一，导言
本指南为药物或生物制品开发计划中的随机对照临床试验中的安慰剂和盲法用于治疗血液系统恶性肿瘤和肿瘤疾病的行业提供了建议。本指南未涉及在这些试验中数据被揭盲时可以考虑的统计分析。
一般而言，FDA的指导文件不构成法律上可执行的责任。相反，指南描述了FDA当局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 背景
安慰剂，定义为没有药理活性的惰性物质，常用于双盲，随机对照临床试验。这些试验中的研究者和患者对治疗患者的致盲正在减少对有效性结果进行偏倚观察的可能性，可能会减少患者脱落率，并允许对结果测量进行无偏见的观察，这在评估包括主观终点时尤为重要。例如，安慰剂对照研究设计在维持治疗，附加试验设计，辅助治疗试验（监护标准为监测）以及无法治疗的适应症中可能是有用的或优选的（最好的）可以为双臂增加支持性护理，以确保为患者提供所有可用的护理）。然而，在恶性血液病和肿瘤疾病的发展计划中，在双盲，随机对照临床试验中使用安慰剂可能存在实际和伦理问题。
在许多情况下，由于活性治疗的毒性特征，患者和研究者可能推断患者接受哪种治疗，因此使用安慰剂对照可能不会使治疗保持盲态。对于具有标准有效治疗方法的血液系统恶性肿瘤和肿瘤疾病患者，使用安慰剂（非活性治疗）通常不会被视为符合伦理，因此应进行活性的对照试验。一种这样的主动控制优效试验设计选项是进行开放标签试验，医生选择几种标准疗法之一作为比较物。在研究者偏倚可能引起关注的开放标签比较试验中，对扫描的盲法中央独立审查可以减轻关于终点评估的偏倚.另一种选择是将研究药物产品与安慰剂进行比较，每一项都添加到标准中护理（附加试验）。
在疾病进展或发生严重不良事件时患者和研究者持续致盲通常是不可接受的。例如，在盲法免疫治疗试验中，在对照组中发生疑似药物相关严重不良事件的患者可能会接受不必要的治疗（例如免疫抑制药物产品，包括高剂量的糖皮质激素，环磷酰胺，白细胞介素-6拮抗剂或英夫利昔单抗） ）用于管理不正确地归因于研究药物产品的不良事件。
在疾病进展后维持盲态也可能影响患者随后治疗的选择和时间安排，可能会阻止已经接受安慰剂组的患者接受批准的治疗或延迟或阻止患者进入其他临床试验（对于那些试验）可能具有基于事先用活性药物或一类药物治疗的特定排除标准的类似药物产品。因此，在这些情况下揭盲将允许对其他治疗方案做出明智的决策（见下文）。
III 关于使用PLACEBOS和BLINDING的考虑因素
鉴于在治疗的随机对照临床试验中使用安慰剂来治疗已知有效治疗的血液系统恶性肿瘤和肿瘤疾病在道德上是不可接受的，申办方应该考虑仅在特定情况下使用安慰剂对照设计（例如，当监测是标准时护理）或具有某些试验设计特征（例如，当试验使用附加设计时）。在考虑安慰剂控制时，申办者应考虑以下因素：
I. INTRODUCTION
This guidance provides recommendations to industry about the use of placebos and blinding in randomized controlled clinical trials in development programs for drug or biological products2 to treat hematologic malignancies and oncologic diseases. This guidance does not address the statistical analyses that can be considered when data are unblinded in these trials.
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.
II. BACKGROUND
Placebos, defined as inert substances with no pharmacologic activity, are commonly used in double-blind, randomized controlled clinical trials. Blinding investigators and patients in these trials to the treatment patients are receiving decreases the likelihood of biased observations of the effectiveness outcomes, may decrease differential patient drop out, and allows for unbiased observation of outcome measures, which are particularly important when the assessment includes subjective endpoints. For example, a placebo-controlled study design may be useful or preferred in maintenance therapy, in add-on trial designs, in trials of adjuvant therapies (for which standardof care is surveillance), and for indications where no treatment is available (best supportive care can be added to both arms to ensure all available care is provided to patients). However, in development programs for malignant hematologic and oncologic disease, the use of a placebo in double-blind, randomized controlled clinical trials may present practical and ethical concerns.
In many cases, because of the toxicity profile of the active treatment, patients and investigators may infer which treatment patients are receiving, so using a placebo control may not blind the treatment. For patients with hematologic malignancies and oncologic diseases that have standard effective therapy available, using a placebo (not an active treatment) generally would not be considered ethical, so an active control trial should be conducted. One such active control superiority trial design option is to conduct an open-label trial with a physician’s choice of one of a few standard therapies as the comparator. In open-label comparative trials for which investigator bias may be of concern, a blinded central independent review of scans may mitigate bias regarding endpoint assessment.3 Another option has been to compare the investigational drug product with the placebo, with each added to the standard of care (an add-on trial).
Continued blinding of patients and investigators at the time of disease progression or occurrence of serious adverse events is usually not acceptable. In a blinded immunotherapy trial, for example, a patient who develops suspected drug-related serious adverse events on the control arm may receive unnecessary treatments (e.g., immunosuppressive drug products including a high dose of glucocorticoids, cyclophosphamide, interleukin-6 antagonist, or infliximab) for management of adverse events incorrectly attributed to the investigational drug product.
Maintaining the blind after disease progression could also affect the selection and timing of a patient’s subsequent therapy, potentially preventing a patient who had been on a placebo arm from receiving an approved therapy or delaying or preventing the patient’s entry into other clinical trials (for those trials of similar drug products that may have specific exclusion criteria based on prior treatment with an active drug or class of drugs). Unblinding in those cases would therefore allow informed decision-making about additional treatment options (see below).
III. CONSIDERATIONS FOR USING PLACEBOS AND BLINDING
Given that using a placebo in randomized controlled clinical trials of therapies to treat hematologic malignancy and oncologic disease for which there is known effective therapy is ethically unacceptable, sponsors should consider using a placebo-controlled design only in selected circumstances (e.g., when surveillance is standard of care) or with certain trial design features (e.g., when the trial uses an add-on design). When considering a placebo control, sponsors should take the following into account:
· Sponsors should provide the rationale for the trial design. Justification is particularly important in the setting of a sham surgical procedure, when invasive methods are required to administer a placebo (e.g., intrathecal administration, intratumoraladministration, repeated intravenous administration via an indwelling catheter), when primary adverse event prophylaxis is required (e.g., antihistamine, acetaminophen, and/or corticosteroids to prevent infusion reaction), when there is an available therapy, or when a placebo is given as monotherapy and not combined with an active drug or drugs.
· FDA does not require patient-level maintenance of blinding at the time of disease recurrence or progression. Unless there are no available appropriate treatment alternatives, FDA recommends unblinding only the patient and the investigator at the time of documented disease recurrence or progression by an objective measurement or measurements to ensure optimal patient management. If sponsors intend to maintain patient-level blinding when disease recurs or progresses and there are existing available treatments, the informed consent document should acknowledge the risks of this approach, and the protocol should include justification for the potential added risk.
· As stated in the guidance for industry and investigators Safety Reporting Requirements for INDs and BA/BE Studies (December ), FDA recommends unblinding the patient and the investigator when the patient has an adverse event suspected to be related to the investigational drug product and for which management of the adverse event with one or more drug products with substantial toxicity or invasive procedures is being considered. In such cases of unblinding, the patient can be removed from treatment based on benefitrisk analysis, but the patient data should not be removed from the trial. If sponsors intend to maintain patient-level blinding when a suspected drug-related serious adverse event occurs, the informed consent document should acknowledge the risks of this approach, and the protocol should include justification for the potential added risk.·申办方应提供试验设计的基本原理。当需要使用侵入性方法来施用安慰剂时（例如，鞘内施用，瘤内施用，通过留置导管重复静脉内施用），当需要进行主要不良事件预防时，证据对于假手术过程尤为重要（例如，当有可用疗法时，或当安慰剂作为单一疗法给予并且不与活性药物或药物组合时，抗组胺药，对乙酰氨基酚和/或皮质类固醇以防止输注反应。
·FDA在疾病复发或进展时不需要患者级别维持致盲。除非没有适当的治疗方案，否则FDA建议在记录疾病复发或进展时仅通过客观测量或测量来揭示患者和研究者，以确保最佳的患者管理。如果申办方计划在疾病复发或进展时保持患者水平致盲并且存在可用的治疗方法，则知情同意文件应承认此方法的风险，并且方案应包括潜在增加风险的理由。
·如行业和研究人员对IND和BA / BE研究的安全报告要求指南（12月）中所述，当患者发生疑似与研究药物相关的不良事件时，FDA建议对患者和研究者进行揭盲。对一种或多种具有实质毒性或侵入性程序的药品的不良事件的管理正在考虑之中。在这种揭盲的情况下，可以基于益处风险分析将患者从治疗中移除，但不应从试验中移除患者数据。如果申办方打算在发生疑似药物相关严重不良事件时保持患者水平致盲，则知情同意书应承认此方法的风险，并且该方案应包括潜在增加风险的理由。· Sponsors should provide a detailed description in the protocol and in the statistical analysis plan of the proposal for blinding (including whether the physiological effects or adverse events associated with the investigational drug product would lead to some degree of unblinding) and planned unblinding (unblinding driven by potential need for medicines with substantial toxicity or invasive procedures for managing adverse events).
·申办者应在协议和盲法提案的统计分析计划中提供详细描述（包括与研究药物产品相关的生理影响或不良事件是否会导致某种程度的揭盲）和计划的揭盲（揭盲驱动） 可能需要具有实质毒性的药物或用于管理不良事件的侵入性程序）。
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