The Cancer Therapy Evaluation Program

The Cancer Therapy Evaluation Program (CTEP) takes in a number of mechanisms for funding clinical trials, including the Cooperative Oncology Group (COG) Program, NCI-sponsored IND studies (which require that NCI file an IND with FDA), and investigator-initiated grants to carry out clinical trials. Each mechanism has a different review process, but the scientific standards and criteria for approval are the same.

Investigator-Initiated Grant Applications The peer review process used throughout NIH also applies to grant applications for cancer clinical trials. This process has been written about extensively, and will not be described in detail here (see, e.g., NIH, 1996; Chubin and Hackett, 1990). A few aspects of the peer review process are worth noting, however. One key feature is the “dual review” of grant applications, which separates the assessment of scientific merit (carried out by scientific review groups composed of experts in relevant areas) from policy decisions about which areas of investigation are to be emphasized and the levels of funding that will be allotted across areas. The latter decisions are made by national advisory boards (in the case of cancer, this would be the National Cancer Advisory Board), which includes not only scientific experts, but also lay representatives. Final decisions about funding are made by NIH, taking into account both scientific and policy assessments (NIH 1992).

Members of scientific review groups, who are chosen from the national pool of researchers for their expertise and experience, are provided with guidance for evaluating grant proposals. Table 2 summarizes the areas of review interest and criteria to be applied in the review. When the review is complete, the proposal is either deemed to be: 1) “of significant and substantial merit,” (meaning that the question being asked is important and the plan to address it is scientifically sound) in which case it is assigned a “priority score;” 2) it is not recommended for further consideration; or 3) it is deferred until additional information is obtained so that a final determination can be made (NIH, 1992).

TABLE 2.

Review of Investigator-Initiated Grants at NIH.

Priority scores (ranging from the highest score, 1.0, to the lowest, 5.0) are based on each SRG member's rating of the scientific merit of the proposal relative to the state of the art in the relevant area. The average of all individual reviewers' priority scores becomes the overall priority score. The ranking of each proposal relative to all others is a major factor in the final determination of whether a project is funded. The important point here is that all proposals receiving a priority score (hence, all funded projects) have met the criteria for scientific merit (NIH 1992).

Cooperative Group Clinical Trial Protocols About a dozen Cooperative Oncology Groups (including some affiliated groups outside the United States), that are actually networks of academic and research organizations around the country, carry out large-scale multicenter cancer clinical trials, as well as smaller phase I and II trials. Some groups concentrate on specific types of cancer (e.g., leukemia, breast and bowel cancers) and others run trials in all types of cancer. Each has its own internal organization, through which ideas are generated and developed, but all are under the umbrella of CTEP. CTEP has its own standing protocol review committee to review Cooperative Group proposals. After review by the Cooperative Oncology Group itself, all protocols must be filed with CTEP, and all those meeting the following criteria must be subject to a “full” review:

• all protocols utilizing resources provided to the Group by NCI and investigational agents or investigational devices, regardless of who the sponsor is;
• all protocols requiring accrual of 100 or more patients;
• all Phase III protocols; and
• protocols requiring fewer than one hundred patients, which utilize commercial agents only, will receive full review. However, approval will be based only upon consideration of safety and regulatory issues. This includes bone marrow transplantation studies.

Proposals that do not meet these criteria are mainly those with accrual targets of fewer than 100 patients (generally, phase I and II trials). These are subject to a “limited” CTEP review, which eliminates review for scientific merit; however, the proposals receive the same scrutiny for safety and administrative aspects as in the full review. (Montello, 1998).

All trials using investigational drugs or devices also will have been through FDA review during the IND process. In addition, as with all other government-funded studies, the safety of human subjects, including an adequate informed consent procedure, must be in place at all institutions at which studies take place.

Protocols are judged on the following factors:

• importance and relevance of the issue being investigated;
• soundness of the study's scientific rationale;
• adequacy of the design to evaluate the specific research question(s);
• appropriateness of statistical methodology (early stopping, sequential design, etc.);
• timeliness with which the trial will be completed;
• adequacy of the modality sections (e.g., chemotherapy, surgery, radiation therapy, pathology) in describing the study's operation;
• representation as Study Chairs or Co-Chairs of investigators within the disciplines involved in the study (e.g., medical, pediatric, surgical, gynecologic);
• group's prior performance in similar studies;
• apparent feasibility of the study;
• resources required to mount the trial (dollars, patients, agents, etc.);
• regulatory, human subjects protection, and administrative and contractual concerns, (e.g., industry collaboration, NCI technology transfer objectives); and
• adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated (NCI, 1996).

Proposals are classified as:

• approved as written,
• approved with recommendations,
• request for clarifications,
• request for revisions, or
• disapproved.

If a study is disapproved, it is not eligible for funding by NCI. Studies that receive a request for clarifications or revisions are subsequently reviewed again, and cannot be funded until approved. All proposals that receive approval are not necessarily funded, however.

The Cancer Centers Program

Starting in the early 1960s, cancer institutions around the country were offered the opportunity to apply for program funding for clinical research. The Cancer Centers Program, established as a result of the National Cancer Act of 1971, formalized the concept, building on that early experience. The program has grown steadily, and there are now 58 officially designated cancer centers in the country, nearly all of which organize and run clinical trials as part of their cancer center grant activities. All Cancer Centers must reapply and be peer-reviewed at a minimum of every 5 years, but NCI may decide to award a grant for a shorter period. Cancer Center grants go mainly to fund the administrative and statistical resources required generally of an active clinical trials center, but they may also be used to fund clinical trials directly.

Clinical trials funded through a number of mechanisms take place at all Cancer Centers engaged in clinical research. NIH grants for individual trials or trial programs, trials approved through the Cancer Therapy Evaluation Program, and industry-sponsored trials all will have gone through appropriate review before they are conducted (the review mechanisms for those trials are described in the appropriate portions of this report). In addition, clinical trial protocols must be approved and study conduct reviewed for their progress by the Cancer Center itself, in accordance with NCI policy, through the Protocol Review and Monitoring System (PRMS). In addition, all trials, funded by all sources, must first pass review by the Cancer Center Institutional Review Board (IRB). Each Cancer Center has its own specific set of procedures, but all should carry out the same general functions.

Cancer Centers are required to submit annual progress reports to NCI about their activities under active Cancer Center Support Grants. The content of the report is not dictated by NCI, but is intended to cover the major functions and systems of the Cancer Center. The report of the PRMS, for example, usually includes a summary of the number of protocols reviewed, approved, terminated, etc. These reports are reviewed by NCI officials, who may request further information, for instance, if an unusual event is reported, such as termination of a clinical trial because of a high incidence of adverse events. This is unusual, however.

When new Centers apply for Cancer Center Support Grants, or when renewal applications are received, a site visit is made by a committee of external reviewers (i.e., not by NCI staff) who conduct interviews with key staff, review log books, read committee meeting minutes, etc. Using this information and the detailed application, NCI may identify deficiencies and recommend improvements, should the new grant be approved. (Bhorjee, 1998).

Protocol Review and Monitoring System (PRMS) The PRMS must have the following elements (NCI, 1997):

1.

a qualified review and monitoring committee of sufficient size and breadth of expertise to conduct a critical, fair scientific review of institutional research protocols involving human subjects;

2.

clear criteria for scientific review which take into account the specific rationale, study design, duplication of studies already in progress elsewhere, adequacy of biostatistical input, and feasibility for completion within a reasonable time frame;

3.

clear criteria for determining whether ongoing research is making sufficient scientific progress, including adequate patient accrual rates;

4.

a mechanism for overseeing the prioritization of competing protocols and thus for insuring optimal use of a center's clinical resources for scientific purposes; and

5.

authority and process for initiating, monitoring and terminating all cancer-research protocols in the center.

Cancer Centers must reapply for Cancer Center Support Grants periodically. The portion of the application related to the PRMS must include consideration of:

• appropriateness of the composition of the review committee;
• appropriateness of the criteria for scientific review and decisionmaking; and
• effectiveness of the committee in monitoring the conduct of clinical protocols, overseeing prioritization of competing protocols, and closing those that are not performing adequately.

NCI does not, therefore, review individual clinical trial protocols or the conduct of individual studies conducted under the auspices of Cancer Centers, but instead, reviews the mechanisms and criteria in place at each Cancer Center for those tasks.

The Cooperative Studies Program

The Cooperative Studies Program is a well-established entity within the VA medical research program, and has developed clear standard operating procedures for the planning, review, and conduct of clinical trials. Four coordinating centers assist investigators from all VA medical centers in developing study protocols, and one specialized coordinating center assists with pharmaceutical and medical device issues (VA 1997).

As with NIH-funded trials, the scientific merit and ethical issues related to human subjects are considered by separate groups. In addition to review by the Human Rights Committee of the Cooperative Studies Program Coordinating Center (which also participates in the development of the trial), the Subcommittees on Human Studies (the IRB equivalent) of each medical center that will enroll patients must approve all studies.

Review for Human Rights Issues—The Cooperative Studies Program Coordinating Center Human Rights Committee Each Coordinating Center has a standing Human Rights Committee composed of individuals from the community and from VA, including physicians and at least one member who is not a physician or scientist, usually a member of the clergy, an attorney, a veteran, and a member of a recognized minority group. All proposals are reviewed by this group in the planning phases, and must be approved by it before they can be submitted to the Cooperative Studies Evaluation Committee for review of scientific merit.

The Human Rights Committee is responsible for ensuring that protection of patients' rights and welfare will be adequately protected. The protocol, informed consent procedures and documents are reviewed for this purpose. If the study involves use of a medical device, the Committee follows FDA guidelines to determine the degree of risk inherent in the device.

Based on human rights considerations alone, the Human Rights Committee may accept unconditionally, accept with conditions, or reject the proposal.

Review for Scientific Merit—The Cooperative Studies Evaluation Committee Once the Human Rights Committee accepts proposals, they may be submitted to the Cooperative Studies Evaluation Committee for further consideration. Proposals are reviewed for scientific merit first by ad hoc reviewers, selected for expertise in the area of the proposal, who provide written comments. A formal review by the standing Cooperative Studies Evaluation Committee (CSEC), augmented by an ad hoc member with expertise in the specific area, is then held. The CSEC has members representing the range of medical practice, epidemiology, biostatistics, and health services research, as well as representation from FDA. The aspects singled out for review are:

• importance of the project;
• feasibility;
• clarity and achievability of objectives;
• adequacy of the investigation plan;
• correctness of technical details;
• adequacy of safeguards for the welfare of patients; and
• character and definition of response variables, measurement, data collection, frequency of observations, sample size, plans for data processing and analysis (this falls to the biostatistician).

After review, each proposal is placed into one of four categories:

1.

unconditional approval;

2.

conditional approval—after agreed upon changes are made, the project will be approved with an abbreviated re-review;

3.

rejection; or

4.

recommend for resubmission with major revisions.

The approved studies are assigned a numeric score for scientific merit and forwarded to the VA Chief Research and Development Officer, who makes the final determination of which studies will be funded. As is the case at NIH, approval does not necessarily lead to funding, but all approved studies do meet the criteria for scientific merit and protection of human subjects.

Review by Participating Medical Centers Once a proposal has received funding approval, the protocol and other documents are sent to each center scheduled to participate in the study, where it is reviewed by the Research and Development Committee and the Subcommittee on Human Studies. These groups may suggest changes, which will be considered by the study staff. All centers must agree to carry out the study as finally described in the protocol before it can begin.

VA-Funded Research at Single VA Medical Centers

Investigators at any VA Medical Center may apply for VA funds to carry out research studies within his or her institution. The reviewing body for cancer treatment trials would be the VA Medical Research Service. The system for review is modeled on the NIH peer review system, using what are called Merit Review Boards. These studies also would be under the purview of the Human Studies Subcommittees for approval of the human subjects aspects.