may be made, all participating centers must conform to the final protocol requirements as well as the standard policies of the Cooperative Studies Program. In addition to the scientific aspects, the R&D Committee should address questions of feasibility. There must be an individual who is willing to serve as Pl and who is eligible to receive research funding (i.e, at least 5/8 VA time or approved by the VA Headquarters Eligibility Committee). Usually, the PI will require active support from the PI's service and other services, e.g., Pharmacy, Clinical Laboratory. There may be a need for space. R&D Committee approval to participate implies that adequate staff, space, and other resources are available and that the medical center is willing to make a commitment to the study.

Recruitment of a sufficient number of patients is often a chronic problem in conducting cooperative studies. If the R&D Committee is aware of any circumstances that would seriously compromise the medical center's ability to contribute their quota of patients, these limitations should be taken into consideration in the review of the proposal (e.g., if there is another CSP study or a local study involving identical or very similar patients).

Although it is the preference of the CSP that a single standard consent form be used at all participating centers, the ultimate responsibility for the welfare of the patient resides at the individual center. The consent form document, developed by the Principal Proponent and approved by the CSPCC Human Rights Committee, should be considered as a prototype. If the Subcommittee on Human Studies from a participating medical center makes suggestions for changes, they will be seriously considered. Similarly, local variations can be incorporated into a standard document for use in all or most medical centers. When necessary and appropriate, variations across centers will be permitted with the approval of the Chief, CSPCC. Major changes must have the approval of the CSPCC Human Rights Committee.

Medical centers that approve participation in the study must submit a copy of the minutes indicating approval by their R&D Committee and Subcommittee on Human Studies or local IRB to the CSPCC as soon as they are available. VA Form 10-1223 should be used for reporting approval by the Subcommittee on Human Studies. If the study involves drugs/devices, a copy of these minutes must be sent to the Chief, CSPCRPCC by the CSPCC before any study agents can be distributed to the participating medical centers. A VA Form 10-9012 (Investigational Drug Information Record) must be completed and forwarded to the local Pharmacy Service by the PI prior to dispensing study drugs. Additionally, if the study is conducted under an IND, completion of VA Form 1572 (Statement of Investigator) will be required. In the case of an IDE, a signed agreement from the PI is required.

A. Study Chairperson

IV. INITIATING A CSP COOPERATIVE STUDY

Once a study is funded, the Principal Proponent is designated as the Study Chairperson. The Chairperson is responsible to the CRDO, through the Chief, CSPCC, for the conduct of the study. The appointment of a Co-Chairperson may be considered, e.g., when a study involves two major disciplines. However, there must be a clear and justifiable need, and the request for a Co-Chairperson must be approved by the CRDO. This decision is made most appropriately at the time of the initial planning meeting, but may occur after CSEC reviews the protocol. The Study Chairperson should not be a member of VA Headquarters staff, a current chairperson of a CSP study, nor function as the Study Biostatistician. It is not advisable to be concurrently Study Chairperson and PI of another CSP study. The Study Chairperson may not serve as the PI at his/her own facility.

There are a number of steps to be taken before patient intake can begin. These should be done in a timely fashion or there will be delay in funding and/or patient intake. These steps include:

Final review and approval of study data forms, and submission for OMB approval.

Collaboration with CSPCC on development of an Operations Manual.

Collaboration with CSPCRPCC on pharmaceutical and FDA issues.

Nomination of members of the Executive Committee.

Selection is based on indication of patient availability and other information. When the medical centers are identified, the Study Chairperson sends the list of nominations to the Chief, CSPCC. If there has been a significant delay (more than 12 months) between approval by the local R&D Committee and the Subcommittee on Human Studies and the initiation of the study for any reason (e.g., delay in release of funding, hiring freeze), it may be necessary for these committees to re-review the proposal or at least reaffirm their commitment to participate. In these instances, the CSPCC Human Rights Committee will also conduct a re-review.

When a medical center is informed that it has been chosen to participate, the PI, with the assistance of the ACOS/R&D, prepares a formal request for funds to the CRDO that is signed by the Medical Center

Director. This request duplicates the budgetary estimates provided by the CSPCC. Any deviation from the approved budget requires the endorsement of the Chief, CSPCC and the approval of the CRDO.

C. Forms Approval and Printing

Forms approval and printing are initiated soon after the CSPCC is advised that a study is likely to be funded. Although the forms were reviewed by CSEC, there should be another review before they are sent to VA Headquarters for approval. The Study Biostatistician will initiate this review with the Study Chairperson, the Study CRP, and relevant members of the CSPCC. The Study Chairperson may visit the CSPCC for the review. The Study Biostatistician prepares the request for VA and Office of Management and Budget (OMB) approval. If time permits, prospective Participating Investigators should be asked to review the forms prior to the approval and printing stage, since it becomes progressively more difficult to make changes later.

Some studies may use electronic forms in a distributed data entry system. In this case, the CSPCC will develop the system and provide the appropriate equipment and training to the participating centers. D. The Study Operations Manual and Training Materials

After funding is approved, the Study Chairperson, Study Biostatistician, Study CRP, and other study members prepare an Operations Manual. This manual is used by the data collectors at each participating medical center and is intended to ensure that the study procedures are followed as uniformly as possible. It includes details of data collection, flow, recording and encoding, as well as procedures for reporting adverse medical events. A section on ethical conduct of the study should be included. In addition, the Pls' responsibilities to the Pharmacy Service concerning prescription writing or drug ordering, the Pharmacy Service's responsibility to the PI and other items germane to the conduct of the study are clearly defined. If appropriate, the Operations Manual should also include instructions for using investigational or study supplies. The manual frequently consists of two volumes: Volume I is typed, assembled and distributed by the CSPCC; Volume II is typed, assembled and distributed by the CSPCRPCC. Other training materials may need to be prepared for the Organizational Meeting; e.g., videotapes or demonstrations.

CSP study personnel are generally hired on term appointments. When an emergency situation arises concerning FTEE shortages or cuts, use of an IPA (through a non-profit organization or a service contract through the Acquisition & Materiel Management Service) will be used. The CSPCC needs to be fully informed of all IPA agreements. Approval authority for IPA agreements is delegated at the local VA medical facility level.

Training sessions for study personnel may take place before patient entry begins, usually at the time of the initial organizational meeting.

During the patient recruitment phase of the study, staffing will vary depending on estimated workload. Generally, many participating centers will employ full-time research assistants, though less than full-time may be sufficient. During follow-up, a part-time appointment is generally sufficient.

F.

Investigational New Drug (IND) Application and Investigational Device Exemption (IDE)

The CSPCRPCC will determine if an IND or IDE is required and provide the necessary guidance regarding required FDA approvals and submissions. In most instances, the VA CSP is designated as the sponsor of the IND/IDE. In addition, the Study Chairperson and every investigator who will be participating in the study must be registered with the FDA and meet specific requirements. The CSPCRPCC will coordinate the preparation and submission of the IND or IDE in accordance with FDA requirements. The Study CRP will be the CSP representative to the FDA and will work closely with the Study Chairperson to resolve FDA-related issues and problems regarding the study: All correspondence with the FDA from study personnel is directed through the Study CRP.

The FDA will notify the sponsor in writing of the date they receive an IND or IDE application. Drug and significant risk device studies may begin 30 days after the FDA receives the application, unless the FDA notifies the sponsor to the contrary. Copies of FDA approved submissions must be on file at the CSPCRPCC before study articles can be distributed to participating medical centers. The CSPCRPCC will obtain a signed FDA Form 1572 (Statement of Investigator) or device agreement from the Study Chairperson and each Pl as soon as the participating medical centers are selected. Drugs/devices cannot be shipped until the signed documents have been received by the CSPCRPCC. Routine updating of FDA Form 1572 will be coordinated on behalf of the sponsor by the CSPCRPCC at required intervals.

When a pharmaceutical company or device manufacturer acts as a sponsor of a study, the company accepts the responsibility for filing the IND or IDE with the FDA. In these cases, CSP requires a letter from the pharmaceutical company or manufacturer identifying their FDA assigned IND or IDE number. In such cases, a Letter of Understanding is also advisable to delineate all requirements of the CSP that are necessary to enable the company to meet its obligations as sponsor of the IND or IDE.

The CRDO delegates responsibility for each CSP study to the respective Chiefs, CSPCC who will in turn keep him fully informed and will forward to him those actions or recommendations that require his approval. Each study will be considered in a probationary status for the first year. Towards the end of this period, the Chief, CSPCC will provide a detailed report of progress to the CRDO with special attention to patient accrual and/or problems that might affect the successful completion of the study. The CRDO may discuss the contents of this report with the Study Chairperson and the Chief, CSPCC in writing or by telephone and recommend appropriate actions. Any study that does not reach at least 90% of the targeted accrual for the first year will be at risk for termination. The decision to continue a study is at the discretion of the CRDO.

Five groups share the responsibility for conducting and/or monitoring a CSP Study: the Study Group. the Executive Committee, the Data Monitoring Board, the CSPCC Human Rights Committee and the Cooperative Studies Evaluation Committee. The first three committees meet to review the operational and monitoring aspects of the study before patient intake begins. After patient intake begins, appropriate progress reports are distributed to these committees by the CSPCC at least three weeks before regularly scheduled meetings, and interim updates are provided between meetings. Studies lasting more than four years are reviewed by CSEC at three-year intervals or more often, should a specific need arise. Studies lasting four years or less are reviewed by CSEC at the halfway point of the study.

The standard schedule of meetings for the Study Group, Executive Committee and Data Monitoring Board consists of an initial meeting for organizational, informational and training purposes prior to patient intake, a meeting six to nine months after the initiation of patient intake, and annual meetings thereafter. After the first year, meetings will be scheduled as needed. In some cases, annual meetings may not be required, particularly during the follow-up phase. Ordinarily, meetings will not be held if the remaining period of patient follow-up is less than six months.

1. Study Group

The Study Group is chaired by the Study Chairperson and includes the Study Biostatistician, the Study CRP, all Participating Investigators and permanent consultants to the study. At the Organizational Meeting, the Study Biostatistician or Chief, CSPCC will make a presentation on research ethics and inform the group that site visits routinely take place. Two to three weeks prior to Study Group meetings, the Study Biostatistician prepares and distributes a report to the Study Group. At their meetings, the Study Group reviews the progress of the study, discusses any problems the investigators have encountered, and provides suggestions for improving the study. Results of blinded data related to study endpoints are not discussed with this group. When appropriate, the Research Assistant(s) from each center and other CSP personnel may also attend these meetings. It is the Study Chairperson's responsibility to write a report of each Study Group meeting within three weeks of the meeting, and send it to the Chief, CSPCC for distribution.

2. Executive Committee

The Executive Committee, chaired by the Study Chairperson, consists of four to eight members and includes the Study Chairperson, the Study Biostatistician, the Study CRP, the head(s) of any special central support unit(s) related to the study, two or three Participating Investigators, and selected consultants when necessary. If there are no more than five investigators, they may all be members of the Committee. This Committee acts as the management group and decision-making body for the operational aspects of the study. It decides on all proposed changes in the study and on any subprotocols or use of the study.data, on publications of study results, and recommends actions on medical centers whose performance is unsatisfactory. As with the Study Group, the interim results of blinded portions of the study will not be presented to this group.