2.

3.

Nominate the members of the Planning Committee for approval by the CRDO and choose a date for the first planning meeting.

Develop an agenda and distribute relevant material prior to the first meeting.

Serve as Chairperson at meetings.

· Coordinate the writing of the protocol.

Present and defend the protocol before the Cooperative Studies Evaluation Committee (CSEC).

Cooperative Studies Program Coordinating Center (CSPCC)

During the planning phase, the CSPCC, represented primarily by the Study Biostatistician, will:

· Help select members of the Planning Committee.

Provide logistical support for the planning meetings, including identification of the meeting site, coordination of travel, and other related activities.

Design the biostatistical and operational aspects of the protocol, including statistical and experimental design, definition of end points and data to be collected, data flow, sample size determinations, planned interval and final statistical analyses and data summaries, forms design and budget estimation.

· Arrange for review by the CSPCC Human Rights Committee.

Arrange administrative support (e.g., typing, copying and distributing the proposal to members of the Planning Committee, and preparing and submitting the final document to CSP/VA Headquarters for review by CSEC).

Cooperative Studies Program Clinical Research Pharmacy Coordinating Center (CSPCRPCC)

For studies involving drugs, biologicals or investigational devices, the CSPCRPCC, represented primarily by the Study CRP, will:

Assist in the development of the study design, particularly with regard to drugs, dosage regimens, packaging, and randomization and blinding strategies, pharmacokinetics and pharmacoeconomics.

• Assure compliance with drug or device accountability regulations and other legal requirements through the development of drug or device treatment and handling procedures.

Act as liaison between the pharmaceutical industry or manufacturers and the Principal
Proponent in the possible procurement of study drugs or devices, and develop a Letter of
Agreement (LOA) with industry.

Provide comprehensive drug information to study participants including pharmacological mechanisms, absorption, half-lives, steady-state levels, adverse reactions, interactions and similar items of interest in the formulation of drug studies.

Prepare a Drug Information Report (DIR) for each primary study drug.

Submit all DIRS to the CSPCC for review by the Human Rights Committee.

Develop an adverse medical event reporting system for documenting and reporting routine and special adverse events, to assure FDA reporting guidelines are followed.

4. Planning Committee

The Planning Committee is responsible for preparing a final study protocol, which should reflect a collaborative, in-depth effort in its development with agreement on all major issues of the proposed study.

The Committee includes the Principal Proponent, the Study Biostatistician, the Study CRP (when appropriate), at least two potential participating investigators and VA or non-VA consultants. An expert in economic analyses will be included when this is an objective of the proposed study. If several disciplines are involved (e.g., medical and surgical), they should be reflected in the composition of the Committee. The total planning group consists of eight to ten people. Participation does not require VA affiliation. If industry support is planned, an industry representative may be invited to participate in the planning process.

E. Planning a Cooperative Study: The Process

The planning will usually require two meetings typically lasting two days each. Under special circumstances, additional planning activities may be funded.

The Principal Proponent submits a list of proposed attendees to the Chief, CSPCC as early as possible but no later than six weeks prior to a meeting. Clinical expertise other than the specialty of the Principal Proponent should be considered for representation on the Planning Committee. Requests for travel should be submitted to CSP/VA Headquarters at least four weeks prior to scheduled meetings.

The first planning meeting is held in Washington D.C. to facilitate the attendance of the CRDO. The final planning meeting is held in the vicinity of the CSPCC to permit attendance of other relevant CSPCC staff and to facilitate the review of the proposal by the Coordinating Center's Human Rights Committee. Meetings will not be funded unless all major participants are able to attend.

If the first planning meeting is not held within three months of the notification that planning is authorized, or if subsequent planning meetings and activities do not occur within six months of the first meeting, it will be assumed that the planning activity has ceased, and no further support for planning will be provided. It is the responsibility of the Chief, CSPCC to notify the CRDO to discontinue support for planning or, if the Chief, CSPCC concurs that the circumstances in a given situation are unusual and justify an exception from this practice, to petition the CRDO for an extension. Funding for the second meeting is contingent upon a satisfactory first meeting. After the first meeting, the Chief, CSPCC is required to reaffirm in writing to the CRDO that the study is viable and that planning activity should continue.

The CSPCC is responsible for sending the following materials to the Planning Committee prior to the first planning meeting. Relevant material should be submitted to the CRDO as well.

· Planning Request - including relevant publications submitted by Principal Proponent.

· Reviews of the preliminary proposal.

Detailed analysis of reviewers' comments by Principal Proponent and/or Study Biostatistician, including a point-by-point response to the reviewers' criticisms.

A review of the literature to provide the Planning Committee with a basis for design decisions (e.g., effect sizes, estimates of variability, outcome measures).

Secondary questions of importance. Secondary objectives, if any, should be restricted to a minimum.

The population to be studied: inclusion/exclusion criteria. If women and/or minorities will be excluded, a compelling rationale for exclusion should be provided.

Schedule and frequency of observations, laboratory tests and/or data collection.

· Comparison's of interventions/treatments/subgroups.

Anticipated magnitude of differences in outcome measures to be detected.

The number of patients needed and how they will be assigned to regimen groups. Patient accrual is often a problem in cooperative studies.

Randomization procedures (if appropriate).

Other specifics of the experimental design, (e.g., blinding techniques).

· Procedures to assure the scientific integrity of the study such as masking, independent endpoint assessment, quality assurance and audit procedures, and participating site performance standards.

Preliminary estimates of budgetary support (personnel, travel, and "all other") needed for the
Chairperson's office, participating medical centers and central laboratories (if any).

.

· Patient rights and informed consent issues.

If the Planning Committee decides that the study is not feasible, its clinical importance is questionable, or the study is untimely or irrelevant, this decision and the reasons for it will be communicated to the CRDO by the Chief, CSPCC. Otherwise, there should be some preliminary discussion of potential participating medical centers and specific planning for a formal determination of patient availability. This determination consists of prospective (preferred) or retrospective screening of actual patient intake by each of these

medical centers using the inclusion/exclusion criteria agreed upon. The review should be over a sufficient period of time to provide a reasonable estimate of the availability of study patients. This information should be available before the second planning meeting.

A plan for publications should be considered and incorporated in the planning process. Although it is early in the course of the study, it is recognized that publications are in fact the end product of a clinical trial (see Section VI.C. of these Guidelines). Therefore, it is the responsibility of the Principal Proponent, the Coordinating Center and the Planning Committee to anticipate that product. At the CSEC review, members will be instructed to pay particular attention to the publications plan.

Development of the protocol is a joint responsibility of the Planning Committee members. However, the primary responsibility lies with the Principal Proponent, the Study Biostatistician and the Study CRP.

The final planning meeting is spent refining the protocol and data collection forms, assessing preliminary patient availability estimates, formulating the final budget and conducting the Human Rights Committee review. (See Section III.A. for a description of the Human Rights Committee review.) To ensure that these goals are accomplished, and that there is a thorough human rights review, the Principal Proponent mails an essentially complete protocol including research data forms and informed consent documents to each member of the Planning Committee and the Human Rights Committee at least three weeks prior to the meeting. A preliminary budget (including justification of equipment or unusual items and brief but informative job descriptions) is also required by the CSPCC. The Principal Proponent must brief the HRC conceming material changes made at the final planning meeting. If submission of this material is late or if it is substantially incomplete, as determined by the Chief, CSPCC, the final planning meeting will be rescheduled. After the final planning meeting, the CSPCC will prepare the final proposal for submission to the Cooperative Studies Evaluation Committee, through CSP/VA Headquarters, by the required deadline.

If appropriate, the Study CRP begins negotiating with the pharmaceutical company early in planning to secure commitments for drug/device supplies for the study. The Principal Proponent usually makes the initial contact with the company, and the Study CRP follows up and completes the negotiations. The CRDO should be informed of all discussions. The Study CRP should attempt to secure a written commitment from each involved company during planning or at least prior to CSEC review. It is important that these negotiations be completed prior to CSEC review so that the start of the study will not be delayed once funding is approved. Industry representatives may participate in planning meetings, since they have detailed knowledge of the drugs involved (see Section V.Q.). If the Principal Proponent is negotiating with the drug company for securing funds in support of the study, the Chief, CSPCC should be involved in these discussions and if possible a letter indicating this support should be obtained prior to CSEC review.

The Biopharmaceutics/Pharmacokinetics Laboratory at the Albuquerque CSPCRPCC must be considered first when planning a laboratory component for the study. If the Principal Proponent determines that a core lab is required, the Chief, Biopharmaceutics/Pharmacokinetics Laboratory Section at the CSPCRPCC should be consulted. If this laboratory will be used in the study, the Chief should be included in the planning of the study, although not necessarily as a member of the Planning Committee.

In some cases, it may be necessary to conduct a pilot study or feasibility trial before embarking on a full-scale study. Protocols for such pilot studies are generally developed through the usual planning process and presented to the CRDO who will determine if CSEC review is required. The completed pilot study may be reviewed by CSEC prior to the initiation of the full-scale trial.

Install equipment at two to three additional medical centers. Continue evaluation of equipment and monitor patient recruitment.

Install equipment in all remaining centers.

The objective of the planning meetings is to produce the final proposal. The CSPCC will be responsible for preparing the proposal for submission to CSP/VA Headquarters for CSEC review. To facilitate review, the proposal will be assembled in two volumes. The first volume contains the study protocol, study budget material, selected human rights documents and CVs of the Principal Proponent(s), Study Biostatistician, and any other members of the Planning Committee who will attend the CSEC meeting. When there is an economic analysis, the associated protocol, budget and CV are also included. All reviewers of the proposal are provided with this section. The second volume, containing a variety of supporting information, is provided to those individuals assigned as primary reviewers.

If there are issues that should be called to the attention of CSEC, the CSPCC Chief will include them in the cover letter. The Chief will also comment on the appropriateness of the statistical analysis plan, take note of the budget, and address any budget issues that CSEC should consider. Similarly, the CSPCRPCC Chief will call the attention of CSEC to particular drug or device considerations that should be addressed during the review.

2) For a resubmission of a proposal:

If the proposal is a resubmission, the following documents are also required:

CSEC Report: A copy of the CSEC report, which contains the recommendations made by CSEC at the time of the first review.

Letter from the CRDO to the Principal Proponent that summarizes the results of the first CSEC review.

A statement by the Principal Proponent or the Study Biostatistician that summarizes the specific changes made in response to CSEC recommendations, including a point-by-point response to each concern listed in the CSEC report and notification letter.

C. Executive Summary/Abstract

The first page of the study protocol is a one-page abstract that succinctly states the research question(s) and the salient elements of the proposed study design including such information as the number of patients and participating sites, duration of patient intake and treatment (follow-up), definition of patient samples, treatment arms, and endpoints.