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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents
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5.1 Scientific Policies of CTEP
5.1.1.1 Planning and Coordination of Phase 2 Trials by CTEP
As a sponsor, DCTD must devise and implement a plan for Phase 2 trials of new agents. An adequate Phase 2 plan, while conceptually straight-forward, is often difficult to execute. A reasonable plan presupposes answers to the following questions:
The plan of Phase 2 development is prepared by CTEP staff working with the industrial sponsor during late Phase 1 and is announced in the solicitation of LOIs.
5.1.1.2 Single Agent Phase II Studies
A Phase 2 study:
In addition, well-designed Phase 2 trials do not permit the entry of more patients than necessary to ensure detection of a medically significant level of activity.
Phase 2 studies are disease-oriented. The various tumor types are tested in Phase 2 as distinct clinical entities, as each has differing prognostic factors, eligibility requirements, and patterns of responsiveness to a particular agent. As there may be many unknown or uncontrollable factors contributing to variability in outcome, CTEP attempts to sponsor two Phase 2 trials in each of the tumor types.
The goal of these initial Phase 2 trials is to determine whether the new agent has activity against particular cancers. These trials, therefore, serve as a screen for further study. For this reason, every effort should be made to avoid false results. Although false-positive results are certainly undesirable, false-negative Phase 2 results are especially misleading, as the discovery of a potentially useful antitumor agent may be significantly delayed or overlooked altogether.
CTEP has adopted guidelines concerning eligibility requirements based on patient characteristics that appear to have a particular impact on likelihood of response. Specifically, for initial Phase 2 studies, we currently seek trials that restrict patient eligibility to the minimum extent of prior therapy consistent with ethical medical practice. Protocols for the initial Phase 2 trials of an agent whose MTD has been well characterized should restrict patient entry in the following ways:
This policy will have the following desirable consequences:
Clearly, the population of patients defined in this way is highly selected, and the results of these initial trials will not necessarily be representative of the agent's activity in the general population of patients with the disease in question. Once a new agent shows significant activity in this initial, relatively favorable, subset of patients, eligibility criteria in subsequent studies will permit entry of patients with less favorable prognostic characteristics, so that such patients may have an opportunity to benefit from an active agent. In this second stage of the new agent's Phase 2 evaluation, a more accurate assessment of its activity in the general population of patients with cancer may be obtained.
5.1.1.3 Combining Agents
As a general rule, two or more agents should be combined when there is definite evidence of the activity of each alone against a particular cancer. We believe that the most rational approach to the development of a new cancer agent dictates that it should not be combined with another agent(s) until it has shown reproducible evidence of activity in at least two single-agent trials in a disease. Alternatively, or in addition, combinations may be proposed when there is a rationale firmly grounded on laboratory evidence that is relevant to the clinical circumstance.
In the past, much development of agent combinations occurred intuitively; oncologists combined two, three, or more putatively active agents in uncontrolled studies of antitumor effect and adverse effects. To be sure, some very real therapeutic advances were achieved by this process, but the lack of a systematic and stepwise approach and the frequent absence of proper control groups have often left the oncology community in the uncertain position of not knowing whether results with a particular regimen represented progress or not. More particularly, the overall impact of a new agent on both efficacy and adverse events may remain unclear without a systematic approach. Finally, the process of NDA or BLA approval is impeded when available data do not elucidate the specific contribution of the new agent.
Clearly any intelligently designed and flexible new agent development program must provide room for both approaches. Well-conceived small pilot trials testing new hypotheses will always have an important place in the developmental therapy of cancer. We shall, however, continue to pay close attention to the rationale behind all proposed combinations and shall continue to ask whether certain proposals for therapeutic research might not be better approached by a Phase 3 design rather than Phase 2.
Although the activity of a single agent is the most common basis for its inclusion in a combination, CTEP will certainly consider other rationales. There may be substantial laboratory evidence of synergy between two cancer agents. Such evidence is particularly compelling if it is also based on a knowledge of mechanism of action. Alternatively, an agent inert against cancer might be added because of evidence that it alters the pharmacodynamics or pharmacokinetics of the cancer agent. For example, the modified porphyrins are being tested as both radio- and chemo-sensitizers, even though they themselves have little antitumor activity. In such cases, CTEP will carefully scrutinize the rationale and evidence offered in support of a proposal based on these kinds of considerations.
When combination studies are submitted to CTEP for review, therefore, it is particularly important to make clear the goals, background, and rationale of the proposal. If experimental results in the laboratory are the basis for the study, they should be relevant to the clinical circumstance and cited in adequate detail. If preliminary clinical results are the motivation, they should be similarly cited; unpublished results should be provided as part of the background or in an attachment to the protocol document. If the trial proposes a feasibility pilot, the protocol should state clearly what kinds of results the investigators would regard as medically significant and where they would propose to go next if a significant result is obtained. We are not requesting a detailed plan of a follow-up study or detailed speculations about likely outcomes. Rather, we are seeking an understanding of how the pilot proposal will fit into a strategy of development of the new therapeutic idea.
5.1.2 Individual Protocol Considerations
5.1.2.1 Single Disease Studies
Each tumor should be considered for Phase 2 study separately. With few exceptions, this means that there should be separate protocols for each tumor type. If there is a compelling reason for including several under one protocol, such as uncommon tumors, then there should be separate statements for each tumor type regarding: (a) eligibility requirements, including extent of prior treatment, (b) acceptable sites for measurable disease, (c) response criteria, and (d) accrual objectives.
5.1.2.2 Eligibility Requirements
In certain diseases, common sites of involvement are either not bidimensionally measurable or the techniques for assessment do not permit quantifiable measurement. Under these circumstances, tumor response may be evaluated without quantification by an investigator; in such cases, it is particularly desirable that responses be assessed by more than one observer. Examples include bone metastases, lymphangitic pulmonary disease, and many parenchymal brain lesions.
Performance Status:
Under most circumstances, entry to initial Phase 2 studies should be confined to patients who are largely ambulatory (ECOG =<2). Patients should be expected to survive a sufficient period of time that adequate observations can be made.
Organ Function:
Evidence that the function of major organs is normal is required. This includes creatinine level of =< 1.5, cardiac function at least Grade 2, pulmonary function moderately compensated, and no neurologic, gastrointestinal or endocrine impairment that would compromise the safe use of the investigational agent.
Gender:
Where appropriate, both women and men should be studied. NIH policy requires that women and members of minority groups must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification establishes inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Please include a separate section regarding the "Inclusion of Women and Minorities" that describes the inclusion of women and members of minority groups appropriate to the scientific objectives of the study. In the protocol, the investigators must describe the composition of the proposed study population in terms of gender and racial/ethnic group, and provide a rationale for selection of such subjects.
5.1.2.3 Accrual and Statistical Considerations
The accrual goals of a study should be specified in advance, with a maximum number of patients stated explicitly. Justification for the target sample size, in terms of precision of estimation or levels of type I and type II error, should be provided. Multistage designs for distinguishing an unacceptable level of response from a promising level are recommended {e.g., Fleming, Biometrics 38:143 (1982); Simon, Controlled Clinical Trials 10:1, (1989)}. The accrual rate of eligible patients that can be realistically anticipated should be given. Mechanisms should be in place for early stopping of negative trials.
Statistical considerations for Phase 2 trials of combinations should base unacceptable and promising levels of response on activity levels of the components or other combinations. References to those levels should be cited.
5.2 Who is Eligible to Study Phase 2 Agents
The following categories of physicians are eligible to serve as investigators in Phase 2 trials.
5.2.1 Cooperative Groups
All registered physicians of the Cooperative Group, including those at full member institutions, in Community Clinical Oncology Programs (CCOP), Cooperative Group Outreach Programs (CGOP), at cancer control, or at affiliate institutions may participate as investigators on CTEP's Phase 2 and Phase 3 trials.
Note: A Cooperative Group may have policies that place further restrictions on investigator eligibility.
5.2.2 Cancer Centers
Staff physicians at institutions designated as comprehensive or clinical Cancer Centers by the NCI may participate on CTEP's Phase 2 and Phase 3 trials. Such physicians may be:
5.2.3 Affiliates
Physicians affiliated with a research base may participate as investigators on CTEP's Phase 2 and 3 clinical trials provided that:
5.2.4 New Agent Development Contractors and Cooperative Agreement and Grant Awardees
This category includes those with Phase 1 or Phase 2/3 contracts or cooperative agreements awards and NCI-funded Consortiums including (a) Adult CNS Phase 1/2 Clinical Trials Consortium, (b) AIDS Malignancies Clinical Trials Consortium, (c) Pediatric Phase 1 Clinical Trials Consortiums and (d) Pediatric Brain Tumor Clinical Trials Consortium. This category also includes investigator-initiated grants to study new agents (e.g. R01, R03, R21 and P01).
5.2.5 Multicenter Phase 2 Trials
CTEP expects that Phase 2 trials will be performed only at the proposing research base. If a protocol chair wishes to collaborate with other institutions not formally affiliated with his or her research base, the protocol should include a description of the procedures by which the collaborating institutions will manage the conduct of the protocol and should list on the protocol face sheet each institution and the name of responsible investigator at each. The protocol should specifically address the issues described in Section 7.2.14.
5.3 Who is Eligible to Administer Phase 2 Agents
For a particular clinical protocol, physicians who may administer DCTD investigational agents are:
5.4 Restriction on Participation in Phase 2 Studies
Please note that CTEP may restrict the testing of any investigational agent to a very limited number of locations. Although most new agents proceed to a Phase 2 program open to all eligible investigators, some are restricted to single centers or to specific centers until a safe, reliable Phase 2 dose has been defined and CTEP and the investigator community are confident that the agent is ready for general testing among all investigators. Limitation due to inadequate supply of the agent may also occur.
5.5 How to Obtain Information About Phase 2 Agents
5.5.1 Investigator's Brochure
This document contains all relevant information about the agent, including animal screening, preclinical toxicology, detailed pharmaceutical data, pharmacology and mechanism of action. The brochure also contains information about the clinical adverse events observed in clinical trials. CTEP has an Investigator's Brochure for each investigational agent it sponsors. These are routinely provided to investigators who are approved to conduct a clinical trial of the agent at the time the LOI is approved and when the Investigator's Brochure is updated. When necessary, investigators with approved LOIs or protocols may obtain the Investigator's Brochure from the address listed in Appendix IV.
5.5.2 IDB Physicians
Each DCTD investigational agent is assigned to an IDB staff physician, who is responsible for coordinating the clinical development of the agent. When an investigator has important concerns about the design of a contemplated trial, he or she should contact that physician.
5.5.3 Clinical Research Pharmacists
The Pharmaceutical Management Branch has a staff of clinical research pharmacists that interact closely with IDB and Clinical Investigations Branch (CIB) staff physicians. Clinical research pharmacists are available to provide pharmaceutical and agent information data on DCTD investigational agents and are responsible for processing and approving all compassionate requests for DCTD agents. (See Appendix IV for addresses and telephone numbers).
5.6 The Letter of Intent
5.6.1 Definition
The Letter of Intent (LOI) is an investigator's declaration of interest in conducting a Phase 1 or 2 trial with a specific investigational agent in a particular disease. Approval of the LOI by CTEP reserves that "slot" for the investigator's protocol if it is submitted within a defined time frame (see Section 5.6.7) and signifies agreement that the investigator shall submit a protocol based on the terms stated in the LOI.
5.6.2 Purpose
CTEP has devised the LOI system to maximize the efficiency and fairness by which experimental agents are allocated to investigators for study. Proper use of the system ensure both CTEP and investigators of a steady flow of new agents into the clinical trials system. It enables CTEP to plan the development of several agents simultaneously. For the investigator, the LOI system also promotes much saving of time and effort, because its use should spare him or her the writing of a protocol that might not be approved. Protocols submitted subsequent to favorable review of an LOI are much more likely to be approved without request for major modification, because many of the crucial features of a Phase 2 proposal must be specified in the LOI itself. The LOI system also is used for the submission of combination pilot studies. In these cases, reviews typically focus on the rationale for combining the agents, the proposed sample size, and the adverse events of each agent when given alone. The system also provides the investigator with an opportunity to explore the proposal with CTEP staff at the concept stage.
5.6.3 Ground Rules for the LOI System
LOIs should be submitted for all Phase 1 or 2 trials that include a DCTD investigational agent. They should be submitted according to the following schedule:
Each Phase 1 or 2 protocol should be preceded by an approved LOI. Our experience demonstrates that protocols submitted without a previously approved LOI are more likely to be rejected as unnecessarily duplicative or needing major modification. If a Phase 1 or 2 protocol is submitted without a prior LOI having been submitted, the protocol will initially receive an "LOI-level" review before being reviewed as a protocol.
5.6.4 Submission of LOIs
In order to review the LOI properly, CTEP must have the following information:
All of this information should be provided on the LOI Submission Form (Appendix VI) and submitted to the Protocol and Information Office, CTEP (address provided on the form).
Cooperative Group LOIs must be cosigned by the protocol chair and either the Group chair or the Group's executive officer.
Agent development contractor LOIs must be cosigned by the contract principal investigator.
We encourage protocol chairs to submit, where appropriate, a letter accompanying the LOI that explains in greater depth the rationale, where not obvious, or any unique features of the study. Such additional explanation is not usually necessary for single agent Phase 2 trials but may assist in the review of more complex proposals involving experimental agents.
5.6.5 Review of LOIs
On receipt of a LOI, CTEP sends an acknowledgment to the investigator. Letters of Intent are reviewed by the CTEP Protocol Review Committee (PRC). A consensus review will be sent to the Principal Investigator within approximately 30 days of submission.
5.6.6 CTEP LOI Review Criteria
At the time of LOI review, the PRC has available information on other studies in that agent/disease combination by other investigators, and other studies in the proposed disease by the investigator submitting the LOI. The committee considers the following in its deliberations:
A letter of approval or disapproval, together with comments, is sent to the proposer.
5.6.7 After LOI Approval
Following approval of an LOI, the LOI Principal Investigator has 60 days in which to submit a protocol. It is expected that the protocol will conform to the plan agreed to at the LOI stage of development. At 45 days, a reminder letter is sent notifying him or her that the LOI will shortly expire. After the 60-day period has expired, CTEP will not be bound by previous approval of a LOI.
5.6.8 Information About the Status of an LOI
Further information about the status of a particular LOI may be obtained by calling the CTEP LOI Coordinator (see Appendix IV).
| 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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