发稿时间：2019-03-14 来源：FDA
I.INTRODUCTION
This guidance is one in a series of guidances that provide recommendations regarding eligibility criteria for clinical trials of drugs or biological products2 regulated by CDER and CBER for the treatment of cancer.3 Specifically, this guidance includes recommendations regarding the inclusion of pediatric patients (i.e., children and adolescents). This guidance is intended to assist stakeholders, including sponsors and institutional review boards (IRBs), responsible for the development and oversight of clinical trials.
A clinical trial’s eligibility criteria (for inclusion and exclusion) are essential components of the trial, defining the characteristics of the study population. Because there is variability in investigational drugs and trial objectives, eligibility criteria should be developed taking into the mechanism of action of the drug, the targeted disease or patient population, the anticipated safety of the investigational drug, and the ability to recruit trial participants from the patient population to meet the objectives of the clinical trial. However, some eligibility criteria have become commonly accepted over time or used as a template across trials without clear scientific or clinical rationale. Unnecessarily restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials, and lead to trial results that do not fully represent treatment effects in the patient population that will ultimately use the drug.4,5
Broadening cancer trial eligibility criteria can maximize the generalizability of trial results and the ability to understand the therapy’s benefit-risk profile across the patient population likely to use the drug in clinical practice without jeopardizing patient safety. Early evaluation and development of potentially effective drugs, particularly targeted drugs, in pediatric patients may provide information on safe and effective use, therefore reducing risks associated with off label use, and accelerate the development of effective, innovative therapies for pediatric patients.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
一.导言
本指南是一系列指南中的一个，为CDER和CBER监管的用于治疗癌症的药物或生物制品临床试验的入排标准提供建议.具体而言，本指南包括有关纳入儿科患者的建议（即，儿童和青少年）。本指南旨在帮助利益相关者，包括申办方和机构审查委员会（IRB），负责开发和监督临床试验。
临床试验的合格标准（包含和排除）是试验的重要组成部分，定义了研究人群的特征。由于研究药物和试验目标存在差异，因此应制定资格标准，考虑药物的作用机制，目标疾病或患者群体，研究药物的预期安全性以及从中招募试验参与者的能力。患者人群达到临床试验的目的。然而，一些资格标准已经逐渐被普遍接受，或者在没有明确科学或临床基本原理的情况下用作试验的模板。不必要的限制性资格标准可能会减缓患者的应计，限制患者进入临床试验，并导致试验结果不能完全代表最终将使用该药物的患者群体的治疗效果.4,5
扩大癌症试验资格标准可以最大限度地提高试验结果的普遍性，并且能够在不影响患者安全的情况下了解可能在临床实践中使用该药物的患者群体的治疗益处 - 风险概况。在儿科患者中对潜在有效药物（特别是靶向药物）的早期评估和开发可提供安全有效使用的信息，从而降低与标签使用相关的风险，并加速为儿科患者开发有效的创新疗法。
一般而言，FDA的指导文件并未建立法律上可执行的责任。相反，指南描述了原子能机构目前对某一主题的看法，应仅视为建议，除非引用了具体的法规或法定要求。在机构指南中使用“应该”一词意味着建议或推荐某些内容，但不是必需的。
II. BACKGROUND
This guidance discusses minimum age eligibility criteria for pediatric patients in cancer clinical trials and addresses specific situations in which the inclusion of pediatric patients may be appropriate (based on disease biology and clinical course, molecular target of the investigational drug, and/or its molecular mechanism).
Historically, pediatric patients have not been included in adult clinical trials, which generally specify 18 years as the minimum age of eligibility. Pediatric trials of the same drug generally have been initiated after the completion of one or more adult clinical trials, or after the initial approval in adults, delaying development of and access to potentially effective new cancer drugs for the pediatric population. In some cases, separate pediatric trials may have been infeasible because the disease occurs so rarely in pediatric patients. This delay in or absence of formal evaluation in a clinical trial results in product labeling that includes no pediatric-specific information about dose, safety, efficacy, and long-term effects to inform patients and providers on a drug’s use in this population. Designing clinical trials that include pediatric patients and then including this information in the labeling promotes the safe and effective use of these products across a broader patient population likely to use the drug in clinical practice.
This guidance focuses on providing recommendations for eligibility criteria for pediatric populations including both children (for purposes of this guidance, ages two years to less than twelve years) and adolescents (for purposes of this guidance, ages twelve years to seventeen years).
III. RECOMMENDATIONS
Eligibility of a specific pediatric population for a cancer clinical trial should be considered when there is clinical evidence or a strong scientific rationale to suggest that pediatric patients with a specific cancer diagnosis, histologic subtype, or tumor associated with the same relevant molecular target may benefit and when there is compelling nonclinical and/or adequate clinical information to sufficiently justify patient risk.
A. Considerations for including pediatric patients in adult cancer clinical trials
1. Ethical considerations
There are several important ethical considerations specific to including pediatric patients in clinical trials outlined in the FDA regulations addressing human subject protection at 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations. These safeguards restrict the allowable risk to which a pediatric patient may be exposed to an investigational agent to certain situations, including those in which the interventions or procedures in the trial offer a prospect of direct clinical benefit to the individual subject. Use of an investigational agent in an oncology trial should be restricted to situations in which there is the prospect of direct clinical benefit to the individual pediatric patient. These clinical investigations may involve children if: (1) the risk is justified by the anticipated benefit to the subject, (2) the anticipated risk-benefit profile is at least as favorable as that presented by available alternative treatments, and (3) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.6
Furthermore, under 21 CFR 56.111(c), in order to approve research in which some or all of the subjects are children, an IRB must determine that all research complies with 21 CFR part 50 subpart D.7 Protocols that enroll pediatric patients should include pediatric oncology expertise for the design and conduct as well as adequate pediatric expertise in IRB review.
2. Regulatory considerations
Sponsors may be able to meet the requirements in sections 505A and 505B of the Federal Food, Drug, and Cosmetic Act (FD&C Act)8,9 by including pediatric patients in adult clinical trials as discussed in this guidance.
3. General considerations for all trial phases
Sponsors seeking to include pediatric patient populations should evaluate pediatric formulations taking into account the age, size, physiologic condition, and treatment needs of pediatric patients to be studied. Depending upon the mechanism of action of the drug and its potential for impacting development, growth, and causing late effects, prospective long-term follow-up of pediatric patients may be warranted. Additionally, monitoring for clinically important age-related differences in the safety profile of the drug should be conducted.
a. Considerations for children
Types of evidence that could support inclusion of patients from two years of age10 to under age twelve years include:
• Clinical studies: Natural history and preliminary adult studies demonstrate children will likely exhibit similar responses to the investigational drug based on a clinical efficacy endpoint and concerns for the potential for severe growth and developmental toxicities are absent. Assessment of data, if available, from adult clinical programs may support decisions related to enrolling children.
• Nonclinical studies: In vivo and in vitro preclinical data (including in silico or mechanism-based in vitro evidence), particularly when conducted using pediatric tumor model systems may help increase confidence to support inclusion of pediatric patients. Modeling and simulation should be used to understand potential differences in pharmacokinetic (PK) and pharmacodynamic (PD) as well as dose selection.
• Sufficient non-clinical or early clinical experience in adults that suggests minimal risk of adverse effects on growth and development, and that can be used to guide benefit-risk assessment for children.
• Predictive biomarkers when available.
• Evidence from other drugs in the same pharmacological class or with similar mechanism of action.
Presentation of more than one of these types of evidence increases the strength of the evidence for including children in adult clinical trials.
b. Considerations for adolescents
As discussed in the guidance for industry Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials,11 sponsors should consider including adolescents (i.e., ages twelve years to seventeen years) in disease- and/or target-appropriate adult cancer clinical trials at all stages of development when appropriate conditions are met (see sections III.4.b and III.5).
4. Early phase trial considerations
FDA encourages including pediatric patients for conditions without known curative options in early-phase trials that assess dose, safety, and PK in a variety of tumor types when compelling nonclinical data and/or early adult clinical data suggest activity.
Prospective planning to include pediatric patients in select first in human (FIH) studies intended for adults can be accomplished by designing studies to include an expansion cohort,12 which would begin enrollment of pediatric patients when adequate data on dose and safety in adults are available to assure that the clinical trial provides the prospect for direct clinical benefit to pediatric patients to justify the risks. In addition to evidence of activity, the study drug dosage and the duration of treatment must be expected to support a prospect of direct clinical benefit to children.
Potential ways to include pediatric patients after a sufficient number of adult patients have been evaluated to provide adequate safety and toxicity data include:
• Enrolling a cohort of pediatric patients starting one dose level behind the highest dose level studied in adults in which there are no dose-limiting toxicities identified.
• The pediatric starting dose should be lower than the adult maximally tolerated dose (particularly for monoclonal antibodies) (i.e., the pediatric starting dose may be the adult recommended phase 2 dose (RP2D) if the dose is not the adult maximally tolerated dose).
• A limited dose escalation may occur in the pediatric cohort depending on the therapeutic product and the clinical indication(s) as well as the specific age eligibility for the pediatric cohort.
• In general, for children < 12 years of age and for adolescents < 40 kg defined adult flat doses would be converted to body surface area or body weight adjusted dosing.
• Enrolling pediatric patients in a separate cohort that will accrue concurrently with the adult cohort when sufficient information to permit dose modeling based on adult PK and exposure data are available.
As discussed in the draft guidance for industry Expansion Cohorts: Use in First-in-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,13 in exceptional circumstances, substantive nonclinical evidence of activity in tumor-derived cell lines or patient-derived xenografts of pediatric tumors alone may provide sufficient justification for enrollment of a pediatric cohort before the availability of full clinical data in adults. In these situations, sponsors should consider staged enrollment of older children or adolescents before younger children.
a. Considerations for children
In situations where there may be a concern regarding differential efficacy between adults and pediatric patients for the same or different indication, sponsors could consider enrolling an expanded population with patients under 12 years of age with the goal of including them in the safety analysis but not in the primary adult efficacy analysis.
Possible strategies for the evaluation of efficacy in the pediatric population or indication(s) include:
二.背景
本指南讨论了癌症临床试验中儿科患者的最低年龄合格标准，并解决了包括儿科患者在内的特定情况（基于疾病生物学和临床过程，研究药物的分子靶点和/或其分子机制）。
从历史上看，儿科患者尚未纳入成人临床试验，通常将18年作为最低资格年龄。在完成一项或多项成人临床试验后，或在成人初步批准后，推迟对儿童人群开发和获得可能有效的新抗癌药物，开始对同一药物进行儿科试验。在某些情况下，单独的儿科试验可能是不可行的，因为这种疾病在儿科患者中很少发生。在临床试验中延迟或不进行正式评估会导致产品标签中不包含有关剂量，安全性，有效性和长期影响的儿科特定信息，以告知患者和提供者药物在该人群中的使用情况。设计包括儿科患者在内的临床试验，然后在标签中包含这些信息，可以促进这些产品安全有效地用于可能在临床实践中使用该药物的更广泛的患者群体。
本指南的重点是为儿科人群的资格标准提供建议，包括儿童（本指南的目的，年龄为2岁至12岁）和青少年（本指南的目的，年龄为12岁至17岁）。
三.建议
当有临床证据或强有力的科学依据表明具有特定癌症诊断，组织学亚型或与相同相关分子靶标相关的肿瘤的儿科患者可能受益时，应考虑特定儿科人群进行癌症临床试验的资格。当有令人信服的非临床和/或足够的临床信息来充分证明患者风险。
A.将儿科患者纳入成人癌症临床试验的考虑因素
1.道德考虑
在21 CFR第50部分D部分，临床研究中的儿童附加保障措施中，FDA法规中针对人体受试者保护中列出的临床试验中列出了一些重要的道德考虑因素。这些保护措施限制了儿科患者可能在某些情况下接触研究药物的可允许风险，包括试验中的干预措施或程序为个体受试者提供直接临床益处的预期风险。在肿瘤学试验中使用研究药物应限于可能对个体儿科患者具有直接临床益处的情况。如果出现以下情况，这些临床调查可能涉及儿童：（1）风险通过对受试者的预期收益来证明是合理的，（2）预期的风险 - 收益概况至少与现有替代治疗所呈现的一样有利，并且（3）足够规定是为了征求儿童的同意和父母或监护人的许可。
此外，根据21 CFR 56.111（c），为了批准部分或全部受试者为儿童的研究，IRB必须确定所有研究符合21 CFR第50部分D.7规定的儿童患者入选的方案应包括在IRB审查中，儿科肿瘤学专业知识的设计和实施以及足够的儿科专业知识。
2.监管考虑因素
赞助商可以通过将儿科患者纳入本指南中讨论的成人临床试验，满足联邦食品，药品和化妆品法案（FD＆C法案）8,9第505A和505B节的要求。
3.所有试验阶段的一般考虑因素
寻求纳入儿科患者人群的赞助商应评估儿科配方，同时考虑到要研究的儿科患者的年龄，大小，生理状况和治疗需求。根据药物的作用机制及其影响发育，生长和引起晚期效应的可能性，可能需要对儿科患者进行前瞻性长期随访。此外，应监测药物安全性的临床重要年龄相关差异。
对儿童的考虑可以支持将患者从2岁10岁纳入12岁以下的证据类型包括：
• Continue to enroll restricted and expanded populations in the same clinical trial, and analyze efficacy separately if the biology/clinical course of the disease for which an indication is sought differs in adults and children.
• Use an expanded cohort design to build knowledge including assessment of safety and efficacy in particular populations. This approach would be particularly useful when the adult and pediatric indications ultimately under evaluation differ and in the setting of histology/tissue agnostic development strategies.
b. Considerations for adolescents
There should be a strong biologic rationale and absence of potentially curative therapies to support enrollment of adolescents in early phase adult trials, but given similarities in drug exposure between adolescents and adults (based on similar body weight and metabolic processes), adolescents may be enrolled concurrently with adult patients after some initial adult PK and toxicity data are obtained.14
5. Late phase trial considerations
The minimum age of eligibility specified in late-phase trials should be tailored to the biology of the disease under study, the scientific objectives of the trial, and the existing data regarding the mechanism of action and safety profile of the drug.
•继续在同一临床试验中注册受限和扩大的人群，并且如果在成人和儿童中寻求适应症的疾病的生物学/临床过程不同，则分别分析疗效。
•使用扩展的队列设计来构建知识，包括评估特定人群的安全性和有效性。当最终评估的成人和儿科适应症不同以及组织学/组织不可知发展策略的设置时，这种方法将特别有用。
对青少年的考虑应该有一个强大的生物学理论和缺乏潜在的治疗疗法来支持青少年入组早期成人试验，但鉴于青少年和成人之间药物暴露的相似性（基于相似的体重和代谢过程），青少年可能同时登记一些初始成人PK后获得成年患者并获得毒性数据
5.晚期试验考虑因素
在晚期试验中规定的最低资格年龄应根据所研究疾病的生物学，试验的科学目标以及关于药物作用机制和安全性的现有数据进行调整。
