In addition, certain federally sponsored and much privately sponsored research is subject to the regulations of the Food and Drug Administration (FDA) at 21 CFR Parts 50 and 56. FDA regulations confer protections on human subjects in research when a drug, device, biologic, food additive, color additive, electronic product, or other test article subject to FDA regulation is involved. FDA regulations and the provisions of the Common Rule are largely congruent, although some significant differences exist.

The Common Rule defines "research" as "a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge." Activities which meet this definition constitute research for purposes of the Common Rule, whether or not they are conducted or supported under a program which is considered research for other purposes. Some demonstration and service programs, for example, may include research activities.

The Common Rule defines “human subject” as “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information."

Institutional Review Boards

The cornerstone of our system of protection of human research subjects is the local Institutional Review Board at the research site. The IRB is, by federal regulation, to consist of 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 members must have varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution.

The IRB must be sufficiently qualified through the experience, expertise, and diversity of its members to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review specific research activities, the IRB must be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice. The IRB must therefore include persons knowledgeable in these areas.

Under the Common Rule, 17 federal Departments and Agencies cannot provide funds for human subjects research unless an IRB approves the protocols for such studies. No human-subjects research supported by a Common Rule Department or Agency may be initiated, and no ongoing research may continue, in the absence of an IRB approval.

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

risks to subjects are minimized;

risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result;

selection of subjects is equitable;

there is proper informed consent and documentation of informed consent;

when appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects;

when appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data; and

additional safeguards have been included in the study to protect the rights and welfare of any subjects likely to be vulnerable to coercion or undue influence

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.

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. Federal regulations specify 14 elements of informed consent, 8 of which are required:

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.

A description of any reasonably foreseeable risks or discomforts to the subject.

A description of any benefits to the subject or to others which may reasonably be
expected from the research.

(4)

(5)

(6)

(7)

(8)

A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.

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.

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.

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 all of these elements of information in language understandable to the potential subject is not obtaining informed consent.

Assurance of Compliance

Within DHHS, OPRR oversees implementation of the human-subject regulations in all DHHS facilities as well as domestic and foreign institutions or sites receiving DHHS funds. In keeping with the provisions of the Common Rule, 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. Under the Common Rule, OPRR has authority for approving an Assurance at DHHS-funded institutions for federal-wide use.

An Assurance with OPRR 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

2OPRR utilizes several types of Assurance documents. Multiple Project Assurances cover all of an institution's federally-supported research. Cooperative Project Assurances cover participation in DHHS-supported multicenter clinical trials. Single Project Assurances cover individual DHHS-supported projects.

if there is a problem. Where noncompliance has occurred, OPRR has the authority to require corrective actions under the Assurance or to withdraw its approval of the Assurance.

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 (MPA). A Multiple Project Assurance, as the term implies, is an institution's pledge of full human subject protections for multiple projects at the institution.

At present, OPRR holds some 430 Multiple Project Assurances that cover some 730 research institutions in the United States and Canada. Most of these Multiple Project Assurances, at the voluntary election of the research institution, commit all activities at the institution--irrespective of funding source--to the DHHS regulations for Protection of Human Subjects. OPRR appreciates the willingness of many institutions to choose this voluntary option.

From 1987 to 1998, the VA West Los Angeles held Multiple Project Assurance #M-1097, and the VA Sepulveda held Multiple Project Assurance #M-1292. [First approved in 1982, MPA #M-1097 initially covered only the Wadsworth facility. The Sepulveda MPA #M-1292 was first approved in 1983.] Coincident with an administrative merger and at the request of these institutions, a new Multiple Project Assurance, #M-1087, was approved in 1998 for the VA Greater Los Angeles Healthcare System.

On March 22, 1999, OPRR deactivated Multiple Project Assurance #M1087 for reasons I will describe in a moment. First, I will describe the history of OPRR's interaction with the VA West Los Angeles.

OPRR's oversight of compliance by the VA West Los Angeles with DHHS human-subject rules In 1993, as OPRR was investigating informed consent in schizophrenia research at the University of California Los Angeles, OPRR received an allegation that informed consent procedures for schizophrenia research at the VA West Los Angeles also failed to meet regulatory standards. Upon investigation, OPRR found that numerous informed consent documents lacked basic, required information such as a complete description of (i) the procedures for manipulation and withdrawal of medications; (ii) reasonably foreseeable research risks; and (iii) potentially advantageous alternatives to research participation.

OPRR required correction of these deficiencies in July 1994. OPRR also required that the VA West Los Angeles implement four additional protections for subjects of psychiatric research; specifically, (i) that the IRB include, at every meeting where such research is reviewed, a special representative who could give voice to the perspective of potential subjects in safeguarding their rights and welfare; (ii) that informed consent documents disclose when medication is determined by the research protocol rather than by clinical need; (iii) that informed consent documents disclose when the treating clinicians are also the research investigators; and (iv) that a special Data and Safety Monitoring Board (DSMB) be established to monitor such research (i.e., where the treating clinicians are also the research investigators). The VA West Los Angeles agreed to

implement these corrective actions, and its Multiple Project Assurance was restricted to require quarterly progress reports to OPRR documenting implementation.

In January 1995, I led an OPRR site visit to the VA West Los Angeles. The site visit revealed a number of deficiencies in the Institutional Review Board's operating procedures and record-keeping practices that undermined the effectiveness of systemic protections for human subjects. These deficiencies included (i) inadequate monitoring of changes required by the IRB; (ii) inappropriate designation of exemptions; (iii) inappropriate use of expedited review procedures; (iv) inadequate continuing review procedures; and (v) inadequate procedures for reporting unanticipated problems involving risks to subjects or others. The site visit also revealed the need for (i) a comprehensive education program for IRB members and investigators; and (ii) increased support staff for the IRBs.

These findings were communicated to VA West Los Angeles officials orally at the conclusion of the site visit, and in writing on February 14, 1995. The facility's Multiple Project Assurance remained restricted, and quarterly progress reports documenting appropriate corrective actions were required.

OPRR continued to receive progress reports from the VA West Los Angeles in 1996, but no progress reports were received in 1997. OPRR requested additional information in April 1998, because it was still not clear that all required actions had been successfully implemented. The VA West Los Angeles provided reports to OPRR in June and November 1998.

Review of this information by OPRR revealed continuing, serious deficiencies in human subject protection procedures at the West Los Angeles facility. In specific, OPRR reviewed the minutes of 9 IRB meetings conducted in May, June, and July 1998. OPRR found that in 7 of those 9 meetings, the IRB conducted business (i.e., approved human subjects research) without a valid quorum, either because a majority of members failed to appear or because there was no nonscientist member present, as the regulations require. Two of those meetings lacked both a numerical quorum and a nonscientist member.

In addition, you will recall that in 1994 OPRR required that the IRB include a special subject representative when reviewing psychiatric research. In OPRR's 1998 review of 9 IRB meetings, 1 of the 3 meetings at which psychiatric research was approved failed to include such a representative.

Moreover, OPRR found that the VA West Los Angeles failed to document implementation of the 1994 requirement for a Data and Safety Monitoring Board to oversee psychiatric research. In fact, the VA West Los Angeles Policy and Procedure Manual for Human Subjects Research, provided to OPRR in November 1998, states that "DSMB monitoring procedures have not been finalized yet" (page 22), 4 years after OPRR imposed the requirement.

In addition, OPRR was concerned that individual IRB members did not appear to be receiving and reviewing sufficient written information to ensure substantive continuing review of research, as the DHHS human subjects regulations require. In specific, the VA West Los Angeles Policy