Drug Treatment and Handling Procedures (DTHP).

Tentative list of participating medical centers and a report of the patient availability survey. Administrative issues, if any.

Other sections can be included as appropriate, e.g., description of training procedures, reliability studies, special laboratory procedures, definition of endpoints, central readings, etc. a.- Biostatistical and Research Data Processing Procedures (BRDP)

This section contains plans for analysis that are as complete as can be envisioned for both periodic (monitoring summaries) and final analyses. It includes a statement of the variables to be analyzed and the intervals at which summaries and analyses will be done. The plan includes prototype tables, charts, data summaries, summaries of analyses, etc., and an outline of the format of the progress reports to be provided to the relevant committees. The anticipated final data summaries and biostatistical analyses are defined and described in detail. This section may also include a summary of: case report form completion and data flow; data quality monitoring procedures; and computing software/hardware to be used.

b. Research Data Forms

A complete set of essentially final research data forms is required when the proposal is submitted to CSEC for scientific evaluation.

Properly designed data forms are required for the collection of complete and accurate data in a clinical trial. The forms contain all information essential to the study. They should include only data that will be needed in the analysis; it is important to practice parsimony in developing data forms. Forms should be designed to ensure that data collected will be unbiased. They should also be easy for the researcher to use so that errors can be minimized. The forms should be formatted so that data can be efficiently entered into a computer for later retrieval and processing. Individual questions on the form should be constructed so that they are objective, singledimensional and unambiguous. For these reasons, the data forms are designed jointly by the researchers including clinicians, the Study Biostatistician, Study CRP, and data processing personnel.

The order of the data forms and the elements in each form should be arranged to follow the sequence of the procedures required for conduct of the study. In addition to clear instructions for completion of the forms, self-explanatory codes and criteria should be available on the data forms for immediate reference.

Deficiencies in data forms can often be uncovered by a preliminary field trial so that revision can be made before the forms are distributed for use in all the participating sites. The CSPCC has responsibility for final approval of the data forms.

When the proposed study involves the use of drugs, the Study CRP develops a Drug Information Report (DIR) on each primary study drug. This report provides comprehensive information on the pharmacology, toxicology, and previous experience in the proposed indication. The report supplements the information presented in the background and rationale section of the protocol, and may be expanded by the Principal Proponent or other members of the Planning Committee. When determined appropriate, investigator brochures - prepared by pharmaceutical companies - may be included in the Drug Information Section in the Operations Manual and/or be distributed to investigators after the study begins.

A detailed procedure for handling drugs is written by the Study CRP in accordance with VA and FDA regulations. The DTHP includes detailed instructions for the receipt, distribution, administration and use, proper disposition and report requirements of the drugs or devices.

e. Medical Center Participation and Patient Availability

This section contains a list of medical centers that have expressed interest in participation in the study and describes the methodology and results of the assessment of patient availability. Other Supporting Information

f.

Additional sections can be included as appropriate. For example, if a central laboratory is needed, the protocol should include a detailed description of the procedures for obtaining specimens, evaluating results and transmitting data. Other material might include descriptions of training procedures, reliability studies, or definitions of endpoints.

Submitting the Proposal

All CSP proposals are submitted through the assigned CSPCC. After the final planning meeting and review by the CSPCC Human Rights Committee, the Principal Proponent sends the final version of the proposal to the CSPCC, where it is reviewed, typed in the required format and duplicated for submission to CSP/VA Headquarters. If the proposal is typed elsewhere, it should be provided on diskette to the CSPCC so that it can be reformatted according to CSP conventions.

CSEC meets twice each year in April and October. The associated deadlines for submission of completed proposals to the CSP/VA Headquarters for CSEC review are outlined in the following table:

To allow sufficient time for review, typing, duplication, binding and distribution of the proposal, a complete final draft must reach the CSPCC at least six weeks before the deadline for submission to CSP/VA Headquarters. These deadlines must be observed or the review will be deferred to the next meeting. A protocol that is deficient in any important aspect will be returned to the Principal Proponent for appropriate action before it is resubmitted.

III. CSP REVIEW PROCEDURES

Ethical, scientific, professional, manuscript preparation and administrative aspects of the proposal are evaluated by the CSPCC Human Rights Committee (HRC), and the Cooperative Studies Evaluation Committee (CSEC). In addition, each proposal is reviewed prior to the CSEC meeting by at least three independent reviewers who provide written critiques. Finally, after CSEC scientific approval and CSP funding approval, the proposal is submitted for review by the R&D Committee and Subcommittee on Human Studies at each medical center being considered for inclusion in the study. If non-VA centers are participating, the proposal is submitted to the local Institutional Review Board (IRB) for review.

A. The CSPCC Human Rights Committee

Any study involving the use of human subjects requires consideration of the protection of the rights and welfare of the person volunteering to participate in the study. A Human Rights Committee (HRC) has been established at each CSPCC to provide these safeguards.

The Committee is composed of individuals from the community and VHA who have the interest and background required to consider the ethical and legal issues involved in the participation of human subjects in research. The Committee is chaired by a person who currently holds a VA appointment. At least two members are non-VA appointees who have no direct connection with research within a VA facility. At least one practicing physician from the community and one non-physician scientist will be on the Committee. Additional representation usually includes a member of the clergy, an attorney, a veteran and/or a member of a recognized minority group. Membership and procedures are consistent with appropriate sections of M-3, Part I.

2. Responsibilities

The responsibility of the HRC at the planning stage of the study is to determine if the protection of the patient's rights and welfare in the proposed study is adequate. Assessment is usually done at the final planning meeting but always prior to submission for CSEC review. The Committee must ensure that the patient (or guardian, if the patient is judged incompetent) will be fully informed of the meaning of and any risk in participation. This review should include an in-depth consideration of the protocol and the informed consent procedures and documents. If the study involves the use of a medical device, the HRC must make a determination (based on current FDA guidelines) as to the degree of risk inherent to the device.

The HRC may, on consideration of human rights issues only, accept the study as proposed, accept it with conditions, or reject it outright. If the study is rejected, the revised protocol must be approved by the HRC before it is submitted for CSEC review. A recommendation by a HRC may not be reversed except by its own action. Therefore, no study can be submitted to CSEC for evaluation until it has been approved by the HRC. If the study is accepted with conditions, the Study Biostatistician is responsible for ensuring that the conditions have been met before it is submitted for CSEC evaluation. A letter to this effect signed by the Chairperson, HRC is required.

The HRC provides a general assessment of the human rights aspects of the proposal. Neither this review nor the general assessment of feasibility, scientific merit, relevance and professional ethics by CSEC is a substitute for review by the local participating centers' R&D Committees and the Subcommittees on Human Studies or local IRBS.

B. Drug Information

When a study involves drugs, the Study CRP develops a Drug Information Report (DIR) on each primary study drug that provides comprehensive information including known side effects, adverse effects, contraindications and precautions. This report(s) is sent to the Chief, CSPCC who will distribute it to the Human Rights Committee, the Planning Committee and others as appropriate. A Drug Information Section containing all DIRs for a given study is incorporated into Volume II of the CSEC submission. This information is provided for use by CSEC, the PI's, and their R&D Committees and Subcommittees on Human Studies or their local IRBs.

C. Written Reviews for Cooperative Studies Evaluation Committee

Once CSP/VA Headquarters receives the proposal, it is reviewed to ensure that all the required information is included. Copies of the proposal are then sent to ad hoc reviewers who provide written critiques to the Cooperative Studies Evaluation Committee. These written critiques are available to the Principal Proponent, Study Biostatistician, and Study CRP prior to the meeting. The reviewers may request anonymity.

Reviewers are asked to comment on the importance of the project, its feasibility, the clarity and achievability of its objectives, the adequacy of the plan of investigation, the correctness of the technical details, the adequacy of safeguards for the welfare of the patients and any other pertinent features of the proposal. The biostatistical reviewer also is asked to comment on the character and definition of response variables, measurement, data collection, frequency of observations, sample size, plans for data processing and analysis and any other relevant features.

The Cooperative Studies Evaluation Committee (CSEC) reviews new and ongoing CSP studies and makes recommendations to the CRDO regarding the scientific merit of the studies.

1. Committee Members

Members of CSEC are appointed by the Secretary of the Department of Veterans Affairs upon recommendation by the CRDO. There are members representing many medical specialties as well as representatives from the FDA, the fields of epidemiology and biostatistics, and from health services research. All members have had extensive experience in clinical research and in the conduct of clinical trials. Members are appointed for a four-year term. Two members of CSEC, usually a biostatistician and a clinician, are assigned primary responsibility for reviewing each protocol. In addition, for new proposals, the Committee is augmented by an ad hoc member knowledgeable in the particular subject matter of the protocol being reviewed. The Chairperson of CSEC is nominated by the CRDO. The responsibilities of the Chairperson are to conduct the meeting and summarize the deliberations of the Committee. The CRDO and his staff serve as coordinators for the meetings. Appendix B lists CSEC members as of the publication date of these Guidelines.

2. The CSEC Review Process

The Principal Proponent and the Study Biostatistician appear before the Committee. If the proposal includes an economic analysis component, the consultant appears as well.

At the meeting, the Principal Proponent will be asked to make an opening statement not to exceed ten minutes, followed by a five minute statement from the Study Biostatistician. If there are CoProponents present, only one will make a formal statement. If there is an economic component, the individual responsible for preparing that protocol will also be expected to make a five minute statement. At the request of the Principal Proponent and with the concurrence of the CRDO, additional consultants may be available to answer questions and may make a five minute statement. These statements should be based on written documents that are distributed to CSEC members prior to the meeting.

They should provide a concise summary of the research problem and state why it should be supported by VA.

The Principal Proponent and the Study Biostatistician should take relevant notes at the meeting since in-depth reports of the CSEC proceedings are usually not provided.

After the formal statements, the ad hoc reviewer, the CSEC primary reviewers and the remaining CSEC members question the proponents on problems and issues they have identified. The proponents defend the protocol in an interactive discussion.

After the open session, the proponents are excused for the CSEC Executive Session. The ad hoc reviewer remains and participates as a voting member in this closed session, during which the Committee formulates recommendations.

3. CSEC Recommendations

Generally one of four actions is taken:

Unconditional approval. The study is approved without changes and is recommended for funding.

Conditional approval. The Committee approves the study with the understanding that the Principal Proponent and the Study Biostatistician will make certain changes or additions to the protocol. When the changes are made and are approved by the CRDO, the Chairperson of CSEC, and the CSEC primary reviewers, the study will be recommended for funding.

Reject the study. The Principal Proponent will have an opportunity to review the CSEC report. If the Principal Proponent wants to resubmit the proposal to the CSP, a new request for planning must be sent to the CRDO.

Reject or defer consideration of the study with recommendation for resubmittal. In unusual circumstances the Committee finds the study worthwhile, but in need of major revisions. In this case, should the investigator choose to submit a revised protocol, the CRDO may waive the requirement for an initial planning request and review.

The Principal Proponent(s), the CSPCC Chief, and the Study Biostatistician are informed of the CSEC recommendation immediately after the close of the Executive Session.

For new studies that are approved, CSEC assigns a numeric rating of the scientific merit of the proposal. Approval of a proposal by CSEC does not ensure funding. Action by this Committee constitutes a recommendation to the CRDO. Written notification by the CRDO constitutes the official action on the proposed study. Studies approved but not funded are reviewed on a continuing basis and will be dropped from the awaiting funding list if the CRDO determines that funding will not become available within 18 months after CSEC approval. If the Principal Proponent then chooses to resubmit a proposal, a new request for planning must be sent to the CRDO.

When the Principal Proponent has been notified that funding is available, the CSPCC will then send the study protocol to the selected medical centers for their review. In order to avoid delay, the Participating Investigator (PI) should schedule the Research and Development (R&D) Committee and Subcommittee on Human Studies reviews (or, for non-VA centers, the Institutional Review Board (IRB] review) as soon as possible.

Comments, criticisms and/or suggestions for improvement of the proposal by the local R&D Committees are welcomed by the Cooperative Studies Program and will be seriously considered by study staff in preparing the Operations Manual (the primary procedural guideline for the study). Although some changes