Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI Table of Contents Part A 1 2 3 Part B 4 5 6 Part C 7 8 9 10 11 Part D 12 13 14 15 16 Part E 17 18 19 Appendices

Part B: The Development of a Clinical Trial

6. Phase 3 Trials

• 6.1. Scientific Policies of CTEP
• 6.2. Who Is Eligible to Conduct Phase 3 Trials
• 6.3. Eligibility Requirements
• 6.4. Coordination of Planning With CTEP Staff

6. Phase III Trials

6.1 Scientific Policies of CTEP

If significant activity is observed in any disease during Phase 2, further clinical trials usually compare the efficacy of the experimental therapy with that of a standard or control therapy. If reasonable standard treatment can be defined for the disease in question, we generally wish to know whether the new agent or therapy constitutes a significant contribution in terms of patient benefit. A variety of trial designs may be suitable, according to the state of the art treatment in the particular disease. The most satisfactory ones are the controlled trial that compares the new agent to a standard single agent or a standard regimen plus the experimental agent to the standard regimen alone. Whatever design is selected, however, an appropriate control group must exist and relevant endpoints must be used to measure relative effects. Of greatest medical importance, of course, are relative survival and quality of life. Other measures, such as complete remission rate or disease-free survival, may also be of interest.

These studies, which attempt to isolate the role of a new agent in the treatment of a specific cancer, are of obvious importance to industrial sponsors, because the results are pivotal in applications to register the agent for commercial distribution. They are of no less importance to the oncology community, because such approval makes the agent generally available for patient care. The results of such trials may be of great medical importance as well. If the control group is properly selected and the experimental treatment is constructed as imaginatively as possible, such trials may yield valuable information for the care of cancer patients.

Every protocol must contain a section that discusses the study design and the plan for evaluation of the data. The major objectives of the study should be stated as hypotheses to be tested, and a target sample size should be clearly specified. Justification for the sample size goal, in terms of precision of estimation or of levels of type I and type II error, should be provided. In a Phase 3 study, it is insufficient simply to give the number of patients to be accrued on each arm. The protocol should specify the test to be used to compare the treatment groups, and the probabilities of drawing incorrect conclusions when performing this test with the proposed sample size should be given. The magnitude of improvement in outcome that can be reliably detected using the planned sample size should also be specified. The accrual rate of eligible patients per year that can be realistically anticipated should be stated and documented. The protocol should describe specific statistical plans for interim analysis of accumulating data.

The committee for monitoring interim results should also be indicated.

If evaluation of treatment effect will require use of nonrandomized controls, a thorough description of the control group to be employed should be part of the protocol. This description should include a detailed discussion of comparability issues and analytic techniques.

6.2 Who Is Eligible to Conduct Phase III Trials

Phase 3 trials may be submitted from any source eligible to submit a Phase 2 trial (see Section 5.2) Because the sample sizes required for such studies are usually quite large, however, a multicenter approach is frequently the only feasible one. It is expected, therefore, that the clinical Cooperative Groups will be the major research bases for such trials. Proposals for Phase 3 studies from single institutions should be very specific in documenting adequate accrual potential.

Furthermore, if the proposal includes collaboration with institutions not formally affiliated with the research base, the protocol should include a description of the procedures by which the collaborating institutions will manage the conduct of the protocol (see Section 7.2.14).

6.3 Eligibility Requirements

Phase 3 clinical trials must include a review of the available evidence to show whether or not clinically important gender or race/ethnicity differences in the response to the intervention are to be expected. The design of such trials must reflect the current state of knowledge about any such expected differences. Phase 3 clinical trials are, in addition, required to provide valid analysis to measure differences of clinical or public health importance in intervention effects based on gender or racial/ethnic subgroups where there is evidence supporting differences.

Investigators should consider the following circumstance when planning a Phase 3 clinical trial:

• Prior data strongly indicate that the intervention will show significant clinical or public health differences among gender, racial, and/or ethnic subgroups. In this case, the primary question(s) to be addressed and the design of that proposed Phase 3 trial must specifically accommodate these differences. For example, if men and women are thought to respond differently to an intervention, the Phase 3 trials must be designed to answer two separate primary questions, one for men and the other for women, with adequate sample size for both.
• Prior data strongly support no significant clinical or public health differences among subgroups from the intervention. In this case, gender, race, and/or ethnicity will not be required as subject selection criteria. However, the inclusion of gender, racial, and/or ethnic subgroups is still strongly encouraged.
• Prior data neither strongly support nor negate the existence of significant clinical or public health differences among groups. In such cases, the Phase 3 trial must include sufficient and appropriate gender, racial, and/or ethnic subgroups, so that valid analysis of the intervention effects on subgroups can be performed. However, the trial will not be required to provide high statistical power for each subgroup.

Cooperative Group Phase 3 studies:

Effective October 1, 1995, all Phase 3 protocols must include accrual targets for males, females, and minorities (protocol specific accrual targets for Phase 1 and 2 studies are NOT required). The accrual targets should reflect the expected accrual over the life of the study. The NCI suggests the accrual targets be based on data from similar trials completed by the Cooperative Group during the previous 5 years. It is hoped that the accrual targets will resemble the gender, racial, and ethnic composition of the U.S. population as closely as possible. A worksheet, including a description of the currently recognized HHS racial and ethnic categories, is attached for your reference.

Protocols that do not address the above gender and minority issues will be returned without Protocol Reviewed Committee (PRC) review.

Planned Gender and Minority Inclusion:

I. American Indian or Alaskan Native: A person having origins in any of the original peoples of North America, and who maintains cultural identification through tribal affiliation or community recognition.
II. Asian or Pacific Islander: A person having origins in any of the original peoples of the Far East, Southeast Asia, the Indian subcontinent, or the Pacific Islands. This area includes China, India, Japan, Korea, the Philippine Islands, and Samoa.
III. Black, not of Hispanic Origin: A person having origins in any of the black racial groups of Africa.
IV. Hispanic: A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin, regardless of race.
V. White, not of Hispanic Origin: A person having origins in any of the original peoples of Europe, North Africa, or the Middle East.

Special Populations:
Individuals from special populations (minorities, cancer survivors, HIV+ individuals, pregnant and breast-feeding women) can NOT be arbitrarily excluded from participation on a study. All exclusions must be justified based on establishment that inclusion is inappropriate with respect to the health of the research subjects or the purpose of the research.

6.4 Coordination of Planning With CTEP Staff

Large clinical trials involve years of effort and a substantial expenditure of resources. Accordingly, a certain amount of coordination is necessary for the optimal planning of specific studies of this type. Staff members of CTEP are in an excellent position to advise investigators on the existence of other proposed or ongoing studies that are closely related or even identical to ones being planned. In addition, CTEP staff can advise investigators contemplating large-scale trials concerning the concordance of the proposed trial with CTEP program goals.

We have therefore adopted procedures by which ideas for clinical trials can be evaluated by CTEP staff before the investment of time and energy in development of a complete protocol. For Phase 1 and Phase 2 studies using CTEP resources, investigators are required to submit a Letter of Intent (LOI); for Phase 3 studies, investigators are required to submit a written concept for the proposed trial.

In general, these provide a sketch of the proposed study, including the hypothesis to be investigated, its rationale, and relevant design considerations. CTEP can then formally review and provide a written Program Concept Review commenting on study originality and programmatic interest.

Table of Contents

Part A 1 2 3

Part B 4 5 6

Part C 7 8 9 10 11

Part D 12 13 14 15 16

Part E 17 18 19

Appendices

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