DISCLAIMER The following is a staff memorandum or other working document prepared for the members of the Advisory Committee on Human Radiation Experiments. It should not be construed as representing the final conclusions of fact or interpretation of the issues. All staff memoranda are subject to revision based on further information and analysis. For conclusions and recommendations of the Advisory Committee, readers are advised to consult the Final Report to be published in 1995. * * * * * *STAFF MEMORANDUM* * * * * * TO: Members of the Advisory Committee on Human Radiation Experiments FROM: Advisory Committee Staff DATE: June 3, 1994 RE: Follow-Up: Ethics At the May 18-19 meeting of the Advisory Committee, the Committee requested that the staff continue in its efforts to determine all policies, rules, and guidelines that have been or are currently in effect governing research with human subjects at the Department of Energy, Department of Health and Human Services, Department of Defense, Department of Veterans Affairs, the Central Intelligence Agency, and the National Aeronautics and Space Administration. Staff has begun to identify all such published statements by federal departments and agencies, sometimes as exemplified in particular research projects and documents. The purpose of this exercise is to gain an overall grasp of the evolution of federal standards in this area. Below is an update on the status of our data collection efforts in this area, for four of the departments/agencies of the Interagency Working Group. A review of policies for DOE and the VA is now being initiated. (See report on the VA in this briefing book.) Department of Defense Department of the Army--A 1975 report by the Inspector General evaluates compliance in the Chemical Corps with the 1953 Wilson memorandum on the use of human subjects. The investigation was stimulated by media reports of the secret testing of LSD on humans, but includes all studies conducted by the Corps for the past two decades. Concerning ethics, the report concludes that there is no evidence of harm to service personnel, that the Army did not implement its own rules concerning the assurance that participants had no undue incentives, and that the Army did not follow its own consent procedures. By way of a contemporary comparison, the DOD has a memorandum of understanding (MOU) with the VA to follow a number of Desert Storm veterans who were victims of "friendly fire" and as a result have shrapnel injuries that contain depleted uranium (DU) from projectile and armor casing fragments. (MOU dated December l, 1993.) DU has some intrinsic radioactivity but it is unknown what risk these fragments may pose, though uranium is known from animal and human studies to be nephrotoxic. Thirty five veterans are known to be affected. Since surgery is not currently recommended for these injuries (because it is regarded as impractical for these splintered fragments and could do more harm than good), it would be important to know whether the DU is a source of kidney damage over the long term and whether the standard approach in future cases should be revised in favor of surgery. The MOU states that the informed consent process will explicitly distinguish between what is clinical care and what is research. (See Attachment A, p. 13). Action: Staff intends to obtain copies of the consent form in order to ascertain current disclosure standards, and other background materials. Department of the Navy--A research proposal approved 26 June 1950 for a study of "Radiation treatment: Correlation or predisposition to radiation illness to other clinical findings in patients receiving radiation therapy". Location was St. Albans Naval Hospital, Queens, New York. The proposal form states that "Certain studies using human subjects require SecNav approval - BuMed obtains clearance". (See Attachment B). The Manual of the Medical Department of the Bureau of Medicine and Surgery listed a number of relevant changes in policy on experimentation on personnel from 1951 to 1970 (Sec Attachment C): 26 September 1951 - forbids experiments involving Navy personnel except when design has had prior approval of Secretary of the Navy; participation shall be voluntary; participants shall not be required to release Navy from liability for negligence (Attachment C, pp. 1-3). 22 April 1963 - Reasserts need for prior approval of experimental design by Secretary of the Navy (Attachment C, p. 4). 27 August 1970- Forbids hazardous experiments except when the study and use of volunteers has been approved by Secretary of the Navy. Voluntary participation only; full information and written consent required but not a negligence release. (Attachment C, p. 5). The Navy located a 1932 protocol for the approval of human experimentation stating that all subjects should be informed volunteers Action: In light of these published policies, staff has requested documentation relating to the genesis of these 1953 and earlier policies and their implementation. Department of Health and Human Services (DHHS) Previously known milestones in this department and its predecessor are summarized below. This brief reconstruction is included for Committee members' convenience in order to begin to formulate a comparison with other departments and agencies. DHHS "Protection of Human Subjects" regulations in May 30, 1974 Federal Register establish requirement that all institutions receiving federal funds submit human subjects research to prior review by a local ethics panel. Codified in 45 CFR Part 46. National Institutes of Health 1937 - From the beginning of the modern NIH and its extramural grants program, there was a peer review process through which ethical questions may have been raised, but there was no prior review with power to decide about research until 1953. 2 1953 - With founding of Clinical Center, the Clinical Research Committee of the Medical Board was formed for prior group review of all proposed studies to be conducted at the Clinical Center that were to involve normal volunteers and for innovative or risky experiments to patients. Committees,also formed in each Institute's intramural program to consider risks and benefits to patients. "Group Consideration of Clinical Research Procedures Deviating from Accepted Medical Practice or Involving Unusual Hazard," November 17, 1933 - Requires "oral information suitable to his [patient's] comprehension, supplemented by general written information or other appropriate means, of his role as a patient in the Clinical Center, the nature of the proposed investigation and particularly any potential danger to him." With procedures that "deviate from accepted medical practice" a note is to be made in the chart; in cases involving "unusual hazard" a signed statement is required and is to be entered in the patient's chart indicating his understanding of the procedure, its purpose and hazards to him, and his willingness to participate. 1957 - Modification of above policy dated October 23, 1957 requires volunteer to sign an "understanding and consent form." 1966 - Office for Protection from Research Risks organized and required by law to educate investigators and others about research ethics. "Group Consideration and Informed Consent in Clinical Research at the National Institutes of Health," July 1, 1966, supersedes November 17, 1953 document. Therapeutic/non-therapeutic research distinction appears. Especially in the latter case, importance of informed consent and group consideration are emphasized. Specific consent form for normal volunteers, and a list of procedures that require specific written consent. Public Health Service (PHS) Revised policy dated July 1, 1966 requires for grant approval that grantee institution provide prior review by a committee of the investigator or program director's "institutional associates". Review should include rights of subjects, "appropriateness of methods used to secure informed consent", and risks and potential benefits of study. Action: Staff will request any relevant PHS policy prior to 1966. 1962 - Drug Amendments require informed consent of subjects or their representatives except when the experts deem it not feasible or, in their professional judgment, contrary to the best interests of such human beings. 1966 - Consent required in all nontherapeutic drug studies and in all but exceptional cases of an experimental drug. 1971 - Requires IRB review of clinical investigations subject to regulation by the agency. 3 1990 - 55 FR 52814. Interim Rule, Informed Consent for Human Drugs and Biologics; Determination that Informed Consent is Not Feasible (in response to a request from DoD). Action: Staff intends to pursue background of DoD request and VA rationale for exception for consent requirement. NASA Included among the first set of materials submitted by NASA are two "NASA Management Instructions" (NMl's): 1. The NMI dated February 2, 1972 requires written consent, following an explanation in "language understandable to" the subject concerning nature, duration, purpose, manner and risks of the research. An advisory committee may be appointed by appropriate officials. This Instruction did not apply to NASA contractors or grantees. 2. The NMI dated November 18, 1986 replaces the February 2, 1972 NMI, and states that it follows the provisions of 45 CFR Part 46. It requires a NASA-approved IRB, and applies to NASA contractors. This NMI is currently being revised. Action: Staff is requesting all earlier NMI's from NASA. CIA Since 1977, CIA policy has specified that the CIA shall only conduct or find research on human subjects consistent with DHHS regulations, including subject's informed consent. The Human Subjects Research Panel, established in 1981, evaluates documentation and certifications of human research by CIA, in compliance with DH@S guidelines. Executive orders issued in 1986 and 1978 required the CIA's research involving human subjects to comply with DHHS standards. A 1976 Executive order required that all human experiments with drugs comply with National Commission guidelines. In 1984 the Human Subjects Research Panel recommended to the Executive Director the establishment of an IRB for research proposals that would be executed by Agency employees rather than outside contractors, whose proposals would be evaluated by IRBs at their own institutions. In 1980 the Agency reported to the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research that it funded ten grants or contracts involving human research that year. According to document HN 7-47 (no date), "the documentation on this research was reviewed favorably by staff members of the President's Commission." Action: Staff is requesting any earlier relevant CIA documents and a year-by-year count front the Agency of their research contracts or grants involving human subjects, and titles, as well as the number and titles of internal projects involving human subjects. 4 Attachments: Attachment A: Excerpts (pp. 1-3, 12-13) from September 23, 1993 draft of VA Depleted Uranium Follow- up Study Attachment B: Navy research proposal form regarding radiation treatment study Attachment C: Excerpts from Navy Bureau of Medicine and Surgery, Manual of the Medical Department, on human experimentation (from 1951, 1963, 1970, 1973, 1980, 1986, copied exactly as sent from agency). Attachment D: Excerpt from Navy Bureau of Medicine and Surgery, History of the Research Division, by Charles W. Shilling re: 1932 policy