A Manual for Participants in Clinical Trials of Investigational Agents ...

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5 Phase 2 Trials 5.1 New Agent Development Considerations 5.1.1 Planning and Coordination of Phase 2 Trials by CTEP As a sponsor, DCTD must devise and implement plans for phase 2 trials of novel therapeutics. An adequate phase 2 plan, while conceptually straight-forward, is often difficult to execute. A reasonable plan presupposes answers to the following questions: • What doses and schedules emerging from phase 1 ought to be carried forward into phase 2 • What diseases should be targeted for testing • How does the new agent fit into CTEP's priority list for various targeted disease studies • How does the new agent fit into the priorities of the clinical investigators who form the core of the NCI-supported clinical trials network • How can the CTEP assure that each agent is adequately tested in each disease that is studied How many studies should be mounted in each disease category What kinds of patients are suitable for study entry What are suitable stopping rules for phase 2 trials • How should we perform phase 2 studies if there are limited supplies of the new agent • What important laboratory correlates can be made within the context of a clinical trial • How can the proposed study be completed within a suggested timeline (i.e. multicenter vs. single center) CTEP staff collaborates with each agent’s industrial sponsor and the Investigational Drug Steering Committee (IDSC) during late phase 1 to plan phase 2 development; CTEP announces the plan via solicitation of LOIs. 5.1.2 Single Agent Phase 2 Studies A phase 2 study: 1. determines whether an agent has antitumor activity and 2. estimates the response rate in a defined patient population. Well-designed phase 2 trials limit enrollment to just the number of patients needed to ensure detection of a medically significant level of activity. Phase 2 studies are disease-oriented. 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 tumor type. 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, investigators must make every effort to avoid false results. Although false-positive results are certainly undesirable, false-negative phase 2 results are also damaging, as they may delay significantly or prevent discovery of a potentially useful antitumor agent. Section 5 - Investigator’s Manual 2009 18
CTEP has based its guidelines concerning eligibility requirements 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 current medical practice. If an agent’s MTD is well characterized, protocols for its initial phase 2 trials should restrict patient entry in the following ways: • For diseases that currently lack effective systemic therapy (e.g. liver and pancreas), trials should be limited to patients with no prior chemotherapy. • For diseases in which systemic therapy may cause objective tumor regression but has little or no impact on survival, entry of patients with no prior therapy will also be sought, whenever possible (e.g. carcinomas of the head and neck, cervix, esophagus, prostate, bladder, large bowel, kidney, stomach, non-small cell lung, and melanoma). • For diseases that are potentially curable with systemic treatment (e.g. acute leukemias, diffuse non-Hodgkin's lymphomas, Hodgkin's disease, testicular cancer, limited small cell lung cancer, and ovarian cancer), patients having the minimum extent of prior treatment consistent with current ethical standards of care are selected. This policy will have the following desirable consequences: • Patients initially entered into phase 2 trials will have the best chance of benefit from treatment and should be able to tolerate any adverse effects of therapy better than patients with poorer performance status, agent-resistant disease, and possible compromised major organ function from prior chemotherapy. • Fewer patients are exposed to inactive agents. • The chance of missing potentially active agents will be minimized. Clearly, the population of patients defined in this way is highly selected, and the results of these initial trials will not necessarily represent 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. If an agent shows promising anti-tumor affects, CTEP may perform a “Special Response Review.” The audit may be conducted at CTEP or on-site. Auditors are selected to participate according to their expertise, pharmaceutical representatives and IDB staff may also be present. Selecting only responding patients, the investigator(s) presents a written and oral summary and review of each claimed responding patients. The coordinating site is responsible for providing all materials, such as MRIs, scans and all tumor measurements according to the response criteria and evaluation schedule stated in the protocol. CTMB prepares a full report including patient summaries, tumor measurements and endpoint results. The CTMB-prepared final report is approved by the lead expert auditor and the CTEP agent or disease coordinator. The PI may include a statement in subsequent manuscripts that CTEP has verified the responses. This statement may not be used if all claimed responding patient’s results were not verified. Section 5 - Investigator’s Manual 2009 19
Page 1 and 2: A Manual for Clinical Investigators
Page 3 and 4: 7.1.3 Purpose .....................
Page 5 and 6: 13.4 Responsibilities of Clinical S
Page 7 and 8: 1 Introduction This manual explains
Page 9 and 10: drugs and biologics rests with the
Page 11 and 12: costs might include additional labo
Page 13 and 14: 3 The Clinical Trial Site and the I
Page 15 and 16: CTEP's site visit monitoring progra
Page 17 and 18: 4 Phase 1 Trials The Development of
Page 19 and 20: Because the correlation between sch
Page 21 and 22: for organ dysfunction studies. The
Page 23: efore writing a formal LOI. IDB sta
Page 27 and 28: 5.1.4 Randomized Phase 2 Studies A
Page 29 and 30: • Physician members of CCOPs for
Page 31 and 32: 6 Phase 3 Trials 6.1 Scientific Pol
Page 33 and 34: completed by the Cooperative Group
Page 35 and 36: clinical trial participation to all
Page 37 and 38: proposer that the submission will n
Page 39 and 40: at the FDA, and for the listing of
Page 41 and 42: expected adverse events that the pa
Page 43 and 44: • How dose modifications will be
Page 45 and 46: consent forms. However, the informe
Page 47 and 48: Investigators’ failure to submit
Page 49 and 50: espond to this re-review in the sam
Page 51 and 52: 9 Ordering Investigational Agents f
Page 53 and 54: the local oncologist(s) must regist
Page 55 and 56: phase 1 include the first time the
Page 57 and 58: investigator send an additional cop
Page 59 and 60: • Altering existing research by m
Page 61 and 62: CTEP has devised a detailed policy
Page 63 and 64: 13 Affiliate Investigators The part
Page 65 and 66: 13.4.3 Cancer Centers The Cancer Ce
Page 67 and 68: 14.3 Administration of Investigatio
Page 69 and 70: • Agents are stored in various pl
Page 71 and 72: 16 Monitoring and Quality Assurance
Page 73 and 74: 16.5 Components of the Quality Assu
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Also, please note that medical reco
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• Even if the agent has been repo
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Appendix I NCI-Cooperative Group-In
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Phase 0 trials do not replace phase
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phase 2 trials enroll 20-30 patient
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the study should be ordered under t
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Appendix IV Key Contact Information
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Appendix V Informed Consent Checkli
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2. Describe risks as outlined in th
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CLINICAL SITE: An institution, coop
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RAB: Regulatory Affairs Branch, htt
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• Agent preparations must be perf
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Procedure for Acute Exposure or Spi
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Appendix VIII National Cancer Insti
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7) Investigational Drug Accountabil
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• Write treatment instructions cl
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• For agent admixtures that can b
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A Manual for Participants in Clinical Trials of Investigational Agents ...

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