發稿時間：2019-03-14 來源：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.導言
本指南是一系列指南中的一個，為CDER和CBER監管的用于治療癌癥的藥物或生物制品臨床試驗的入排標準提供建議.具體而言，本指南包括有關納入兒科患者的建議（即，兒童和青少年）。本指南旨在幫助利益相關者，包括申辦方和機構審查委員會（IRB），負責開發和監督臨床試驗。
臨床試驗的合格標準（包含和排除）是試驗的重要組成部分，定義了研究人群的特征。由于研究藥物和試驗目標存在差異，因此應制定資格標準，考慮藥物的作用機制，目標疾病或患者群體，研究藥物的預期安全性以及從中招募試驗參與者的能力?；颊呷巳哼_到臨床試驗的目的。然而，一些資格標準已經逐漸被普遍接受，或者在沒有明確科學或臨床基本原理的情況下用作試驗的模板。不必要的限制性資格標準可能會減緩患者的應計，限制患者進入臨床試驗，并導致試驗結果不能完全代表最終將使用該藥物的患者群體的治療效果.4,5
擴大癌癥試驗資格標準可以最大限度地提高試驗結果的普遍性，并且能夠在不影響患者安全的情況下了解可能在臨床實踐中使用該藥物的患者群體的治療益處 - 風險概況。在兒科患者中對潛在有效藥物（特別是靶向藥物）的早期評估和開發可提供安全有效使用的信息，從而降低與標簽使用相關的風險，并加速為兒科患者開發有效的創新療法。
一般而言，FDA的指導文件并未建立法律上可執行的責任。相反，指南描述了原子能機構目前對某一主題的看法，應僅視為建議，除非引用了具體的法規或法定要求。在機構指南中使用“應該”一詞意味著建議或推薦某些內容，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
本指南討論了癌癥臨床試驗中兒科患者的最低年齡合格標準，并解決了包括兒科患者在內的特定情況（基于疾病生物學和臨床過程，研究藥物的分子靶點和/或其分子機制）。
從歷史上看，兒科患者尚未納入成人臨床試驗，通常將18年作為最低資格年齡。在完成一項或多項成人臨床試驗后，或在成人初步批準后，推遲對兒童人群開發和獲得可能有效的新抗癌藥物，開始對同一藥物進行兒科試驗。在某些情況下，單獨的兒科試驗可能是不可行的，因為這種疾病在兒科患者中很少發生。在臨床試驗中延遲或不進行正式評估會導致產品標簽中不包含有關劑量，安全性，有效性和長期影響的兒科特定信息，以告知患者和提供者藥物在該人群中的使用情況。設計包括兒科患者在內的臨床試驗，然后在標簽中包含這些信息，可以促進這些產品安全有效地用于可能在臨床實踐中使用該藥物的更廣泛的患者群體。
本指南的重點是為兒科人群的資格標準提供建議，包括兒童（本指南的目的，年齡為2歲至12歲）和青少年（本指南的目的，年齡為12歲至17歲）。
三.建議
當有臨床證據或強有力的科學依據表明具有特定癌癥診斷，組織學亞型或與相同相關分子靶標相關的腫瘤的兒科患者可能受益時，應考慮特定兒科人群進行癌癥臨床試驗的資格。當有令人信服的非臨床和/或足夠的臨床信息來充分證明患者風險。
A.將兒科患者納入成人癌癥臨床試驗的考慮因素
1.道德考慮
在21 CFR第50部分D部分，臨床研究中的兒童附加保障措施中，FDA法規中針對人體受試者保護中列出的臨床試驗中列出了一些重要的道德考慮因素。這些保護措施限制了兒科患者可能在某些情況下接觸研究藥物的可允許風險，包括試驗中的干預措施或程序為個體受試者提供直接臨床益處的預期風險。在腫瘤學試驗中使用研究藥物應限于可能對個體兒科患者具有直接臨床益處的情況。如果出現以下情況，這些臨床調查可能涉及兒童：（1）風險通過對受試者的預期收益來證明是合理的，（2）預期的風險 - 收益概況至少與現有替代治療所呈現的一樣有利，并且（3）足夠規定是為了征求兒童的同意和父母或監護人的許可。
此外，根據21 CFR 56.111（c），為了批準部分或全部受試者為兒童的研究，IRB必須確定所有研究符合21 CFR第50部分D.7規定的兒童患者入選的方案應包括在IRB審查中，兒科腫瘤學專業知識的設計和實施以及足夠的兒科專業知識。
2.監管考慮因素
贊助商可以通過將兒科患者納入本指南中討論的成人臨床試驗，滿足聯邦食品，藥品和化妝品法案（FD＆C法案）8,9第505A和505B節的要求。
3.所有試驗階段的一般考慮因素
尋求納入兒科患者人群的贊助商應評估兒科配方，同時考慮到要研究的兒科患者的年齡，大小，生理狀況和治療需求。根據藥物的作用機制及其影響發育，生長和引起晚期效應的可能性，可能需要對兒科患者進行前瞻性長期隨訪。此外，應監測藥物安全性的臨床重要年齡相關差異。
對兒童的考慮可以支持將患者從2歲10歲納入12歲以下的證據類型包括：
? 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.
?繼續在同一臨床試驗中注冊受限和擴大的人群，并且如果在成人和兒童中尋求適應癥的疾病的生物學/臨床過程不同，則分別分析療效。
?使用擴展的隊列設計來構建知識，包括評估特定人群的安全性和有效性。當最終評估的成人和兒科適應癥不同以及組織學/組織不可知發展策略的設置時，這種方法將特別有用。
對青少年的考慮應該有一個強大的生物學理論和缺乏潛在的治療療法來支持青少年入組早期成人試驗，但鑒于青少年和成人之間藥物暴露的相似性（基于相似的體重和代謝過程），青少年可能同時登記一些初始成人PK后獲得成年患者并獲得毒性數據
5.晚期試驗考慮因素
在晚期試驗中規定的最低資格年齡應根據所研究疾病的生物學，試驗的科學目標以及關于藥物作用機制和安全性的現有數據進行調整。
