Over the past few months, many experts, including the U.S. Inspector General and the External Advisory Committee that reviewed the NIH Intramural Research Program (IRP), have brought to the attention of NIH administrators several deficiencies in the internal quality control and review of clinical protocols at NIH. In May 1994, Michael Gottesman, NIH Acting Deputy Director for Intramural Research (DDIR), assembled a committee of NIH experts to address these concerns. In response to the committee discussions, John Gallin, the newly appointed Director of the Clinical Center and NIH Associate Director for Clinical Research, has recommended changes in the way clinical protocols are reviewed at NIH. The proposed changes are designed to improve the existing review system and at the same time, preserve the independence of ICD research programs.

One fundamental component of the proposed changes is that twice a year, ICDs will receive retrospective and prospective data on protocol performance (for example, patient accrual, including women and minorities, and costs), which they will use to develop processes for retrospective and prospective protocol reviews. The processes for protocol review will be evaluated for review quality by the Clinical Center Director and the NIH DDIR. In addition, the proposed plan stipulates that only patients on active protocols will be admitted to the Clinical Center. This will be ensured by requiring that an active protocol number accompanies all requests for admission and all procedures and tests. These recommendations have been approved in concept by the Institute Directors, the NIH Medical Board, and the Scientific Directors. Each ICD will submit his or her process of protocol review by Sept. 1 to Gallin. The proposed plan is expected to be implemented by the fall of 1994. The measures outlined in the draft proposal are summarized below.

1. All research protocols will be written and be specific for and descriptive of research to be performed. So-called omnibus protocols will be phased out of the NIH Intramural Portfolio of Clinical Protocols at the time of their annual review. Intramural NIH Clinical Portfolios will include three types of protocols: Research, Screening, and Training. Research protocols will include phase I - phase IV clinical trials as well as natural history protocols for studying disease pathogenesis. Research protocols may have multiple components for sceening, drug trials, disease pathogenesis, or long term effects of drugs. Projected and actual patient accrual into these categories must be stated and monitored.

2. All screening and training protocols will be written and will indicate what patients are being screened for. At the time of their annual review, screening protocols will be updated. To identify new syndromes, screening protocols may be written for long-term accrual of cohorts of patients with interesting, unexplained disease presentation. However, the projected number of patients to be accrued must be estimated and then subsequently monitored. The Clinical Center will provide ICD Scientific Directors and Clinical Directors with a prospective estimate of the costs of all screening protocols.

3. All protocols will be reviewed annually. At the time of the annual review, they will be revised to ensure that any tests being performed are defined.

4. Twice a year, the Clinical Center will meet with the ICD Scientific Directors and the Clinical Director to review all ICD protocols. During these reviews, the Clinical Center will provide each ICD with a list of all active protocols, including the date the protocol was initiated, the projected patient accrual at the time the protocol was initiated and the yearly patient-accrual rate, the percent of women and minorities accrued, the number of NIH employees working on the protocols, and the yearly protocol costs. These details will provide ICDs with the information necessary to conduct retrospective reviews of each protocol. The ICD retrospective review of protocol costs and performance will be reviewed by the Director of the Clinical Center/NIH Associate Director for Clinical Research and the NIH Deputy Director for Intramural Research.

During the biannual reviews, the Clinical Center will also provide a summary table of all new protocols under review or recently initiated. This table will contain projections for patient accrual, a prospective assessment of Clinical Center Departments that will be heavily affected by the protocol, and prospective estimates of the cost of each new protocol. All protocols, including screening protocols, will be updated at the time of the annual review to reflect new areas of research.

Annually, the ICDs will complete a new Intramural Management Controls Evaluation Survey designed to help them comply with all regulations related to clinical research.

5. NIH does not support a rigid quota of patients to be admitted for screening purposes. This may vary widely among ICDs and within an ICD over time. It will be necessary for the use of screening protocols to be justified by the ICDs each year. In this regard, the biannual protocol review will provide ICDs the information needed to ensure that screening protocols are being used appropriately. After these reviews, ICDs will make adjustments in their accrual rates to comply with their goals. The Clinical Center will monitor patient accrual to screening and training protocols to ensure that there is no abuse.

6. The extent of incidental care associated with each protocol will have to be defined. Incidental care will include management of all medical problems that may affect the research protocol or the patient's immediate well-being. At the time of a protocol's annual review, adjustments can be made to accommodate changes in the requirements for incidental care.

7. The NIH Intramural Research Program (IRP) includes Institutional Review Boards (IRBs) for each ICD whose primary mandate is to protect the rights and welfare of human subjects. Protocol review is designed to ensure that risks to subjects are reasonable in relation to anticipated benefits; that selection of subjects is equitable; and that appropriate informed consent is obtained from each prospective subject.

IRBs conduct initial and continuing (at least annual) review and approval of all Clinical Center protocols, including those for screening purposes. Proposed changes in protocol implementation must receive prospective IRB review and approval.

The IRP IRBs function in accordance with the terms and conditions of the NIH Multiple Project Assurance (MPA), the NIH policy document that describes the NIH IRP's compliance with the Department of Health and Human Services' regulations for the protection of human subjects (45 CFR 46). The NIH Office of Human Subjects Research provides oversight of the activities of the IRP IRBs to ensure that they comply with the MPA.

In determining whether an IRB-approved protocol should be implemented, Protocol Implementation Review Committees (PIRCs) are charged with the responsibility for ensuring that

* IRB minutes fully reflect the IRB's deliberations and document review and approval in accordance with 45 CFR 46.

* Where appropriate, additional safeguards have been provided for human subjects, as set forth in 45 CFR 46, subparts A, B, C, and D.

* The protocol is consistent with ICD research objectives and is likely to yield knowledge that will be important to the mission of NIH.

* All collaborative, cooperative, or multisite arrangements, including Cooperative Research and Development Agreements (CRADAs), are fully documented and free of conflict of interest.

Biannual reviews of protocols will be conducted by the Clinical Center and ICD as described below.

8. Two major changes will be made in monitoring protocols to ensure quality control in our policies and procedures.

* As described above, the Clinical Center Director/NIH Associate Director for Clinical Research will monitor patient accrual and resource utilization.

* The Clinical Center Director/NIH Associate Director for Clinical Research and the NIH Deputy Director for Intramural Research will monitor the process by which individual ICDs review the quality of clinical research.

* The Office of the NIH Deputy Director for Intramural Research will implement a new quality-control process, requiring each ICD to complete a new Intramural Management Controls Evaluation Survey to monitor the administration of protocols. This process will help ensure that ICDs are in compliance with all regulations related to clinical research.