Discussion

Chapter 15: Footnotes

2 . Studies performed upon human tissue were included in this definition of radiation experiments only if a subject's exposure to ionizing radiation occurred prior to the collection of the tissue.

3 . The matrix, shown in the chapter on the Research Proposal Review Project in a supplemental volume to this report, went through several adjustments to account for classification errors in which research abstracts were assigned to the incorrect biomedical category (owing largely to inadequate information in the abstracts).

4 . The approach we used can be described as a modified quota sampling methodology. Quota sampling methodology is described briefly in Earl R. Babble, Survey Research Methods (Belmont, Calif.: Wadsworth Publishing Company, Inc., 1973), 107-108.

5 . The final radiation study sample matrix can be found in the chapter on the Research Proposal Review Project in a supplemental volume to this report. A matrix of these categories was constructed and a criterion was established that every cell of the matrix be filled with no fewer than 3 and no more than 5 studies from the contemporary period of research (fiscal years 1990 through 1993). Where there were more than 5 eligible studies per cell, a sample of 5 was randomly selected. The original target number of studies per cell was set at between 3 and 10; studies were identified for review according to this initial criterion. However, as the Advisory Committee approached the end of its tenure, the sampling of radiation studies was modified slightly. The Committee agreed that reviewing only 5 would enable the Research Proposal Review Project to be completed in enough time for the results to be included in this report without compromising the meaning of its findings. Accordingly, where 5 studies had not yet been reviewed in any given cell, the number of studies needed to reach 5 was randomly selected from those remaining.

6 . Of the 225 research proposals originally chosen by the Advisory Committee, 91 were funded at 43 extramural institutions. As a number of these proposals were deleted during the review process, however, only 32 extramural institutions were represented in the final total sample. Although 31 extramural institutions were represented in the radiation sample, one institution was represented only in the nonradiation sample.

7 . We originally believed that the ratio of the number of extramural to intramural studies would be much closer to 1:1; however, this was not the case with our radiation sample. The discrepancy can be attributed to the fact that VA studies are all intramural and that few extramural studies are funded by DOD.

8 . The final nonradiation (and radiation) study sample matrix, broken down by funding agency, funding type, and disease, can be found in a supplemental volume.

9 . The Advisory Committee received a total of 225 proposals. A number of these proposals were eliminated from the sample because they did not fall within the definitions (for radiation/nonradiation, biomedical category) established by the Advisory Committee. Additionally, approximately 40 proposals were deleted according to the

10 . Grant proposals were requested directly from the funding agencies. All other materials for intramural studies were also requested from the respective agencies, while other materials for extramural studies were requested from the grantee institution performing the research.

11 . Contains a detailed scientific research proposal including references to related work and relevant animal models. Descriptions of the informed consent process and subject selection are not usually well developed in this document. When the proposal was not available, a detailed protocol and summary of research were used in lieu of the proposal. Intramural studies often did not include a full research proposal, but only the IRB application, consent form, and other supporting documents.

12 . May sometimes include the grant proposal, but usually contains a more concise version of the research protocol with greater explanation of and specific attention to the use of human subjects.

13 . The consent form provides a written record of what information is provided by the investigators to research subjects. The original and approved versions of the consent form reviewed together give some insight into the IRB review process for the particular research, the extent to which investigators understand the requirements for informed consent prior to submitting their study proposal for review by the IRB, and the IRB's required changes to the consent form and/or process prior to the approval. In some cases, only the consent form approved by the IRB was available.

14 . Specific changes required for final approval of the proposal are often indicated in this document. When the disposition letter could not be obtained, a record of the IRB minutes for the meeting in which the project was approved served as a substitute.

15 . Such documentation, which generally takes the form of correspondence or annual renewal forms, enabled the Committee to determine if, over time, there were improvements or further problems with the consent procedures, risks and benefits, and selection of subjects.

16 . The RDRC application provides additional justification regarding the dosages of radioactive drugs administered to subjects, which helped the Committee assess risks to which subjects were exposed. The Advisory Committee sometimes received a radiation safety committee (RSC) application in lieu of or in addition to the RDRC application.

17 . D. A. Henderson, University Distinguished Service Professor, The Johns Hopkins University School of Hygiene and Public Health, to Ruth Faden, Chair, ACHRE, 31 July 1995 ("Who would have believed . . .").

18 . A more exhaustive report of the quantitative findings can be found in the Research Proposal Review Project chapter of a supplemental volume of this report. These findings include additional graphs of overall rating distributions according to federal agency, biomedical category, disease, and funding type.

19 . All proposals receiving an overall rating of 4 or 5 were reviewed a second time by Advisory Committee and staff reviewers to identify the core ethical concerns involved in each such proposal.

20 . In light of the analysis that showed that inclusion/exclusion of "maybe greater than minimal risk" studies with those studies that involved "greater than minimal

21 . In correspondence with RPRP extramural institutions, the Advisory Committee promised not to link findings in this report to any institution, investigator, or research proposal. Where individual RPRP proposals are discussed in the final report, no identifying information is provided.

22 . The FDA approval process for the sale and use of drugs and medical devices proceeds through four phases of testing on humans, after being tested in animal models. In Phase I the goal is to establish the dose of a drug or treatment at which toxicity in humans results, in an effort to establish safe levels for human use. In Phase II the goal is to establish a therapeutically effective dose of a drug or treatment whose toxicity has been established. Phase III is testing of a drug or treatment whose therapeutic effectiveness has been shown, to determine its effectiveness as compared with existing drugs or treatments, in preparation for approval and marketing. Phase IV testing is postmarketing data collection to determine the longer term effects of the drug or treatment in a large group of patients, over time.

23 . Of the 5 studies involving children that did not require assent forms, 3 involved sixteen- to eighteen-year-olds, and 2 were follow-up studies in which children were not actively recruited and were not likely to be subjects in the study.

24 . It is important to note that the degree of professional expertise of the person soliciting consent is often considered important to the quality of the consent process. In some cases, consent is solicited by researchers or nurses working on the project, not by the principal investigators themselves. Although there is controversy over whether the influence of the investigator in the consent process is potentially coercive, many argue that it is the responsibility of the principal investigator to make sure that the subject's consent is informed and voluntary.

25 . Institute of Medicine, Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies, Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies (Washington, D.C.: National Academy Press, 1994).

26 . Committee member Katz initiated this independent review of research proposals. Dr. Katz has been a scholar of the ethics of human experimentation for more than thirty years.

27 . Most of these 100 studies reviewed by Professor Katz also appeared in the sample of studies "formally" evaluated by the review teams; however, several were cut from the sample over the course of the review process in the interests of managing the sample size. The studies included in Professor Katz's independent review sample that were eliminated from the "formal" reviews were otherwise relevant to the Research Proposal Review Project and provide additional depth to the scope of the Committee's review of research proposals.

28 . Because Katz reviewed a convenient sample of proposals in the order received and did not apply the Committee's selection criteria, his sample included a number of minimal-risk studies that had been eliminated from the Committee's scope of review. It is, therefore, not surprising that there is a discrepancy between the proportion of minimal-risk studies assessed by Katz and those assessed by the full Committee.

29 . The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research was chartered in 1979 to report biennially on

30 . President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Implementing Human Research Regulations: The Adequacy and Uniformity of Federal Rules and Their Implementation, for the Protection of Human Subjects Biennial Report No. 2 (Washington, D.C.: GPO, 1983), 2, 43.

31 . The National Institutes of Health (NIH) Revitalization Act of June 1993 introduced new requirements to "ensure that women be included as subjects in each project of [clinical] research" and "conduct or support outreach programs for the recruitment of women and members of minority groups as subjects in projects of clinical research." A copy of this act can be found in Institute of Medicine, Committee on the Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies Women and Health Research, appendix B. This report also stresses the need for the inclusion of pregnant women in clinical research and recommends "that NIH strongly encourage and facilitate clinical research to advance the medical management of pre-existing medical conditions in women who become pregnant (e.g., lupus), medical conditions of pregnancy (e.g., gestational diabetes) and, conditions that threaten the successful course of pregnancy (e.g., pre-term labor)." Ibid., 16.