experiments, there was no such assurance. This was ignored and in some cases blatantly violated. I would like to conclude just these opening remarks with one suggestion, in addition to those that have been made in the written record; No. 1, that we establish, as the Congress proposed in 1988, a permanent national research review board. It lapsed in 1980. A charter was rewritten in 1988, but was not signed by the President, I think, President Bush, in connection with the controversy over fetal tissue research-the proposal for an independent group of scientists and physicians and ethicists and public officials to review all the ethics of all Federally-funded research. That should mean both individuals and those situations like those just described or that you referred to today in San Francisco where the public, not as formal subjects, is subject to exposure. It should not be limited to radiation, but to chemical, biological and other forms of toxic exposure in its purview. Second, I think we need to look specifically to the risk that all of this can occur again, and we have been told frequently that by today's standards, no, it can't. What concerns me is the likelihood, the possibility, that we will have some other intense national security scare of the kind that we have in the 1940's and 1950's; that we will have some other development of a new category of weapon or potential weapon, whether chemical, biological, radiological, electronic, or other, and that there will be the same desperate urgency, invoking national security and secrecy, to discover the parameters of this threat, the parameters of the potential usefulness of this agent, and therefore to conduct experiments independently and without public knowledge or scrutiny of the kind that have drawn our attention to these. It seems to me that that is the critical situation that we have to find ways to protect against, and one answer, at least, is that there should be no research, no matter how secret, no matter how classified as involving national security, that should be independent of the scrutiny of an institutional review board which includes nonGovernmental scientists not connected with the agencies that are conducting the research and which will apply the same standards and the same protocols both to individual and to public exposures. Chairman GLENN. Thank you very much, Dr. Geiger. Dr. Piantadosi. TESTIMONY OF STEVEN PIANTADOSI, ASSOCIATE PROFESSOR OF EPIDEMIOLOGY, DEPARTMENT OF EPIDEMIOLOGY, JOHNS HOPKINS SCHOOL OF HYGIENE AND PUBLIC HEALTH Dr. PIANTADOSI. Senator Glenn and Committee Members, I am pleased to have the opportunity to comment on the issues which are the subject of these hearings. I am at present an associate professor of oncology and director of biostatistics in the Oncology Center at the Johns Hopkins University School of Medicine in Baltimore. I also have joint appointments in the departments of epidemiology and biostatistics in the Johns Hopkins School of Hygiene and Public Health. My primary field of expertise is clinical trial methodology, especially the use of quantitative methods in the design, conduct and analysis of such studies. I am not currently, nor have I been in the past, a member of our institutional review board. However, for the past 6 years I have been a member of the Oncology's Center's clinical research committee, a multidisciplinary group which is responsible for performing a scientific and ethical review of cancer center clinical studies prior to their submission to the IRB. Dr. Curtis L. Meinert was originally invited to testify at this hearing, but is unavailable today. I am pleased to take his place to represent my own views, which are similar in many ways to his, and to discuss some additional specific questions that have been addressed to me. I begin by asking that Dr. Meinert's previously prepared written statement be included in the record.1 Chairman GLENN. It will be included in the record. Dr. PIANTADOSI. I want to sketch a few of the problems with the experiments that were performed. I have briefly studied official reports of the radiation experiments on U.S. citizens from the perspective of a clinical trial methodologist trained in the current era of ethical concern and oversight. I refer, in particular, to the report from the Subcommittee on Energy Conservation and Power to the Committee on Energy and Commerce of the U.S. House of Representatives, dated October 24, 1986, in which details of experiments from the 1940's through the 1970's were outlined. There is little doubt in my mind that many of these experiments failed to meet present-day standards for conduct of ethical human trials, and many also fail standards that were commonly accepted at the time of the studies. To gain a perspective on the experiments in question, it is helpful to keep in mind several facts. I will not be an apologist for these studies on the basis of the following points. However, we must view the events through lenses clouded by these and other concerns. First, our society had a more relaxed attitude toward radiation for much of the period in question compared to today. Second, the ethical standards for human trials were less stringent than they are today. A review of landmarks in the ethics and regulation of human research will show this evolution. Third, standards of documentation for medical trials were less 30 and 40 years ago than they are today. We must be careful not to equate poor documentation of consent with documentation of no consent. Fourth, there was a veneer of fear resulting from the cold war which affected many societal and governmental attitudes. We are not immune from similar economic and political pressures today. For example, will the future look unkindly on the ethics of our historically casual attitudes toward lethal effects in our society such as exposure to tobacco smoke and handguns? Fifth, there was no review or dissemination of the facts and issues surrounding the experiments in question that might have contributed to oversight. I will return to this issue below. Sixth, we have retrospectively applied our more enlightened standards to an earlier time. While this is helpful for increasing our vigilance, we must be certain that problems we seek to correct still exist. So we have a persistent problem? A question that concerns scientists, legislators and others is whether or not there is a persist 1 The prepared statement of Dr. Meinert appears on page 114. ent problem in protecting research subjects. Such problems are typified by the radiation experiments, but might be manifest today by ethical shortcomings of a similar nature such as inadequate consent or taking advantage of vulnerable members of our society. I do not believe that there is evidence for or signs of systemic ethical shortcomings in current medical experiments. I say this from the admittedly narrow perspective of a researcher mostly concerned with cancer clinical trials at a well-groomed academic research institution. However, cancer is a very active area of clinical trial investigation which acquaints one with local regulatory practices, NIH review and oversight, other institutional practices and FDA regulation. I am not aware of substantive deficiencies in any of these review mechanisms. My experience with the IRB mechanism for the oversight of research studies suggests that it functions efficiently and appropriately. Our best defense against abuses is via openness and accountability at the level of individual IRBs, as well as on a collective national basis. I emphasize, as did Dr. Meinert, that there are few data to bring to bear directly on this question. We have no mechanism for comprehensively characterizing the types of clinical trials being performed nationally and using such information to address important research and regulatory questions. Potential adverse consequences of this serious deficiency in our information might be seen in recent legislative remedies requiring the inclusion of women and minorities in clinical research projects so as to provide "valid subgroup analyses." There are few data to support or refute the widespread perception that women and minorities have been understudied, but regulations now require valid subgroup analyses, which are potentially very costly or wasteful and could reduce the number of clinical trials performed. I support Dr. Meinert's call for a national system of registering IRB-approved research projects. Such a system would provide useful data regarding questions such as those facing the Committee today and would be a powerful source of information necessary before contemplating new legislation. Also, this system would provide additional accountability that would be advantageous for oversight. I would like to address a couple of specific questions that were posed to me within the past 24 hours. The first is, from a regulatory standpoint, when does the FDA get involved in oversight of clinical trials. I begin by emphasizing that I do not speak for the FDA. In the past 4 years I have served on advisory committees to the FDA, an activity that has acquainted me with many aspects of its role and function. However, I encourage the Committee to address similar questions to FDA officials. The regulatory authority and the active involvement of the FDA in testing new drugs or agents begins prior to the earliest phase of human trials. In the United States, the authority for assuring the safety of the public in matters related to drugs is the FDA. FDA regulations stemming from the Food, Drug and Cosmetic Act have the force of law and govern the circumstances under which work with experimental agents may be performed. When the sponsor of a new drug or agent has sufficient preclinical data to suggest that it is reasonably safe for human testing, a notice of claimed investigational exemption for a new drug, com monly called an IND, is submitted to the FDA. Clinical studies may not begin for at least 30 days while the IND is reviewed by the FDA. IND regulations control the conduct of investigations performed subsequently. In recent years, additional regulations have been adopted governing the rights of human subjects, informed consent, sale of investigational drugs and obligations of sponsors, investigators and IRBS. A comprehensive review and revision of IND regulations was completed in 1987. IRB requirements are a major portion of the IND regulations. Specifics are reviewed in Dr. Meinert's written testimony and in some more detailed summaries which are referenced in my written testimony. The second question: Are there circumstances under which the testing of drugs or products on humans need not follow the regulations adopted by NÎH, FDA, or other Federal agencies? I would be very surprised of such circumstances exist, but I do not have the qualifications to answer this question authoritatively. In summary, my principal concern in appearing here today is to emphasize the need for accurate data to supplement our thinking about the ethics of human trials. Before suggesting legislative remedies, we need to document whether or not there exist substantive and widespread deficiencies in the current practices to protect research subjects. We also need to assure ourselves and the public that any new regulations will correct problems effectively without harming fragile aspects of valuable human research that are functioning well. Thank you. Chairman GLENN. Thank you very much. TESTIMONY OF FRANCIS X. MASSÉ,1 RADIATION SAFETY Mr. MASSÉ. Thank you very much, Senator Glenn. You have my formal statement. Chairman GLENN. It will be included in its entirety in the record. Mr. MASSÉ. If I may, I would like to use my time to hit highlights there, and also to hit on some things that have not been brought out yet, OK? Chairman GLENN. Fine. Mr. MASSÉ. First, let me introduce myself. I am the director of the radiation protection programs at MIT, and also the radiation safety officer at the Tufts complex in Boston, including the New England Medical Center. I have been at MIT for 35 years and Tufts for 42 years, which predates the IRBs and many of the Committees that we are now talking about. I have had full responsibilities in these areas for all of that time and I currently serve on more than a dozen control committees in the Boston area. I typically review about 100 human use research protocols each month, so I am very actively involved today, as I have been for many years. I would agree with everybody that the backbone of the current regulations is clearly the IRB. All of the major institutions, the 1 The prepared statement of Mr. Massé appears on page 119. medical schools, the research universities, clearly follow the IRB and stay on full terms with HHS in terms of the IRB protocols. Basically, all of them are using Federal funding in their research in one way or another, and obviously that is followed very carefully. The IRBS, in my opinion, the ones that I am directly involved with, function very, very well. There are monitoring procedures involved. There is an annual review, at the minimum. I have seen the IRB approve procedures for 3 months at a time because they wanted to monitor it more carefully. I have seen them assign informed consent monitors to be sure that it was done properly under particular situations. I have seen them really function in a very, very solid way in that sense, so I really believe the IRB is doing a yeoman's job in satisfying many of the problems that existed many years ago, and I have seen that transition. Chairman GLENN. Are checkups, in your experience, or looking at what is going on in a project once it has been approved and is ongoing-are those checkups done often enough to catch anyone that would want to go beyond the scope of what was approved by the IRB to begin with? Mr. MASSÉ. Yes, and it is done in several ways. Many times, if we see a difficult protocol that we give approval to, the IRB may be a little uncomfortable with the approval and may give the approval for 3 months at a time, requiring a full report back on the outcome with the first few subjects that are involved, detailed review. They cannot continue until they have the approval of the IRB to continue after reviewing that review. So I think it can be done very well, and I see IRBS operating in a flexible enough way that they really are getting the most out of this. I think it is working well. In addition, something that has not been mentioned yet-when we get into human research involving radiation, we get into other areas and other regulatory controls that have not yet been mentioned and I think it is important to add that to the discussion today. There are roughly four topics of radiation research that I see with human research subjects in institutions that I am working with. The one that is most tightly controlled is tracer studies, metabolic studies, where there is no anticipated benefit whatsoever to the research subject. These are the kinds of tracer studies that are done in human nutrition centers, for example, in research hospitals and in an institution like MIT where metabolic studies are being done. In order to do these today, you must have FDA approval under 21 CFR 361 with the establishment of a radioactive drug research committee, and that is a very tightly controlled kind of protocol. If children, for example, are to be involved in the research, as soon as you approve a protocol under the RDRC you must notify the FDA of the approval of that protocol involving radiation in children. That is a regulation that is in place today that I see operating very tightly. Those are very stringent additional reviews on top of the IRB reviews and the Committees typically work in tandem. The IRB will not fully approve of a research protocol until it has heard from the RDRC to be sure that everything is in place. |