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Testimony on Protecting Human Clinical Research Patients by Gary B. Ellis, Ph.D.
Director, Office for Protection from Research Risks
Office of Extramural Research
National Institutes of Health
U.S. Department of Health and Human Services

Before the House Committee on Government Reform and Oversight, Subcommittee on Human Resources
June 11, 1998

Mr. Chairman and Members of the Subcommittee:

I am Gary Ellis, Director of the Office for Protection from Research Risks (OPRR), Office of Extramural Research, National Institutes of Health (NIH). I am 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.

With the Inspector General (IG) of the U.S. Department of Health and Human Services (DHHS) releasing her final reports on Institutional Review Boards (IRBs) at this morning's hearing, I am pleased to address the system of protection of human research subjects that has been evaluated by the Inspector General and her staff.

This spring season marks the 24th anniversary of the formal promulgation on May 30, 1974 of the DHHS 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 cornerstone 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.

Downstream from the IRB are:

  • the executive official of the research site (e.g., dean, department chair, chief financial officer);

  • the scientific review group at the funding entity (e.g., one of the NIH Institutes or Centers); and

  • the program and administrative staff (e.g., the executive official) of that funding entity.

Each has the authority to express 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. When a study is stopped for such reasons, it is likely due to the action of a DSMB.

While I have emphasized the multiple layers of protection inherent in this system, I know you are most concerned about the possibility that this system could somehow fail. What is the possibility of a catastrophic failure in human judgment running through six or more layers? I would characterize that possibility as "slight."

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. IRB review assures that:

  • risks are minimized;

  • 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 protections are actually 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 IRB's 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 IRB's requirements or that has been associated with unexpected serious harm to subjects.
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--which was highly educational for institutions submitting their initial Assurances in the 1970s and 1980s--is due for streamlining, so that OPRR can devote more effort to working with institutions to better educate IRB members, IRB staff, and research staff. OPRR has been seriously considering a redirection of its intensive Assurance effort toward education, and performance-based reviews of IRBs. 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 would provide postdoctoral training for individuals who seek a concentrated training experience. The other will support 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 Los Angeles, Rochester NY, New Orleans, San Diego, Salt Lake City, Kansas City MO, and Detroit in the next 12 months--the continuation of an ongoing educational conference program that spans two decades. OPRR will participate in the FDA's upcoming National Forum on Human Subject Protection, which will present an opportunity to discuss with the IRB community some promising approaches in the education, orientation, management, and assessment of IRBs.

OPRR is currently recruiting for a senior professional to direct a new Education Branch in our Division of Human Subject Protections. NIH is committed to enhanced Fiscal Year 1999 funding for this Branch, which will have responsibility for: 1) developing and conducting an educational outreach program to provide clarification and guidance on ethical issues related to biomedical and behavioral research involving human subjects; 2) developing the content of human-subjects educational programs and guidance materials, including the OPRR's ongoing series of "Dear Colleague" letters, and extensive Web-based tutorials; 3) implementing a national program of 5 to 7 human-subjects education workshops per year, co-hosted by institutions conducting DHHS-supported human-subjects research; 4) initiating, coordinating, and conducting 12 to 24 educational and technical assistance site visits per year at institutions conducting DHHS-supported human-subjects research, through contact with institutional officials; IRB chairs, staff, and members; and research investigators; and 5) handling OPRR's large volume of Freedom of Information Act requests.

Consideration of Regulatory Change

As I noted, the requirements for IRB membership, function, operations, review of research, and recordkeeping are described by the core DHHS regulations for Protection of Human Subjects at Subpart A of 45 CFR Part 46. The regulations at Subpart A are the DHHS manifestation of a common rule, the 1991 Federal Policy for the Protection of Human Subjects. In addition to DHHS, the 1991 Federal Policy is shared by 16 other agencies. Because any proposal to revise Subpart A of 45 CFR Part 46 would require consideration and concurrence by these 16 other departments and agencies, we have asked that the DHHS Inspector General convey the final versions of her four reports to her counterpart at each respective department and agency.

Also to further the broad appreciation of the recommendations of the DHHS IG, I will take her final reports to the Subcommittee on Human Subjects Research, Committee on Science, National Science and Technology Council, which I chair. The Subcommittee will have great interest in suggestions for any potential changes to the common 1991 Federal Policy for the Protection of Human Subjects, as it is responsible for the uniform implementation of those common regulations. Policy changes are best not imposed unilaterally and will need to be shaped by all of the departments and agencies that will also be affected.


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 our best effort.

Thank you, Mr. Chairman. I am pleased to answer any questions about our system for safeguarding the rights and welfare of human research subjects.

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