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Testimony on Protection of Human Research Subjects by Dr. Gary B. Ellis
Director, Office for Protection from Research Risks
National Institutes of Health
U.S. Department of Health and Human Services

Before the Senate Committee on Governmental Affairs
March 12, 1996

Mr. Chairman and Members of the Committee:

I am Gary Ellis, Director of the Office for Protection from Research Risks (OPRR). The Office for Protection from Research Risks, housed administratively and physically at the National Institutes of Health (NIH), is charged with implementing regulations regarding the Protection of Human Subjects (45 CFR Part 46) that have been promulgated by the Department of Health and Human Services (HHS). In doing so, OPRR oversees a welldeveloped, yet ever-evolving, system of protection of human research subjects. The Food and Drug Administration (FDA) also has human subject protection regulations that apply to research involving products such as drugs, biologics, and medical devices. The FDA has provided a written statement for the record that includes its comments on today's report from the General Accounting Office (GAO). Mary Pendergast, FDA Deputy Commissioner and Senior Adviser to the Commissioner, is present to answer any questions you may have regarding FDA's process.

My testimony, today describes the interests of the Department in protecting human subjects in research--a responsibility of enormous weight.

In response to Executive Order 12975 (October 3, 1995), OPRR conducted a February 1996 review of the protections of the rights and welfare of human research subjects that are afforded by existing policies and procedures for research conducted or supported by HHS.

OPRR's review documents an ever-evolving, dynamic system of protection of human research subjects based on multiple layers of review by expert and lay people exercising their best judgment. As such, this system of protection is highly sensitive to, and readily influenced by, educational efforts. OPRR and the HHS components that conduct and support research are well-invested in education and have specific plans,to enhance that commitment even further. The Department has accepted lead-agency responsibility for support of the new National Bioethics Advisory Commission (NBAC). Taken together, current and planned activities sum to HHS' retaining as a priority continued vigilance over human subjects protection. The recent call by Secretary Shalala to make bioethics "as sophisticated as our science" embraces the intent of Executive Order 12975 and reemphasizes OPRR's charge.

HHS Regulations for Protection of Human Subjects

At Title 45, Code of Federal Regulations, Part 46 (45 CFR Part 46), the Department has codified its regulations for Protection of Human Subjects. There are four subparts:

Subpart A (last revised June 18, 1991) is the Basic DHHS Policy for Protection of Human Research Subjects. Sixteen other Federal departments and agencies are also formally bound to identical text by statute, regulation, or Executive Order. OPRR chairs and staffs the interagency body responsible for fostering uniform implementation of this common rule --the Human Subjects Research Subcommittee. Committee on Health, Safety, and Food, National Science and Technology Council.

Subpart B (last revised November 3, 1978) identifies Additional DHHS Protections Pertaining to Research, Development, and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization. Subpart B is currently undergoing review in the Department.

Subpart C (last revised November 16, 1978) identifies Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects.

Subpart D (last revised March 8, 1983) identifies Additional DHHS Protections for Children Involved as Subjects in Research.

The local Institutional Review Board (IRB) at the research site is the cornerstone of this svstem of protection of human subjects. No human subjects research may be initiated, and no ongoing research may continue, in the absence of IRB approval. HHS cannot provide funds for, or conduct, human subjects research unless one or more IRBs approves the protocol for such studies.

An IRB is established at the local level and, by regulation, has a minimum of five people, including at least one scientist, one nonscientist, and one person not otherwise affiliated with that institution.

IRB review is a prospective as well as continuing review of research by a group of individuals A,ith no formal interest in the research. In reviewing research, IRBs must be knowledgeable about the research site; the resources of the institution; the capabilities and reputations of the investigators and staff; and the prevailing values and ethics of the community and, most important, the likely subject population.

In order to approve research, the IRB must determine that all of the following requirements are satisfied:

  1. Risks to human subjects are minimized.

  2. Risks to human subjects are reasonable in relation to anticipated benefits, if any, to human subjects, and the importance of the knowledge that may reasonably be expected to result.

  3. Selection of human subjects is equitable.

  4. human subject or the human subjects legally authorized representative, in accordance with, and to the extent required by 45 CFR Part 46.

  5. Informed consent will be appropriately documented in accordance with and to the extent required by 45 CFR Part 46.

  6. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of human subjects.

  7. When appropriate, there are adequate, provisions to protect the privacy of human subjects and to maintain the confidentiality of data.

In addition, when some or all of the human subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these human subjects.

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.

Continuing review is substantive and meaningful. In approving the continuation of ongoing research, an IRB attests to its satisfaction that the research continues to be conducted in accord with all relevant provisions of the regulations.

I mentioned that IRBs oversee the informed consent process. The regulations specifN, eight required elements of informed consent:

  1. A statement that the studv 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 anv reasonably foreseeable risks or discomforts to the subject.

  3. A description of anv 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 then, 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.

OPRR implements these regulations by: (i) negotiating formal, written assurances of compliance with institutions engaged in research covered by 45 CFR Part 46; (ii) investigation and oversight of institutional compliance; and (iii) professional and public education.

Assurance of Compliance with 45 CFR Part 46

Each institution engaged in research (i) covered by 45 CFR Part 46 and (ii) conducted or supported by HHS must provide assurance satisfactory to OPRR that it will comply with 45 CFR Part 46. OPRR employs several types of assurance instruments. Institutions with a track record in human subjects protection satisfactory to OPRR are selected for the Multiple Project Assurance (MPA). At present, 448 institutions hold an active MPA. Of these institutions, 98 percent have voluntarily elected to extend the protections of 45 CFR Part 46 to non-HHS-supported research.

In seeking assurances for their respective research portfolios, the 16 other Federal Departments and Agencies that have embraced Subpart A of 45 CFR Part 46 (also known as the "Federal Policy for the Protection of Human Subjects" and the "Common Rule") are often linked to OPRR. In lieu of requiring institutional assurances for work they conduct or support, they are required to accept assurances, appropriate for the research in question, on file with OPRR and approved for Federal-wide use by OPRR.

OPRR also negotiates Single Project Assurances (3,133 currently active) and Cooperative Project Assurances (1,345 currently active) to meet the varying circumstances of HHS-supported research at other- than-MPA-assured institutions.

The recommendations of the Advisory Committee on Human Radiation Experiments (ACHRE) identify three problems in consent forms reviewed by ACHRE: (i) overly optimistic portrayal of the likely benefits of research; (ii) inadequate explanation of the impact of research procedures on quality of life and personal finances; and (iii) incomprehensibility, to lav people. OPRR staff were provided with this ACHRE analysis immediately upon the October 3, 1995 release of the ACHRE report, so that OPRR staff could incorporate this information into OPRR review of IRB handling of informed consent documents prior to approving assurances to comply with 45 CFR Part 46. Additionally, this ACHRE analysis is being featured in professional and public educational activities described below.

Investigation and Oversipht of Institutional Compliance

Under 45 CFR Part 46, there are multiple administrative actions that can be taken for violation of the regulations. OPRR may restrict or suspend its approval of an institution's assurance. Affected research projects cannot be supported by HHS until the terms of the restriction have been satisfied. Examples of such restrictions include, but are not limited to:

  • suspending the assurance's applicability relative to some or all research projects until specified protections have been implemented;

  • requiring prior OPRR review of some or all research projects to be conducted under the assurance;

  • requiring that some or all investigators conducting research under the assurance receive appropriate human subject education;

  • requiring special reporting to OPRR.

OPRR may withdraw its approval of an institution's assurance. Affected research projects cannot be conducted or supported by any HHS component until approval of an appropriate assurance is reinstated bv OPRR.

OPRR may recommend to appropriate HHS officials or Public Health Service (PHS) agency heads:

  • that an institution, a component of an institution (e.g., department or an investigator) be temporarily suspended or permanently removed from participation in specific projects,

  • that HHS peer review groups be notified of an institution's or an investigator's past noncompliance prior to review of new projects; or

  • that institutions or investigators be declared ineligible to participate in HHS-supported research (i.e., debarment or suspension). If OPRR makes this recommendation, the debarment or suspension process may be initiated in accordance with the procedures specified at 45 CFR Part 76. Debarment or suspension of a participant in a program by one agency has government-wide effect.

OPRR currently has 81 open compliance oversight investigations. One-quarter of these derive from non-HHS-funded research, owing to institutions' voluntary commitment of all research to HHS rules. Since January 1, 1990, OPRR has initiated 321 human subject compliance oversight investigations, of which 240 were completed as of January 31, 1996. During this period, OPRR conducted 18 "for-cause" site visits (i.e., in the course of compliance investigations) and 10 "not- for-cause" site visits (i.e., for technical assistance).

Corrective actions based on compliance oversight evaluations are intended to remedy identified noncompliance with 45 CFR Part 46 and to prevent reoccurrence. Because each compliance investigation is different, OPRR tailors its corrective actions to the nature of the violation and to the improvements needed in the affected institution's system of protections. The large majority of the 227 investigations completed from 1990 through 1995 involved some corrective action on the part of the institution. Such actions include institutional sanction or increased monitoring of individual investigators, modification of informed consent documents for specific studies, changes in IRB policies and procedures, and revision of the institutional system of protection for human subjects.

The following are examples of additional oversight mechanisms within HHS:

  • Initial scientific and technical review groups must take into consideration the risks to subjects of proposed research, the adequacy of protection against these risks, the potential benefits of the research, and the importance of the knowledge to be gained. This second level of independent review of research involving human subjects, which requires detailed documentation of the consent process and any additional human subjects concerns, follows local IRB review. OPRR is informed when NIH peer review groups identify concerns about human subject protections, and these concerns must be resolved before an award may be made.

  • Cooperative Oncology Group research supported by the National Cancer Institute is monitored through a program of on-site audits which include an evaluation of human subject protections.

  • Many NIH-supported, multi-center, clinical trials include provision for monitoring by an independent Data and Safety Monitoring Board, which periodically evaluates emerging data to ensure subject safety as the trials progress.

  • HHS benefits from the continuing and detailed inspection of IRBs conducted by FDA field staff. The findings of such inspections are shared with OPRR, when an applicable OPRR-approved assurance exists. In turn, OPRR provides the results of its compliance oversight site visits to FDA.
Professional and Public Education

OPRR responds on a day-to-day and long-term basis to requests for clarification and guidance with respect to ethical issues raised in connection with biomedical or behavioral research involving human subjects, as required by Section 491(b)(1) of the Public Health Service Act. In addition, OPRR promulgates interpretation of 45 CFR Part 46 by means of periodic "Dear Colleague" letters; sponsorship with FDA of 4 to 6 national workshops each year, serving an annual total of approximately 1,000 attendees; free distribution of three instructional videotapes; production of the comprehensive Institutional Review Board Guidebook; and technical assistance site visits. OPRR fulfills hundreds of requests for educational materials each month via a voice mailbox and FAX-on-demand service. Fulltext OPRR materials will soon be electronically retrievable.

In light of the focus of ACHRE recommendations on IRBS, the cornerstone of the HHS response to the ACHRE report is enhanced education directed toward the conununity of IRB members, IRB administrators, institutional officials, researchers, and potential human subjects. OPRR collaborates closely with Public Responsibility in Medicine and Research (PRIM&R), a Boston-based private, nonprofit organization, to stage an annual public meeting for individuals interested in the governance of human subjects research. More than 600 people attended the October 1995 PRIM&R meeting, at which the ACHRE recommendations were presented for the first time to the IRB community.

OPRR has scheduled presentations and discussions of the ACHRE recommendations at upcoming national human subjects protection workshops in Atlanta (April 11-12, 1996), Oklahoma City (June 3-5, 1996), Honolulu (July 26-27, 1996), Peoria IL (September 26-27, 1996). and Houston (November 1-2, 1996). The November 11-12, 1996 PRIM&R annual conference (San Diego) is expected to address IRB implementation of the ACHRE recommendations.

One ACHRE recommendation to IRBs is that they appropriately allocate their time so that the), can adequately review studies that pose more than minimal risk to human subjects. Anticipating this recommendation, OPRR issued a May 5, 1995 "Dear Colleague" letter with guidance on this point. OPRR reminded institutions of the procedures described at 45 CFR 46.110 that permit expedited review of activities that involve no more than minimal risk and are identified on a list of 10 research categories promulgated by the Secretary of HHS in 1981. In its letter, OPRR also reminded institutions of the six categories of research at 45 CFR 46.101(b)(1)-(6) that are exempt from IRB review.

The ACHRE demonstrated the utility of first-hand, external examination of institutional oversight of human subjects research, and there is a consensus among experts and regulators about the benefits of such review. Accordingly, OPRR expects to enhance its educational efforts to include a program of technical assistance site visits. Such visits, to number from 12 to 24 per year, are of mutual educational benefit - strengthening both the institutions program of human subject protections and ensuring the fidelity of OPRR's assurance negotiations and documents.

The ACHRE identified the urgent need for better understanding and implementation of the informed consent transaction between researcher and subject. The specificity of the language about informed consent in 45 CFR Part 46, its endurance through many years, and the enthusiasm with which all parties 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 paucitv of data that bear upon, for example, (i) a research subject's comprehension of a study's methods and procedures; (ii) subject's understanding of relative risks and benefits of participation; (iii) subject's understanding of confidentiality and any exceptions to confidentiality; (iv) subject's understanding of the implications of withdrawal from a study; and (v) subject's ability to distinguish between the roles of clinician and investigator--and the consequences of failure to make that distinction. 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.

In July 1995, the National Institute of Mental Health (NIMH) announced an important program that will make available NIMH research funds for investigations into the informed consent process in research involving individuals with mental disorders. NIMH has thus taken the lead in stimulating investigations into the informed consent process in research, and OPRR hopes that this is an indication of an increasing investment by supporters of research in the development of new knowledge related to informed consent. In addition to the NIMH activity, in November 1995, the NIH Office of Extramural Research convened an interagency group to begin pursuit of a broad research agenda in informed consent.

Taken together, these efforts -- undertaken on a national scale to ensure the centrality of ethics in human subjects research -- maintain and reinforce the trajectory of HHS on the path of preventing misadventures in contemporary human subjects research.

National Bioethics Advisory Commission

There exists a void in our multi-tiered system of human subjects protection, that of a national body that can deliberate and advise on difficult issues in bioethics as they arise. In the past. the Nation has had a demonstrated need for a national, deliberative body of private citizens to offer the Federal Government analysis of the bioethical dimensions of ongoing and ne,,N, activities and problems. From 1974 to 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was highly productive, laying out much of the philosophical basis for our current regulatory system. Following the National Commission, an Ethics Advisory Board was active in the Department of Health, Education, and Welfare. Then, in the early 1980s, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research served an important role.

The need for such a body is arguably greater today than ever before. The ACHRE report recommended establishment of a mechanism to provide for the continuing interpretation and application of ethics rules and principles for the conduct of human subject research in an open and public forum. The ACHRE identified at least three unresolved ethical issues in need of such deliberation:

  • clarification of the meaning of minimal risk in research with healthy children;

  • development of regulations to govem the conduct of research with institutionalized children; and

  • development of guidelines for research involving adults of questionable competence, particularly for research in which subjects are placed at more than minimal risk but are offered no prospect of direct medical benefit.

On October 3, 1995, Executive Order 12975 created the National Bioethics Advisory Commission, to be appointed by the President. OPRR has since been coordinating the initial efforts of administration of the NBAC, so that the NBAC can begin operations and begin to address the recommendations of the ACHRE at an early date.

General Accounting Office Analysis

Today, we are pleased to receive from the GAO its independent analysis of HHS oversight of human subjects protection.

The GAO's "Scientific Research: Continued Vigilance Critical to Protecting Human Subjects" accurately describes the overall functions related to human research subjects of OPRR. including education by means of guidance and workshops; prevention in the form of negotiating written assurances; and oversight through inquiries and investigations.

In particular, the GAO report acknowledges that current oversight activities are working. GAO review of 40 OPRR compliance case files, accompaniment of OPRR staff on a compliance site visit to a major research institution, and interviews found that OPRR effectively identifies noncompliance, requires institutions to take corrective actions, and, in most cases, achieves satisfactory resolution of institutional noncompliance within 12 to 18 months.

The GAO Report identifies a consensus among experts and regulators about the benefits of first-hand review of institutional oversight of human subject research. Accordingly, OPRR expects to enhance its activities to include a program of technical assistance site visits, as I described a moment ago. OPRR expects to continue its program of for-cause and not-for-cause compliance site visits.

The GAO report notes that primary responsibility for OPRR's negotiating Multiple Project Assurances of compilance covering the 450 to 500 institutions that receive most of HHS' funding for human subjects research rests with one individual. The NIH Director honored this part-time, unpaid physician in June 1995 with the NIH Director's Award for her extraordinary service, and OPRR is proceeding to recruit for a health scientist administrator to join her in negotiating Multiple Project Assurances.

NIH is described by the GAO Report as "in the position of regulating itself" and OPRR as in a position of "potential weakness," when OPRR oversees human subjects research conducted by NIH (i.e., by the NIH intramural Research Program.) in fact, OPRR oversees and interacts with NIH just as with any extramural research institution. NIH holds a Multiple Project Assurance approved by OPRR. The NIH institutional official and Multiple Project Assurance signatory is the NIH Deputy Director for Intramural Research, who heads the NIH Intramural Research Program. OPRR's independent oversight and authority are not compromised, as the lines of authority of the NIH Deputy Director for Intramural Research and the OPRR Director do not cross within NIH. The NIH Intramural Research Program's need for 5 years to implement corrective actions after being cited by OPRR in 1991 for compliance violations is best viewed as an index of the complexity of fully implementing the corrective actions rather than a function of weakness in OPRR's ability to enforce human protection regulations within the NIH organizational structure.

In the final analysis, research investigators and institutions 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 (i) minimizes the potential for harm, (ii) enables and protects individual, autonomous choice, and (iii) promotes the pursuit of new knowledge. By doing so, we protect the rights and welfare of our fellow citizens who make a remark able 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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