of Robert Levine, the long-time chair of the Yale Medical School IRB, on a related phenomenon:

Members of IRBs with credibility seem to be invited into the realities of the institution by colleagues who want their advice and assistance in fostering mutual goals. Inspectors without credibility, on the other hand, are shown records (appearances of reality) and then only those to which their access is authorized by regulations.

Robet J. Levine, Ethics and Regulation of Clinical Research, Urban and Schwarzenberg, Baltimore (1981) at 226 (citations omitted).

4 Section 474(b) of Part I, title IV, Public Health Service Act.

Consideration of the Extension of Federal Regulations and Review Requirements to Research Not Federally Funded

In September 1980, the Commission concluded that “extension of HHS regulations to research that is not conducted or supported by the Department should be based upon clearer congressional and statutory authority than now exists in the ambiguous language of Section 474 of the Public Health Service Act."5 In communicating this conclusion to HHS Secretary Patricia Roberts Harris (by whom it was adopted), the Commission indicated, however, that it would consider, at some later date, whether to recommend statutorily-mandated IRB review of research with human subjects regardless of source of funding and, should it conclude that such a requirement is advisable, to recommend appropriate Congressional action. Consideration of this topic, along with other issues about the role of the Federal government, through IRBs, in the protection of human subjects, will be taken up in the Second Biennial Report. Possible Consideration of the Definition of "Phase 1" Drug Testing in Cancer Chemotherapy

The recent attention of Congressional committees and the press to informed consent in cancer research has spotlighted a problem regarding early "Phase 1" testing of new anti-cancer drugs. The FDA defines the first two stages of drug research as follows:

Phase 1 starts when the new drug is first introduced into man-only animal and in vitro data are available-with the purpose of determining human toxicity, metabolism, absorbtion, elimination, and other pharmacological action, preferred route of administration, and safe dosage range; Phase 2 covers the initial trials on a limited number of patients for specific disease control or prophylaxis purposes."

In non-cancer studies, Phase 1 drug tests are usually conducted with healthy volunteers, so that the subjects' pathological condition will not interfere with the measurements of the drug's activity in the human body. In such cases, there is no suggestion that the subjects should expect any health benefit from their participation in the research. With cancer drugs, however, toxicity is such that even Phase 1 tests are usually conducted on persons with cancer, often

5 Letter from Morris B. Abram to Patricia R. Harris (September 18, 1981).

621 CFR §321.1(a), see para. 10(a) of Form FS-1571 described therein.

desperate patients for whom all other possible treatments have proven unavailing.

There is considerable confusion as to whether Phase 1 tests of new cancer drugs can be described as "therapeutic" for the patients who will be asked to participate as subjects. IRB members disagree, at times, on this question," but cancer researchers have testified that they always have therapeutic intent in Phase 1 tests of cancer chemotherapy. Further, in a recent letter to Representative Henry Waxman (commenting on testimony of the Commission's staff), the Assistant Secretary for Health wrote:

8

Notwithstanding the fact that some individuals within HHS may not concur, the official position of the Department, including NCI, NIH and FDA, is to regard Phase 1 trials of anti-cancer drugs as potentially therapeutic. The often small, but real possibility of benefit must be weighed against the nearly 100 percent probability of death if experimental therapy is not attempted for the advanced cancer patients who participate in Phase 1 studies.9

At a recent meeting of the HHS Secretary's Task Force on NCI/FDA [Regulation of] INDs (Investigational New Drugs), the Commission's Executive Director and Deputy Director urged that this definitional problem be given serious attention. The contrast between the FDA regulations and Dr. Brandt's statement of the Department's "official position" is striking. Perhaps the classifications or nomenclature of Phase 1 and 2 should not be applied to research on cancer chemotherapies. More important, attention should be paid to the ambiguity in the term "therapuetic research" as applied to the initial use of new anti-cancer agents in human beings, in research usually designed to test pharmacokinetic and toxiologic matters. Clarity and candor are "One IRB member reviewing the protocol for Phase 1 tests of MHTTF at M.D. Anderson indicated that it was a therapeutic research project; another, that it was nontherapeutic. See IRB review check lists of Alexander Y.M. Wang, Ph.D., and W.W. Sutow, M.D., reflecting their review of protocol DT 78-31 discussed in Chapter Three.

See testimony of Drs. Emil Freireich, James F. Holland and John E. Ultmann before a joint hearing of the Subcommittee on Health and the Environment of the Committee on Energy and Commerce, and the Subcommittee on Investigations and Oversight of the Committee on Science and Technology, U.S. House of Representatives (October 27, 1981).

"Letter from Edward N. Brandt, Jr., M.D., Assistant Secretary for Health, HHS, to the Honorable Henry A. Waxman, Chairman, Subcommittee on Health and the Environment (November 20, 1981) at 3-4 (emphasis added).

needed as much as courage, both in the communication between physician-investigators and patient-subjects and in the unflinching self-appraisal by the cancer research community of the personal (as well as the scientific) meaning of such "heroic" experimentation. The Task Force has indicated a willingness to consider these issues and the Commission awaits its report with great interest.

Report on Problems Identified at IRB Workshops

Senior staff of the Commission will be attending a number of IRB workshops and conferences during the next year. Some of these are under the sponsorship of NIH and FDA; others are being planned by Commission staff to the extent permitted by reduced fiscal resources. If the workshops indicate that IRB members and research administrators have continuing problems understanding or implementing HHS regulations (or those of other Federal agencies), the Commission will consider what remedies might be appropriate. Informed Consent and Problems of Privacy in the Research Setting

The Commission will consider, as part of its next Biennial Report, whether more needs to be said regarding (a) informed consent and (b) privacy in the research setting. The former will depend largely upon whether HHS (and other Federal agencies) adopt the recommendations of the National Commission regarding research involving children and persons institutionalized as mentally disabled; the special principles and procedures set forth in those reports may prove helpful in resolving some difficult issues that have arisen concerning research with patients suffering from senile dementia of the Alzheimer's type. The second topic (privacy) turns on possible enactment of Federal laws that would add statutory guarantees of confidentiality for individuals' medical records.

Recommendations

5

Recommendations for Improving the Adequacy and Uniformity of Federal Laws and Regulations for the Protection of Human Subjects

Analysis of the Federal regulations surveyed in Chapter Two reveals that rules governing research with human subjects are now largely uniform among, and within, the agencies. The Commission regards this uniformity as a salutary development for several reasons. First, it facilitates administration, resulting in an easing of the regulatory burden on research institutions. Second, uniformity makes oversight simpler and more efficient; deficiencies are more readily identified and improvements have a more pervasive effect.

The survey of the present Federal rules and regulations also reveals, however, small variations among the requirements of the different agencies. Varied regulations for the review of research protocols impose upon local institutions unnecessary complexity and uncertainty in assuring appropriate review. Moreover, since IRBs review protocols prior to submission for funding, at the time of IRB review it is not always clear which agency will ultimately support the proposed research. Also, some research activities are supported by more than one agency. Accordingly, the Commission recommends that several steps be taken to standardize the "core" elements of all governmental regulations that specify basic process and standards for the protection of human subjects. Adoption of these recommendations should provide more simplicity, economy and certainty in the Federal regulation of research with human beings.

1. The President should, through appropriate action, require that all federal departments or agencies adopt as a common core the regulations governing research with hu