Spotlight on Compliance

New legislation will change human research oversight

Two bills call for more stringent guidelines

By J. Mark Waxman, JD
General Counsel
CareGroup Healthcare System, Boston

The continuing publicity surrounding both ever increasing public financial support for clinical research and claims of improper human research activities has led to calls for additional oversight of the clinical research enterprise. Two bills — H.R. 4697 and S.3060 — introduced this year illustrate important, but fundamentally different, approaches to the oversight environment.

H.R. 4697 — "The Human Research Subject Protections Act of 2002," introduced May 9, 2002, by Rep. Diana DeGette (I-CO), is designed to accomplish a variety of goals. First, the statute seeks to create a set of standardized guidelines that would be used by all federal entities involved in human subject research. A key thrust of this mandate, echoed in S.3060, is "harmonization" or standardization of rules governing issues such conflicts of interest, attestation requirements by clinical investigators, and provisions related to emergency interventions.

Second, there is a clarification of the definition of "human subject research" as clinical research that is conducted with the "direct involvement" of human subjects. Specifically excluded are the collection, analysis, or abstraction of data not gathered for research or investigation with human subjects, which includes business, health, marketing, or education records.

Third, there would be specific statutory definitions of key terms and processes. Among the most important are those with respect to informed consent and conflicts of interest. The law would mandate that the informed consent process include a consent form, which contains an acknowledgement that seven categories of information, as well as any additional categories that may be required by the Department of Health and Human Services Secretary, have been explained in writing. The categories are:

A. the purpose of the research;

B. the potential risks and benefits of being a subject in the research;

C. if relevant, the difference between research and therapeutic treatment;

D. the right to cease participation at any time;

E. the identity of the sponsors of the research;

F. any conflict of interest that the investigators have in the research;

G. as applicable to the research, the medical tests and procedures that may be necessary as part of the research, and the extent to which their costs will be paid by the sponsor or someone else.

The rules with respect to obtaining the necessary consent will be set forth in regulations, which will include information about contacting the Office for Human Research Protections (OHRP), an agency whose role will be spelled out by the statute, to submit questions.

Conflicts of interest are addressed directly in provisions discussing the role of the IRB. These provisions make it clear that the IRB, the investigator, and the institution served by the IRB will be required to address both actual conflicts of interest, as well as interests that create the appearance of a conflict of interest. The statute would specifically mandate that the institution review actual or apparent conflicts, and seek to reduce or eliminate them, as well as oversee them in appropriate cases.

Fourth, providing further impetus to a growing movement, the proposal envisions that IRBs and the related institutions may be voluntarily accredited by nongovernmental entities recognized by the secretary. This formal recognition of the desirability of accreditation of a clinical enterprise would appear to be a clear signal that more than governmental oversight is envisioned — even though the approach being taken in H.R. 4697 is voluntary as opposed to mandatory.

Fifth, recognizing that the changes desired to enhance the clinical research process will take time and effort, the statute would mandate that those receiving grants provide for a program of education for investigators and board members. To support this mandate, grants will be made to create model education programs, including best practices.

Finally, to assist with the costs of the overall compliance effort, the costs associated with mandated activities would be treated as direct, as opposed to indirect, costs.

S.3060 — "The Research Revitalization Act of 2002," introduced Oct. 4, 2002, by Sen. Edward M. Kennedy (D-MA), seeks to be both more comprehensive and more regulatory in nature than H.R. 4697. While the goals are the same, the means are clearly more aggressively stated.

S.3060 articulates that its desired reach is to all research conducted within the United States. In this regard, the legislation would mandate all such research be conducted in accordance with "Ethical Principles" specifically included by the statute. Those principles, in general, are the standards for approval to be followed by IRBs under either bill.

In the case of S.3060, the voluntary accreditation approach is made mandatory. Within six years of its adoption, IRBs would be required to be accredited by OHRP or an approved accrediting entity. The basis for accreditation would include requirements that board members have appropriate: a) expertise, experience, and education; b) insulation from conflicts; and c) established adequate review processes.

The bill addresses research in countries outside the United States. OHRP, in consultation with the Secretary of State, will be required to publish a list of countries in which research oversight is similar to the United States. In those countries research may be conducted, provided an ethics review board in that country will review it. In cases where there is research involving greater than minimal risk in countries not on the published list, review of the effort must be by an ethics review committee of that country (if it exists) and an accredited IRB.

S.3060 specifically requires regulatory activity in a wide variety of areas. Some will be helpful in hopefully in providing clear rules to IRBs and institutions on what is allowable and what is not. For example, in the area of clinical trial subject compensation, there might be a regulation that says payment may be made to a subject up to "$X" per visit during a clinical trial, as opposed to a general regulation that says payments must be consistent with a goal to protect subjects against coercion or duress. Additionally, there also would likely be a regulation to address payments for recruiting subjects, specifically, the amounts and conditions under which payments may be made. Another mandated area is specific regulation of the appropriate use of placebos in research.

As is the case with H.R. 4697, there is a great deal of emphasis on avoiding conflicts of interest. This proposal addresses institutional as well as investigator conflicts, and particularly where there is receipt of "significant income" from an interested entity — defined as an expectation of more than $10,000 in a 12-month period.

While it is not possible to know the form of any final bill coming out the Congress at this point, the messages being conveyed are clear. First, it will become highly desirable, if not mandatory, for IRBs to put themselves in a position to be accredited. This means that creating an auditable trail of documentation necessary to show compliance with existing regulatory requirements is becoming more important.

Second, if research participants, including industry, desire to maintain a voluntary, as opposed to a much more mandatory or regulatory environment, they will need to become more actively involved in the legislative process.

Third, it simply should not matter to anyone whether federal law, in terms of the approval processes to be applied, governs research.

Finally, the Association of American Medical Colleges reports, as well as others, and these legislative proposals, provide a very clear message that conflict-of-interest oversight and disclosure are high-priority items. Institutions and their related IRBs would do well to make this an area of focus.