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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents
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Introduction
For over four decades, the NCI has supported evaluations of new agents and new treatment approaches for children with cancer. This support has contributed to the identification of curative treatments for over 75% of children with cancer and has allowed children with cancer to have access to a broad range of new anti-cancer agents. However, despite these advances, over 2000 children and adolescents in the U.S. continue to die from cancer each year. New treatment strategies and novel agents are required to identify curative treatments for these patients. An integral component of the NCI research program for children with cancer is the evaluation of new agents in pediatric Phase 1 trials. Phase 1 trials are essential in order for children to benefit from recent advances in molecular biology and agent discovery that have led to the development of new classes of molecularly targeted agents.
Phase 1 trials for children differ in several fundamental ways from those performed in adult populations. Adult Phase 1 trials are usually conducted at single institutions. Because of the relative rarity of cancer in children, pediatric Phase 1 trials can rarely be performed efficiently by a single institution, and for this reason the NCI generally supports multi-institutional pediatric Phase 1 trials. In multi-institutional Phase 1 trials, it is essential that the flow of information between the participating institutions, the Operations/Data Center, the Study Chair, and the NCI be timely and accurate. Pediatric Phase 1 trials also differ from adult Phase 1 trials in the timing of their initiation and in their starting dose. As described in more detail below, it is common practice to begin pediatric Phase 1 trials following completion of the initial adult Phase 1 experience with an agent, and to begin the pediatric Phase 1 trial at approximately 80% of the recommended Phase 2 dose in adults. Additional information about the design and conduct of pediatric Phase 1 trials is available in published position papers and review articles Additional information about the design and conduct of pediatric Phase 1 trials is available in published position papers and review articles (1;2).
Selection of Institutions for Participation in Phase 1 Trials
Most NCI-sponsored pediatric Phase 1 trials are performed by consortia that include 10-20 institutions [e.g., the Children’s Oncology Group (C.O.G.), Phase 1/Pilot Consortium and the Pediatric Brain Tumor Consortium]. The institutions that are members of these consortia are carefully selected based on their experience in developing and participating in early phase trials, their ability to carefully monitor patients treated on Phase 1/pilot studies, their capabilities in reporting clinical data in a timely manner to the Operations/Data Center, their resources for collection of specimens for required correlative and pharmacokinetic studies, and their ability to contribute to the scientific leadership of the Consortium (e.g., pharmacokinetics, pharmacogenetics, and correlative biology). Institutions must be committed to offering patients participation in Phase 1 trials, to timely submission of all required data and blood/tissue specimens, and to compliance with federal regulations for the protection of research subjects.
Timing of Initiation and Starting Dose for Pediatric Phase 1 Trials
Pediatric Phase 1 trials commonly start once the recommended Phase 2 dose has been established in adults. The starting dose for adult Phase 1 trials is often 10% of the dose found to be lethal to 10% of rodents in toxicology studies. This low dose is selected to minimize the risk of severe adverse events among the first humans receiving new agents. Although the initial dose escalations are large in adult Phase 1 studies, it is not uncommon in these studies to evaluate ten or more dose levels before dose-limiting toxicity is reached. Completion of studies with a large number of dose levels requires a substantial number of patients. In contrast, the starting dose for pediatric Phase 1 studies is usually 80% of the adult recommended Phase 2 dose, and the trial escalates in 25-30% increments as successive cohorts of children are accrued to the study. By taking advantage of the adult Phase 1 MTD to determine the pediatric Phase 1 starting dose:
This strategy has been successfully employed for over a decade, and in most cases has allowed the efficient determination of a pediatric MTD that is 80% or more of the adult MTD. With this approach, pediatric Phase 1 studies can commence at a relatively early time point in the adult development program of an agent without waiting until completion of the adult development program for the agent. For those agents that achieve target levels in adults without causing dose-limiting toxicity (DLT), the initial pediatric experience can begin at or near the dose in adults that results in the desired biological/clinical effect.
Prioritization of Agents for Phase 1 Evaluation in Children
Approximately 400 new agents are currently under evaluation for cancer indications in adults. Only a small fraction of these can be evaluated in children with cancer as a result of the thankfully small number of children eligible for clinical trials evaluating new agents. Because of this increasing imbalance between the number of new agents potentially available for pediatric evaluation and the number that can actually be evaluated, it is essential to effectively prioritize new anticancer agents for testing in children. The pediatric consortia are charged with developing procedures for making decisions concerning the agents and regimens for which the consortia will develop clinical trials. Data from pediatric preclinical models may provide information that is useful in prioritizing new anticancer agents for testing in children.
Protocol Development and Approval
Pediatric Phase 1 protocols developed by the NCI-sponsored pediatric consortia should be preceded by a written Letter of Intent (LOI) from the Consortium to the CTEP LOI Coordinator declaring interest in conducting a particular study. The LOI should describe the hypothesis to be investigated, the general design of the contemplated trial, plus relevant information on accrual capabilities to document feasibility. Protocols are to be developed and submitted, and studies are to be conducted, in accordance with the DCTD "Investigator's Handbook". The Operations Center for the consortia communicate the results of the NCI’s LOI and protocols reviews to the consortia’s member institutions and to relevant committees. All protocols utilizing NCI-sponsored investigational agents are to be conducted in accordance with the terms of the “Intellectual Property Option to Collaborators”, http://ctep.cancer.gov/industry/ipo.html, and the NCI Standard Protocol Language for Cooperative Research and Development Agreements (CRADAs) and Clinical Trial Agreements (CTAs).
Agent Distribution
For Phase 1 trials utilizing investigational agents distributed by CTEP, agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution at which the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained.) The CTEP assigned protocol number must be used for ordering all CTEP supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD, through an annual submission of FDA Form 1572, a CV, the Supplemental Investigator Data Form, and the Financial Disclosure Form. If there are several participating investigators at one institution, CTEP supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. Agent may be requested by completing a Clinical Drug Request (NIH-986) and mailing it to the Pharmaceutical Management Branch, DCTD, NCI, EPN Room 7149, Bethesda, MD 20892 or faxing it to (301) 480-4612.
Study Monitoring:
Pediatric consortia conducting Phase 1 studies are responsible for assuring accurate and timely knowledge of the progress of each study through:
Data and Safety Monitoring Policies
Each pediatric consortia conducting Phase 1 trials must establish a Data and Safety Monitoring Policy in compliance with NIH and NCI guidelines for data monitoring in Phase 1 and pilot studies. The policy must be approved by the NCI Program Director. Information concerning NIH policy is available at http://grants.nih.gov/grants/guide/notice-files/not98-084.html
with additional description at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data and safety monitoring plans for clinical trials funded by the NCI is available on the NCI web site, http://www.cancer.gov/, in the “Conducting Clinical Trials” section.
Adverse Event (AE) Reporting
Each pediatric consortia conducting Phase 1 trials is responsible for establishment of a system for assuring timely reporting of all serious and/or unexpected adverse events. For investigational agents sponsored by the NCI, this involves reporting to the Investigational Drug Branch (IDB), CTEP via the AdEERS system, http://ctep.cancer.gov/reporting/adeers.html, according to CTEP guidelines specified in each protocol. Each of the member institutions of the consortia is responsible for implementing the procedures established for assuring timely reporting of all serious and/or unexpected adverse events.
Site Visit Monitoring
The pediatric consortia conducting Phase 1 trials must establish an on-site monitoring program in coordination with the Clinical Trials Monitoring Branch (CTMB, CTEP). For the C.O.G. Phase 1/Pilot Consortium, this involves annual on-site auditing of member institutions by the Clinical Trials Monitoring Service (CTMS). The on-site audit program addresses issues of data verification, protocol compliance, compliance with regulatory requirements for the protection of human subjects, and investigational agent accountability. Any serious problems with data verification or compliance with Federal regulations must be reported to the Clinical Trials Monitoring Branch immediately. The Operations/Data Center will be responsible for coordinating development of and compliance with corrective programs in response to audits.
Pediatric Exclusivity
Section 111 of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act) created section 505A of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355a). Section 505A permits certain marketing applications to obtain an additional 6 months of marketing exclusivity (i.e., “pediatric exclusivity”) if the applicant, in response to a Written Request from the FDA, files reports of investigations studying the use of the agent in the pediatric population. The pediatric exclusivity provisions were extended until October, 2007 by the “Best Pharmaceuticals for Children Act (Public Law 107-109)”. Guidance from the FDA prescribes the general need for pediatric Phase 1 studies as a condition for obtaining “pediatric exclusivity” (see http://www.fda.gov/cder/guidance/3756dft.pdf). The guidance recommends that when planning pediatric protocols, pharmaceutical sponsors should discuss protocol designs with a pediatric cooperative study group, as these groups have experience, expertise, and resources that can help applicants optimize their study designs and accrue patients. The NCI-sponsored consortia for conducting Phase 1 trials, as well as CTEP staff, are available to assist pharmaceutical sponsors in evaluating whether their agents warrant consideration for pediatric exclusivity, and if so, the design of the early phase studies that would be appropriate to conduct in order to obtain exclusivity.
Reference List
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