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Testimony on Do Current Federal Regulations Protect People Who Participate in Medical Research? by Arthur J. Lawrence, Ph.D.
Assistant Surgeon General &
Deputy Assistant Secretary for Health (Operations)
Office of Public Health and Science
U.S. Department of Health and Human Services

Mr. Chairman and Members of the Subcommittee:

I am Art Lawrence, Assistant Surgeon General & Deputy Assistant Secretary for Health, Office of Public Health and Science, within the Office of the Secretary of Health and Human Services. I am accompanied by Gary B. Ellis, Director, Office for Protection from Research Risks, within the Office of the Director of the National Institutes of Health. Dr. Ellis also chairs the interagency Committee on protecting research subjects, in which17 Federal departments and agencies participate. We are pleased to appear before the Subcommittee to describe our well-developed, yet ever-evolving, system of protection of human research subjects. My testimony today thus describes a responsibility of enormous weight.

First, Dr. Satcher has asked that I extend his best regards and his regrets for not being able to be here with you today. He has also asked me to extend to you his personal gratitude for the leadership that you have taken promoting high energy efforts to eliminate racial and ethnic disparities in health status in the United States . He looks forward to continuing to work with you on this and other matters of importance to the public health.

Dr. Satcher asked me to relate that he shares your concerns about research that is conducted in populations that lack diversity, and in particular, about research that is conducted in entirely in minority populations, unless there is a clear and compelling reason to do so. As you know, the Department has recognized the need to increase diversity of participants in clinical trials, and has taken many steps to accomplish this in federally funded research. A good example of this is seen in the diversity of the Women’s Health Initiative studies. The Department is committed to continue these efforts until our goals are met.

In addition, we have made a commitment to involve communities in the design and conduct of research, and are moving forward with plans to be sure that research addresses needs of communities and is responsive to community concerns.

This year marks the 25th anniversary of the formal promulgation on May 30, 1974 of the Department’s regulations for Protection of Human Subjects in research (Title 45 Code of Federal Regulations Part 46). This enduring and vigorous system of protections is designed to prevent physical injury, psychological injury, and harm to the dignity of research subjects, as biomedical and behavioral scientists pursue new knowledge for the common good. We are always interested in improving the system to make research as safe as it possibly can be.

This system of protection of human subjects in research is based on a succession, or chain, of judgments made by people in the context of federal regulations. Thoughtful people, often volunteering large amounts of their time, look at research protocols and weigh risks and potential benefits. There is no computer program for this; there is no generic formula. One size doesn't fit all. This is custom work.

Multiple Layers of Protection for Human Research Subjects

Who is involved in protecting human subjects? The architecture of the current system involves at least half a dozen levels of protection. First, and foremost, there is the interaction between the research volunteer and research investigator. This is where the informed consent process takes place. It must be an ongoing, dynamic process, as new information becomes available or is desired. The informed consent document, or form, is one component--the written component--of the informed consent process. I will describe the particulars of informed consent in a moment. There may also be other parties involved, such as nursing, scientific, or medical staff other than the principal investigator. There may be a consent auditor or monitor, or an advocate for the research subject.

The Institutional Review Board is, by federal regulation, to be established at the local level and has a minimum of five people, including at least one scientist, one nonscientist, and one person not otherwise affiliated with that institution. The nonscientist must be present to achieve a quorum. The local IRB at the research site is the keystone of our system of protection of human subjects. No human-subjects research may be initiated, and no ongoing research may continue, in the absence of an IRB approval. By regulation, DHHS and 16 other federal departments and agencies cannot provide funds for human subjects research unless an IRB approves the protocols for such studies.

IRB review is 1) prospective and 2) continuing review of proposed research by a group of individuals with no formal involvement in the research. Ideally, it is a local review, by individuals who are in the best position to know the resources of the institution, the capabilities and reputations of the investigators and staff, and the prevailing values and ethics of the community and likely subject population.

Once research is underway, the IRB must conduct continuing review of the research, at intervals appropriate to the degree of risk--in any event, at least once per year. I will return to the responsibilities of the IRB in a moment.

In most circumstances, there are additional officials outside of the formal IRB structure who also play a role in reviewing components of research. For example, the Executive officials of the research site (e.g., dean, department chair, and research Administrators). Each has the authority to express specific concerns about human-subjects issues. Exerting oversight of the whole process are OPRR and, when investigational drugs, devices, or biologics are involved, the Food and Drug Administration (FDA).

An additional layer of review that may be employed, especially in large studies, is an independent Data and Safety Monitoring Board (DSMB), appointed to oversee and to evaluate the research investigation. DSMBs are usually appointed by, and report to, the funding organization--not the investigators or the institution doing the study. At periodic intervals during the course of the study, the DSMB reviews the accumulated data and makes recommendations on the continuation or modification of the study. A study can be stopped prematurely because of a toxic effect, or because a strong positive effect was seen and it would be unethical to continue with some subjects not receiving the intervention which has demonstrated benefit. While the most of the studies halted for these reasons are as the result of decisions of the investigator or sponsor, the DSMB plays a significant role in large randomized blinded trials.

It is OPRR’s role to make sure that the IRB process works at institutions within OPRR’s jurisdiction. To give you a sense of the kinds of problems that do occur and actions taken to address them, I will relate brief accounts of some actions taken by OPRR. In one well-publicized instance, the concern was the proper explanation of risks in the informed consent process for a study involving schizophrenia. OPRR 1) rebuked the Institutional Review Board for poor oversight of the informed consent process, 2) directed that the informed consent process be revised, and 3) instituted close monitoring of the institution's human-subjects activities. In a second instance, the concern was misuse of an expedited IRB review process. OPRR identified a failure of leadership within the Institutional Review Board, and the IRB Chairman subsequently resigned. At a third institution, the concern was whether or not the IRB was properly conducting the required continuing, annual review of research. The institution demonstrated to OPRR that some 2,000 research protocols involving human subjects had, indeed, received continuing review in accord with DHHS regulations.

Institutional Review Boards

Let me turn briefly to the specific responsibilities of the Institutional Review Board. In the main, IRB review assures that:

• risks are minimized by using procedures that are consistent with sound research design and which do not unnecessarily expose subjects to risk and, whenever appropriate, by using procedures already being performed on the research subjects for diagnostic or treatment purposes;
  
  
• risks are reasonable in relation to anticipated benefits;
  
  
• selection of subjects is equitable;
  
  
• there is proper informed consent; and
  
  
• the rights and welfare of subjects are maintained in other ways as well. This is particularly important when subjects are likely to be vulnerable to coercion or undue influence.

What populations are judged to be vulnerable? IRBs watch out especially for research involving children, prisoners, pregnant women, individuals with mental disabilities, individuals who are economically disadvantaged, and individuals who are educationally disadvantaged.

Federal regulations provide extra protection for vulnerable subjects in several ways. If an IRB regularly reviews research that involves a category of vulnerable subjects, consideration must be given to including as IRB members one or more individuals who are knowledgeable about, and experienced in working with, the vulnerable subjects. When some or all of the subjects are likely to be vulnerable to coercion or undue influence, IRBs must see that additional safeguards are included in the study protocol. Specific, detailed requirements are written into DHHS regulations pertaining to pregnant women, fetuses, human ova fertilized in vitro, prisoners, and children involved in research.

Once research is initiated, IRBs have continuing responsibilities. These include:

• The conduct of continuing review at intervals appropriate to the degree of risk, and in any event, not less than once per year.
  • Authority to observe or have a third party observe the consent process and the research.
    
    
  • Receipt of prompt reports from investigators of any unanticipated problems involving risks to subjects or others, or any serious or continuing noncompliance with the IRBĵs requirements or determination, or with the regulations.
    
    
  • Authority to suspend or terminate IRB approval of research that is not being conducted in accord with the IRBĵs requirements or that has been associated with unexpected serious harm to subjects.
• IRBs are also responsible for monitoring for the emergence of adverse effects, such as unacceptable and risky responses of human subjects within the research protocol and taking prompt appropriate action .

Assurance of Compliance with Human Subjects Regulations

The DHHS regulations for Protection of Human Subjects are not a set of rules that can be applied rigidly to make determinations of whether a proposed research activity is ethically "right" or "wrong." Rather, this is a framework in which investigators, IRB members, and others can ensure that adequate efforts have been made to protect the rights and welfare of research subjects.

OPRR oversees implementation of the regulations in all DHHS facilities as well as domestic and foreign institutions or sites receiving DHHS funds. OPRR requires that each DHHS agency and extramural research institution that conducts research involving human subjects sets forth the procedures it will use to protect human subjects in a policy statement called an "Assurance" of compliance. At OPRR's discretion, institutions with a large volume of research and demonstrated expertise in human subjects protection may be granted a Multiple Project Assurance. A Multiple Project Assurance, as the term implies, is an institution's pledge of full human subject protections for multiple projects at the institution. By federal regulation, OPRR has authority for approving an Assurance at DHHS-funded institutions for federal-wide use.

An Assurance statement is a formal, written commitment to: 1) widely held ethical principles; 2) the DHHS regulations for Protection of Human Subjects; and 3) institutional procedures adequate to safeguard the rights and welfare of human subjects. The terms of the institution's Assurance are negotiated with OPRR. The detailed, written Assurance statement becomes the instrument that OPRR uses to gauge an institution's compliance with human subject protections if there is a problem.

The DHHS assurance process is due for streamlining, so that OPRR can devote more resources and effort to working with institutions to better educate IRB members, IRB staff, and research staff. In recent months, OPRR has been retooling its intensive Assurance effort to redirect it toward education. As the human subjects protections activities are transferred to a new organizational structure, education and prevention activities will be intensified. Please know that OPRR will not abandon its current preemptive oversight procedures (i.e., negotiation of institutional assurances to comply) before putting in place an education program for assuring competency-based compliance.

Informed Consent

All present today know how integral--how crucial--the process of informed consent is. Many have a general picture of informed consent, and it is useful to add higher resolution to that picture. DHHS regulations specify 14 elements of informed consent, 8 of which are required:

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
   
   
2. A description of any reasonably foreseeable risks or discomforts to the subject.
   
   
3. A description of any benefits to the subject or to others which may reasonably be expected from the research.
   
   
4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
   
   
5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.
   
   
6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
   
   
7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.
   
   
8. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

A researcher who seeks to recruit an individual for research without conveying these elements of information in language understandable to the potential subject is not obtaining informed consent.

Research, Education, and Training

The specificity of Federal regulatory language on informed consent, its endurance through many years, and the enthusiasm with which we all adhere to it all belie the fact that little empirical work exists to document the degree of understanding achieved by research participants. There is a scarcity of data that bear upon, for example: 1) research subjects' comprehension of a study's methods and procedures; 2) subjects' understanding of relative risks and benefits of participation; 3) subjects' understanding of confidentiality and any exceptions to confidentiality; and 4) subjects' understanding of the implications of withdrawal from a study. Such data are needed to aid in designing informed consent procedures that are readily comprehended by prospective participants and, at the same time, impart all critical information.

NIH has recently taken major steps to bring improved understanding to informed consent, including the award in 1997 of fourteen, 3-year research grants to scientists who are studying informed consent. And, to further education and training, NIH has issued two solicitations for training initiatives in bioethics. One provides postdoctoral training for individuals who seek a concentrated training experience. The other supports short-term institutional awards to make increased training in bioethics available to a larger number of scientists.

In the World Wide Web era, OPRR has increasingly made information that is useful to IRBs available on our website. We are also committed to vigorous personal consultation with IRBs and institutional officials. (OPRR logs 175 to 200 phone calls per day!) This level of consultation is instrumental in the development of meaningful performance measures for IRBs. OPRR and FDA are scheduled to meet with numerous IRB members and staff in regional conferences in Houston, Tampa, and Portland OR in the next 12 months--the continuation of an ongoing educational conference program that spans two decades. OPRR participated this week in Boston in the largest meeting ever held of human subject protection advocates -- some 1,200 attendees at the annual meeting of Public Responsibility in Medicine & Research.

Commitment to strengthen and refresh the Department’s effort

Significant advances have been made in the prevention and treatment of disease in recent decades. Advances are, in large part, attributable to research that involves human subjects. At the same time, research methods have been improving and changing in an environment where concerns about human subjects protections have increased as we learn more about the risks and dangers of high tech research.

As the Departmentĵs focal point for human subjects protections, the effective and efficient functioning of OPRR in the contemporary environment is extremely important. In fulfilling its responsibilities, OPRR must not only maintain a high level of performance, but also must be perceived as being in a position to exercise maximal influence over assuring that human subjects protections requirements within its authorized domain are afforded to all human research participants.

Responding to concerns, the Director of the NIH convened an expert review panel to address two main areas of OPRRĵs operations. First, to assess if the NIH-based organizational locus of OPRR remained the most logical and appropriate for its mission; and, second to advise on any need for additional delegated authority to facilitate OPRR accomplishing its mission. The Panel consisted of well respected bioethicists, attorneys, and scientists.

On May 27, 1999, an expert OPRR Review Panel transmitted their report to the Director of NIH. The Panel made the following primary findings:

• OPRR should be relocated from within NIH to the Office of the Secretary;
  
  
• The relocated OPRR Director’s position should be at the Senior Executive Service level;
  
  
• The Secretary should create an independent advisory Committee to provide guidance, assist in setting standards, and review the operation of the office.
  
  
• That the ... Authority presently delegated to OPRR is adequate for it to address the tasks currently assigned to it, but resources available to OPRR may be inadequate for fulfilling its mission.

In turn, the Director, NIH transmitted the Panel’s report to the Secretary indicating their agreement with the Panel and recommending that the Secretary accept and take action on their findings.

In August 1999, the Secretary took action on the central recommendations and findings of the Panel. In addition, she asked the Assistant Secretary for Health and Surgeon General (ASH/SG) to undertake two distinct review processes. She asked that the ASH/SG review the OPRR organization to determine if it would be preferable to relocate OPRR as an intact unit, or to relocate only the human subjects protections component and further requested that a thorough review of resources be conducted. A work group was formed to address the question of organizational structure for the relocated office and a management consulting firm was engaged to examine the question of resources.

In October 1999, the Secretary accepted the recommendation that the newly relocated office focus solely on human subjects protections with animal welfare functions remaining at the NIH. The steps necessary to relocate the human subjects protections components and form a new organizational structure are proceeding. The management study addressing resource questions has not yet been completed. A target of March 2000 has been set for the completion of relocation activities.

The Department currently has out for comment a Notice of Proposed Rule Making (NPRM) on health privacy that contains our commitment to reviewing the human subjects protections regulations with an eye toward enhancing the privacy protections of research subjects. The NPRM solicits comments on how the privacy protections or research subjects can be enhanced and cites that the Secretary of HHS will also consult with other affected departments and agencies. This is another example of the Department’s commitment to another important area in strengthening protections for human research subjects.

Conclusion

Our collective goal is to continuously strengthen our system of human-subjects protection from the federal side and from the institutional side as well. Many promising approaches that IRBs might take are, demonstrably, already within their authority to take. In the final analysis, Mr. Chairman and Members of the Subcommittee, research investigators, institutions, and we are stewards of a trust agreement with the people who volunteer to be research subjects. We have a system in place that to the greatest degree possible 1) minimizes the potential for harm, 2) enables and protects individual, autonomous choice, and 3) promotes the pursuit of new knowledge. By doing so, we protect the rights and welfare of our fellow citizens who make a remarkable contribution to the common good by electing to volunteer for research studies. We owe them nothing less than our best effort.