the authority in the absence of the Chair to approve protocol amendments, and some do this now.

The IRB system is a vital link in the drug development process. It is crucial that patients be protected and that the process function as efficiently as possible. The system has served us well for many years. We have a chance now to make it better but we must proceed carefully and deliberately so that we do not make it more burdensome. We are, after all, dealing with the safety of patients in clinical trials, as well as the health of patients who are waiting for new cures and treatments.

Mr. Chairman, that concludes my statement.

[The prepared statement of Dr. Spilker follows:]

Mr. Chairman and Members of the Subcommittee, I am Bert Spilker, Ph.D., M.D., Senior Vice President of Scientific and Regulatory Affairs of the Pharmaceutical Research and Manufacturers of America. PhRMA represents the nation's leading research-based pharmaceutical and biotechnology companies, which discover and develop most of the new medicines used in the United States and around the world.

I am pleased to present PhRMA's views on the way in which Institutional Review Boards (IRBs) are exercising their oversight of pharmaceutical company sponsored clinical trials.

The IRB process has been firmly established in the United States for many years. IRBs are located primarily in institutions where clinical research is conducted. They review and approve a research plan before the research is conducted and exercise continuing oversight of the research. Federal regulations require that the boards have at least five members with varying backgrounds. At least one member must have primarily scientific interests, one must have primarily nonscientific interests, and one must be unaffiliated with the institution in which the IRB is located.

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PhRMA believes that the IRB system is sound and is working well for pharmaceutical company sponsored clinical trials. Patients are being informed of their rights in accordance with the basic elements required in the informed-consent document they must read and sign (21 CFR 50.25), their safety is being fully considered, and drugs are being appropriately researched.

Modest reforms can be made without new legislative authority to improve the efficiency of the IRB process and reduce duplication of efforts, allow IRBs to spend more time on ethical and safety considerations, and make new cures and treatments available sooner to patients.

IRBs are a critical safeguard to ensure that the rights and safety of patients entering clinical trials are fully considered. This is absolutely essential – and this is occurring in clinical trials sponsored by pharmaceutical companies.

In addition to safety considerations, we must make sure that the IRB system functions as efficiently as possible - so that important new medicines for such diseases as cancer, Alzheimer's, and AIDS can be made available to waiting patients as expeditiously as possible.

With any clinical trial, as with any drug, there are always risks. The potential risks to patients of any trial must be balanced against the potential benefits to be gained from the development and approval of the drug being tested. It is the job of IRBS to determine that the potential benefits to patients exceed the potential risks before they allow a clinical trial to proceed.

PhRMA agrees with the March 1998 draft report of the Inspector General of the Department of Health and Human Services on Institutional Review Boards that changes are needed to streamline the IRB process. Improvements, such as those suggested below, can be made by the Food and Drug Administration (FDA) and the Office of Protection from Research Risks (OPRR) on their own without new legislative authority:

1. A procedure should be established for regional and/or national IRBs to function more broadly and meet more frequently than local IRBs do now. This would help to facilitate the initiation of multi-center clinical research and reduce the growing workload of local IRBs. Duplication of effort would be reduced, local IRBs

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would be able to spend more time on ethical and safety considerations relating to their own single-site trials, and new medicines would be made available sooner to patients.

2. IRBs should be encouraged to hold regional and/or national meetings to exchange ideas, discuss best practices, and help each other improve their efficiency. IRB members may want to consider establishing their own professional society.

3. IRBs should be urged to provide all patients with a copy of their informed-consent form.

4. FDA and OPRR should increase the flexibility of IRBs in whatever ways they deem appropriate. For example, they could encourage IRB Chairs to appoint one or two members who would have the authority in the absence of the Chair to approve protocol amendments.

Amount of Research Increasing

During the past two decades, the amount of clinical research has been increasing and the nature of the research has become more complex. This applies to clinical trials conducted by academicians as well as non-academicians, and to research sponsored by pharmaceutical companies and conducted by clinicians in many different settings.

The result has been a major increase in the workload of most IRBs. While IRBs were initially located primarily in hospitals and academic institutions, the increased number of trials has led some contract-research organizations (CROs), site-management organizations (SMOs), communitybased physicians, and pharmaceutical companies to form IRBs. Even professional for-profit IRBs have been established.

IRBs have dealt with their increased workload in many ways. They have, for example, met more often; formed subcommittees to review protocols and make recommendations to the entire IRB; hired additional administrative staff; charged sponsors a fee to process their protocols, and increased the number of protocol amendments reviewed by the Chair alone and not the full IRB.

Multi-Center Trials

The rise in multi-center trials has been a major factor in the increased workload of IRBs.

One of the major issues faced by government, industry, academic, and other sponsors who want to conduct multi-center trials is that the protocol must be approved by the IRB at every site. Before each site can begin the trial, its own IRB must approve the protocol and informedconsent form. Thus, for a three-center trial, for example, three separate IRBs require essentially the same applications and paperwork. Each of the IRBs may have different comments, suggestions, and requirements for changes in the protocol, informed-consent form, and/or data-collection forms they review.

The premise of a multi-center trial is that every site uses the same protocol. Changes required by one IRB must be sent to all of the others for their review and approval. While minor changes may be approved in some cases through expedited procedures, the Chair may desire that an entire IRB consider any changes required by another IRB. Because IRBs generally meet monthly and sometimes every six weeks, the review-andapproval process can take a take a considerable amount of time.

The difficulties can be compounded when more sites are involved. It is not unusual for more than 100 sites to participate in a clinical trial. This is almost always the case for treatment INDs, a procedure sometimes used for drugs of special value that are administered only to a few patients at many different sites while an NDA is being prepared or reviewed.

With treatment INDs, one or more regional and/or national IRBs often are formed, and they review the protocol. When the protocol is approved, local IRBs can also review it, but most do not choose to do so. Thus, the use of a regional or national IRB serves to cut the Gordian knot of great expense, paperwork, and time required for multiple IRB reviews, while protecting the rights and safety of patients.

The concept of a regional or national IRB could be utilized for multicenter trials of more than a specified number of sites (e.g., five or 10). This would lead to a substantial decline in the number of protocols that local IRBs have to review and would result in a more rapid evaluation of the most complex protocols by national IRBs. The ultimate result: new lifesaving, cost-effective medicines would reach patients more quickly.