Systemic Lupus Erythematosus —Developing Medical Products for Treatment

系统性红斑狼疮 - 开发用于治疗的医疗产品

TABLE OF CONTENTS 目录

 I.         INTRODUCTION    

I. 引言

II.        BACKGROUND 

II. 背景

III.      DEVELOPMENT PROGRAM     

III. 发展计划

A.     General Considerations  

A. 一般考虑因素

1. Early Phase Clinical Development Considerations 

1.早期临床开发注意事项

2. Efficacy Considerations 

2.功效考虑因素

B.     Specific Efficacy Trial Considerations  

B. 药效试验的具体考虑因素

1. Indication  

1.适应症

2. Study Design  

2.研究设计

a.    Superiority trials     

a. 优越性试验

b.    Noninferiority trials  

b. 非劣效性试验

c.    Extension trials 

c. 扩展试验

d.    Alternative trial designs 

d. 替代试验设计

3. Study Duration  

3.学习时间

4. Study Population  

4.研究对象

5. Concomitant Medications    

5.伴随药物

6. Stratification    

6.分层

7. Pediatric Populations   

7.儿科人群

8. Primary Efficacy Endpoints    

8.主要疗效终点

a.    Reduction in disease activity  

a. 减少疾病活动

b.    Complete clinical response or remission    

b. 完全临床反应或缓解

c.    Reduction in flare/increase in time to flare  

c. 减少燃烧/增加燃烧时间

d.    Reduction in concomitant steroids  

d. 减少同时使用类固醇

e.    Treatment of serious acute manifestations  

e. 严重急性表现的治疗

9. Patient-Reported Outcomes 

9.患者报告的结果

10.    Other Endpoints  

10. 其他终点

a.    Damage   

a. 损坏

b.    Biomarkers      

b. 生物标志物

11.    Study Procedures and Timing of Assessments   

11. 研究程序和评估时间 13.

12.    Statistical Considerations     

12. 统计考虑因素

13.    Accelerated Approval Considerations for Human Drugs and Therapeutic Biological Products

13. 人类药物和治疗性生物制品的加速审批考虑因素(Subpart H and Subpart E)

14.    Risk-Benefit Considerations 

14. 风险-效益考虑因素

I.         INTRODUCTION I. 引言

The purpose of this guidance is to assist sponsors in the clinical development of medical products (i.e., human drugs, therapeutic biological products, and medical devices) for the treatment of systemic lupus erythematosus (SLE).  Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the overall development program  and clinical trial designs, and provides specific information on trial design, trial duration, efficacy endpoints, and response criteria.  This guidance is intended to serve as a focus for continued discussions among the FDA, medical industry, sponsors, academic community, and the public.2   As the science of this indication evolves, this guidance may be revised.

本指南旨在协助申办者进行治疗系统性红斑狼疮（SLE）的医疗产品（即人类药物、治疗性生物制品和医疗器械）的临床开发。 具体而言，本指南阐述了美国食品和药物管理局（FDA）目前对整体开发计划和临床试验设计的看法，并提供了有关试验设计、试验持续时间、疗效终点和反应标准的具体信息。 本指南旨在为 FDA、医疗行业、申办者、学术界和公众之间的持续讨论提供一个焦点。2 随着该适应症的科学发展，本指南可能会进行修订。

This guidance applies to general information regarding medical product development for the treatment of SLE.  Organ-specific forms of disease will be addressed in separate guidances.

本指南适用于治疗系统性红斑狼疮的医疗产品开发的一般信息。 器官特异性疾病将在单独的指南中阐述。

This guidance does not contain discussion of the general issues of clinical trial design or statistical analysis.  Those topics are addressed in the ICH guidances for industry E9 Statistical Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical   Trials.3   This guidance focuses on specific medical product development and trial design issues that are unique to the study of SLE.

本指南不包含对临床试验设计或统计分析一般问题的讨论。 这些主题在 ICH 行业指南 E9《临床试验的统计原则》和 E10《临床试验中对照组的选择及相关问题》3 中均有论述。本指南侧重于系统性红斑狼疮研究中特有的医疗产品开发和试验设计问题。

FDA’s guidance documents, including this guidance, 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.

食品及药物管理局的指导文件，包括本指导文件，并不确立可依法强制执行的责任。 相反，指导文件描述了该局对某一主题的当前想法，除非引用了具体的监管或法定要求，否则应仅将其视为建议。 在该局的指导文件中使用 "应"（should）一词，是指建议或推荐某事，而不是要求某事。

II.        BACKGROUND II. 背景情况

SLE is a chronic disease characterized by protean manifestations, often with a waxing and waning course.  In the past, a diagnosis of SLE often implied a decreased life span caused by internal organ system involvement or the toxic effects of therapy, but recent improvements in care have dramatically enhanced the survival of SLE patients.  Nonetheless, increased mortality remains a major concern and current treatments for SLE remain inadequate.4    Many patients have incompletely controlled disease, progression to end-stage organ involvement continues, and the therapies carry risks of debilitating side effects.  Therefore, it is important to facilitate the development of medical products that have the potential to be more effective and/or less toxic.

系统性红斑狼疮是一种慢性疾病，其特点是表现多样，病程时长时短。 过去，诊断为系统性红斑狼疮往往意味着患者的寿命会因内脏器官系统受累或治疗的毒性作用而缩短，但近年来护理水平的提高大大提高了系统性红斑狼疮患者的生存率。 然而，死亡率的上升仍然是一个令人担忧的主要问题，而且目前治疗系统性红斑狼疮的方法仍然不够完善。4 许多患者的病情没有得到完全控制，病情发展到终末期器官受累的情况仍在继续，而且治疗方法有可能产生使人衰弱的副作用。 因此，促进开发更有效和/或毒性更低的医疗产品非常重要。

III.      DEVELOPMENT PROGRAM

III. 发展计划

A.        General Considerations

A. 一般考虑因素

1.        Early Phase Clinical Development Considerations

1. 早期临床开发注意事项

Studies to identify an appropriate (safe and effective) dose are an important component of phase 2 development for human drugs and therapeutic biological products used to treat SLE.  For additional information on the FDA’s current thinking regarding exposure response or dose response, see the ICH guidance for industry E4 Dose-Response Information to Support Drug   Registration and the guidances for industry Providing Clinical Evidence of Effectiveness for     Human Drug and Biological Products and Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications.

对于用于治疗系统性红斑狼疮的人类药物和治疗性生物制品来说，确定适当（安全和有效）剂量的研究是第二阶段开发的重要组成部分。 有关 FDA 目前对暴露反应或剂量反应的想法的更多信息，请参阅《支持药物注册的剂量反应信息》（ICH）行业指南 E4，以及《为人类药物和生物制品提供有效性的临床证据》和《暴露反应关系--研究设计、数据分析和监管应用》行业指南。

We recommend that early studies evaluate concurrent use of a new medical product with commonly used standard therapies to obtain preliminary safety information on potential interactions with medical products used in standard-of-care regimens, although at this stage   studies will not be powered to fully assess safety endpoints.  As discussed in section III.B.8., Primary Efficacy Endpoints, early exploratory clinical studies can be used to gain experience  with a variety of standard clinical outcome measures, which may aid sponsors in determining which endpoints to pursue further in phase 3 trials.

我们建议早期研究应评估新医疗产品与常用标准疗法同时使用的情况，以获得与标准治疗方案中使用的医疗产品潜在相互作用的初步安全性信息，尽管在此阶段的研究不具备全面评估安全性终点的能力。 如第 III.B.8 节 "主要疗效终点 "所述，早期探索性临床研究可用于获得各种标准临床结果测量的经验，这可能有助于申办者确定在第 3 期试验中进一步采用哪些终点。

Biomarker assays thought to reflect disease activity also can be helpful in identifying medical products likely to show a clinical benefit and in choosing doses and regimens.  See section III.B.10., Other Endpoints, for additional information on the use of biomarkers in SLE clinical studies.

被认为能反映疾病活动的生物标志物检测也有助于确定可能显示临床获益的医疗产品，以及选择剂量和治疗方案。 有关在系统性红斑狼疮临床研究中使用生物标志物的更多信息，请参阅第 III.B.10 节 "其他终点"。

2.        Efficacy Considerations

2. 功效考虑因素

The evidence of effectiveness needed to support approval of medical products for SLE is similar to that for medical products for other indications.  For human drugs and therapeutic biological     products, at least two adequate and well-controlled trials generally are needed for approval.

支持系统性红斑狼疮医疗产品获得批准所需的有效性证据与其他适应症的医疗产品相似。 就人类药物和治疗性生物制品而言，一般至少需要进行两次充分且对照良好的试验才能获得批准。

However, a single study can suffice under some circumstances(see the guidance for industry    Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products).  A    single study can be sufficient, for example, if the medical product is being developed for the    treatment of serious acute manifestations and the study shows:  (1) robust evidence of efficacy with resolution of the serious acute manifestations; or (2) a decrease in mortality.  For medical devices, one confirmatory clinical trial generally is sufficient.

不过，在某些情况下，一项研究就足够了（参见《为人类药物和生物制品提供临床有效性证据的行业指南》）。 例如，如果正在开发的医疗产品用于治疗严重的急性表现，且研究显示：(1) 强有力的疗效证据表明严重的急性表现得到缓解，则单项研究就足够了： (1) 有确凿证据表明疗效显著，严重急性表现得到缓解；或 (2) 死亡率降低。 对于医疗器械，一般只需进行一次确证性临床试验即可。

 B.        Specific Efficacy Trial Considerations

B. 药效试验的具体考虑因素

 1.        Indication 1. 说明

 The general indication of treatment of systemic lupus erythematosus will be granted for medical   products if supported by sufficient evidence of effectiveness.  In general, specific efficacy claims (e.g., reduction in disease activity), as discussed in section III.B.8., Primary Efficacy Endpoints,   will not be included in the INDICATIONS AND USAGE section of labeling, but can be discussed in the CLINICAL STUDIES section if well-supported.  If the medical product is studied only in a subset of the general SLE population, then the restricted population in which the medical product was studied would be reflected in labeling.  For medical products that demonstrate a reduction in mortality inadequate and well-controlled trials, appropriate additional labeling reflecting that outcome would be included in the INDICATIONS AND USAGE section.

治疗系统性红斑狼疮的一般适应症如果有足够的有效性证据支持，医疗产品将被批准。 一般来说，具体的疗效声明（如疾病活动的减少），如第 III.B.8 节 "主要疗效终点 "中所述，将不包括在标签的 "适应症和用法 "部分，但如果有充分的证据支持，可以在 "临床研究 "部分进行讨论。 如果该医疗产品只在一般系统性红斑狼疮患者中的一部分人中进行过研究，那么该医疗产品的研究对象将在标签中反映出来。 对于死亡率降低的医疗产品，如果没有进行充分的对照试验，则应在 "适应症和用法 "部分适当增加反映该结果的标签。

 2.         Study Design 2. 研究设计

 a.         Superiority trials

a. 优势审判

 The preferred design for efficacy trials is a parallel, randomized, controlled superiority trial using placebo or active control.  The placebo-controlled trial can compare the test medical product with no treatment, but more commonly adds the test medical product or placebo to standard therapy (add-on trial).

疗效试验的首选设计是采用安慰剂或活性对照的平行、随机、对照优效试验。 安慰剂对照试验可将试验用医药产品与无治疗方法进行比较，但更常见的是将试验用医药产品或安慰剂添加到标准疗法中（附加试验）。

 No patient enrolling in an SLE clinical trial should be denied standard therapy if doing so would lead to irreversible harm.  To avoid denying patients standard of care, superiority trials of new     therapies can use an add-on design, if the medical product is intended as adjunctive treatment, or head-to-head comparisons with an alternative standard of care, if the medical product is intended for primary treatment.  In a head-to-head comparison, it may be appropriate to include early escape provisions to an alternative standard-of-care regimen for patients who worsen during the study to ensure that no patient is denied potentially effective therapy.

如果参加系统性红斑狼疮临床试验会导致不可逆转的伤害，就不应该拒绝给予病人标准治疗。 为了避免拒绝给予患者标准治疗，如果医疗产品是作为辅助治疗，新疗法的优越性试验可以采用附加设计；如果医疗产品是作为主要治疗，则可以与替代标准治疗进行头对头比较。 在 "头对头 "比较中，可能需要为研究过程中病情恶化的患者制定早期转入替代标准疗法的规定，以确保没有患者被剥夺潜在的有效治疗。

 One of the advantages to an add-on trial of this type is that it enables the evaluation of drug effects in the context of commonly used medical products in SLE.  An example of an add-on design would be a trial of corticosteroids plus placebo compared to corticosteroids plus the new medical product.  The protocol should specify the dose of corticosteroids patients will receive,   taking into account the type and severity of the clinical manifestation.  The protocol also should include provisions for tapering of corticosteroids during the trial if the manifestations improve.

这种附加试验的优点之一是可以在系统性红斑狼疮常用医疗产品的背景下评估药物效果。 附加试验设计的一个例子是将皮质类固醇加安慰剂的试验与皮质类固醇加新医疗产品的试验进行比较。 试验方案应根据患者临床表现的类型和严重程度，明确规定皮质类固醇激素的剂量。 方案还应包括在试验期间，如果症状有所改善，可减量使用皮质类固醇的规定。

 b.        Noninferiority trials

b. 非劣效性试验

 If superiority to a comparator is unlikely (e.g., because the new medical product is pharmacologically similar to a standard-of-care medical product) and an add-on study would be unlikely to succeed (again because the new and standard-of-care medical products are pharmacologically similar), sponsors might want to consider a noninferiority design to evaluate    efficacy.  However, this design would be difficult to support in this case (see ICH E10).  To use a noninferiority design, the effect size of the comparator that will be present in the new study must  be identified to define the noninferiority margin.5    Currently, there are no known medical products with an effect size adequately characterized to design an adequate noninferiority trial  for a new medical product in any SLE setting.  A particular problem would also be the inherent variability in outcome and response in different populations.  Sponsors considering a noninferiority design should discuss the design with the appropriate review division before trial initiation.

如果不可能优于比较者（例如，因为新医疗产品与标准医疗产品的药理相似），而且附加研究也不可能成功（同样因为新医疗产品与标准医疗产品的药理相似），申办者可能会考虑采用非劣效性设计来评估疗效。 然而，在这种情况下，这种设计很难得到支持（参见 ICH E10）。 要使用非劣效性设计，就必须确定新研究中的参照物的效应大小，以确定非劣效性边际。5 目前，还没有已知的医药产品具有充分的效应大小特征，可以在任何系统性红斑狼疮环境中为新医药产品设计适当的非劣效性试验。 一个特殊的问题是，不同人群的结果和反应存在固有的差异性。 考虑采用非劣效性设计的申办者应在试验开始前与适当的审查部门讨论该设计。

 c.         Extension trials

c. 推广试验

 If prior evidence suggests clinical activity of the medical product and an acceptable safety profile, sponsors are encouraged to offer patients enrollment into a long-term extension trial to characterize long-term safety.  Long-term controlled trial data are preferred over open-label extension safety data because of the difficulty in interpreting adverse event rates in the absence   of a concurrent control.  Demonstration of long-term benefit would be a critical determination in some settings (e.g., bone marrow transplant).

如果先前的证据表明医疗产品具有临床活性和可接受的安全性，我们鼓励申办者让患者参加长期扩展试验，以确定长期安全性的特征。 长期对照试验数据优于开放标签推广安全数据，因为在没有同期对照的情况下，很难解释不良事件发生率。 在某些情况下（如骨髓移植），证明长期获益是一个关键的决定因素。

 d.         Alternative trial designs

d. 替代试验设计

 Alternative trial designs, all of which should be designed as superiority trials, include randomized withdrawal, dose-response, and replacement trials.  In a replacement trial, patients   on a stable standard-of-care regimen should be randomized in a blinded manner to continue that regimen or switch to study treatment.  A successful trial would demonstrate better outcomes in   the group switched to study treatment.  Sponsors should discuss these alternative designs with    the review division before initiating these studies.

其他试验设计均应设计为优效试验，包括随机停药试验、剂量反应试验和替代试验。 在替代试验中，应在盲法下随机决定使用稳定的标准治疗方案的患者是继续使用该方案还是改用研究治疗方案。 成功的试验将证明改用研究疗法的组别取得了更好的疗效。 申办者在启动这些研究之前，应与审查部门讨论这些替代设计。

 3.         Study Duration

3. 研究时间

 Clinical trials should be of sufficient length to assess the durability of therapy benefits, taking into account the chronic nature of SLE and its waxing and waning course.  In general, a trial evaluating the following endpoints should be at least 1 year in duration:  reduction in disease activity,complete clinical response or remission, reduction in flare/increase in time to flare, and maintenance of response.  The duration should be based on the onset of action of the medical     product and incorporate maintenance therapy for a total of at least 1 year to assess for durability of response as well as safety, depending upon the risks of the medical product.

考虑到系统性红斑狼疮的慢性性质及其时好时坏的病程，临床试验应有足够长的时间来评估治疗效果的持久性。 一般来说，评估以下终点的试验应至少持续一年：疾病活动减少、完全临床反应或缓解、复发减少/复发时间延长以及反应的维持。 试验持续时间应以医疗产品的起效时间为基础，并根据医疗产品的风险情况，将维持治疗的时间累计至少 1 年，以评估反应的持久性和安全性。

 If the investigational medical product is intended for short-term use, such as induction of response, the total duration of follow-up should still be 1 year, but the investigational medical   product does not need to be continued beyond the initial treatment period.  In this case, patients can be switched to another maintenance therapy for the remainder of the follow-up period.

如果研究用医药品是用于短期治疗，如诱导应答，那么总的随访时间仍应为 1 年，但研究用医药品无需在初始治疗期后继续使用。 在这种情况下，患者可以在剩余的随访期内改用另一种维持疗法。

 Studies investigating treatment of serious acute manifestations of SLE (e.g., acute confusional state, acute transverse myelitis, or acute lupus pneumonitis) are considered a special case of induction therapy.  Such studies can also be of relatively short duration depending on the nature of the manifestation, the organ system involved, and the expected time for resolution of the serious acute manifestations under investigation.  As for any other trial of induction therapy, a subsequent assessment of the durability of response and safety should be based on data of at least 1-year duration.

针对系统性红斑狼疮严重急性表现（如急性意识障碍、急性横贯性脊髓炎或急性狼疮性肺炎）的治疗研究被认为是诱导治疗的一种特殊情况。 此类研究的持续时间也可以相对较短，这取决于表现的性质、所涉及的器官系统以及所研究的严重急性表现的预期缓解时间。 与其他任何诱导治疗试验一样，随后对反应持久性和安全性的评估应基于至少 1 年的数据。

4.         Study Population

4. 研究对象

 Trials should enroll patients with established SLE, as defined by the American College of Rheumatology classification criteria.

根据美国风湿病学会的分类标准，试验应招募已确诊的系统性红斑狼疮患者。

 The patient population should reflect the patients who would reasonably be considered for the therapy should it be shown to be effective.  It is important that the studied population be one that can be generalized to an appropriate population for recommended use, and not made artificially   narrow.  However, if existing data (e.g., from exploratory studies) suggest that only a specific, limited population can be expected to benefit from the therapy, the inclusion and exclusion criteria can limit enrollment to that subset of patients with a particular range of disease activity or with a particular serious acute manifestation of SLE.  However, as discussed in section III.B.1.,    Indication, the medical product, if approved, would be labeled to indicate this restricted population.

患者群体应反映出，如果该疗法被证明有效，可合理考虑接受该疗法的患者。 重要的是，所研究的人群应能推广到推荐使用的适当人群，而不是人为地缩小范围。 然而，如果现有的数据（如探索性研究的数据）表明，只有特定的、有限的人群有望从该疗法中获益，那么纳入和排除标准可以将入选人群限制在具有特定疾病活动范围或具有特定严重急性系统性红斑狼疮表现的患者子集。 然而，如第 III.B.1 节 "适应症 "所述，医疗产品如获批准，将在标签上标明这一受限人群。

 5.         Concomitant Medications

5. 伴随药物

 It is important to recognize that changes in concomitant medications, whether steroids, immunosuppressive agents, or other therapies (e.g., angiotensin converting enzyme inhibitors, antihypertensive agents, and agents to control diabetes), can influence outcomes and confound     the effect of treatment.  Treating physicians should respond to patient needs appropriately, but an attempt should be made in the protocol to define the baseline therapy that is acceptable and provide guidance on how therapy should be adjusted.  Sponsors should collect complete information on use of concomitant medications during trials.

必须认识到，无论是类固醇、免疫抑制剂还是其他疗法（如血管紧张素转换酶抑制剂、降压药和控制糖尿病的药物），并用药物的变化都会影响疗效并混淆治疗效果。 主治医生应适当满足患者的需求，但应在方案中明确可接受的基准疗法，并就如何调整疗法提供指导。 在试验过程中，申办者应收集完整的伴随用药信息。

 It is important that investigators consider restricting baseline glucocorticoid use (e.g., stable dose or limit the range of doses) to reduce the variability of dosing that may make interpretation of results more difficult.  The protocol should specify if glucocorticoid dose changes are allowed  during the trial or if patients should be discontinued if they require an increased glucocorticoid dosage. Potential eligible patients should not be deliberately tapered off their concomitant medications to induce a flare in disease activity for purposes of meeting enrollment criteria in a trial.

重要的是，研究者应考虑限制糖皮质激素的基线使用（如稳定剂量或限制剂量范围），以减少可能使结果解释更加困难的剂量变化。 试验方案应明确规定试验期间是否允许改变糖皮质激素的剂量，或者如果患者需要增加糖皮质激素的剂量是否应停止使用。不应为了达到试验的入组标准而故意减少潜在合格患者的伴随药物，以诱发疾病活动的复发。

 We also recommend defining the use of rescue medications and specifying how patients needing such treatment will be treated and analyzed.

我们还建议对抢救药物的使用进行定义，并明确规定如何对需要此类治疗的患者进行治疗和分析。

 6.         Stratification

6. 分层

 If the effects of treatment are expected to differ substantially inpatients with severely active disease as compared to moderately or mildly active disease, it may be desirable to stratify at randomization.

如果重度活动性疾病患者与中度或轻度活动性疾病患者的治疗效果预计会有很大不同，那么最好在随机分组时进行分层。

 The Systemic Lupus Erythematosus International Collaborating Clinics/American College of   Rheumatology (SLICC/ACR) Damage Index was developed, and found to be well-defined and reliable, for measuring organ damage.  It may be particularly useful as a means of stratifying     patients at trial entry because increased damage has been shown to correlate with a worse prognostic outcome.6

系统性红斑狼疮国际合作诊所/美国风湿病学会（SLICC/ACR）制定了损害指数，该指数定义明确且可靠，可用于测量器官损害。 由于损伤的加重已被证明与预后较差相关，因此该指数在试验开始时作为对患者进行分层的一种手段可能特别有用。

 If it is expected that particular demographic groups may respond differently to therapy, sponsors also can consider stratification based on a demographic variable.

如果预计特定人口群体对治疗的反应可能不同，申办者也可以考虑根据人口变量进行分层。

 7.        Pediatric Populations

7. 儿科人群

 To help standardize the conduct and reporting of pediatric SLE clinical trials and enhance identification of new medical products, the Pediatric Rheumatology International Trials Organization, in collaboration with the Pediatric Rheumatology Collaborative Study Group and with the support of the European Union and the National Institutes of Health, has developed a    core set of five domains for the evaluation of response to therapy.  These domains include the    following:

为了帮助规范小儿系统性红斑狼疮临床试验的进行和报告，并加强对新医疗产品的鉴定，小儿风湿病学国际试验组织与小儿风湿病学合作研究小组合作，并在欧盟和美国国立卫生研究院的支持下，制定了一套由五个领域组成的核心内容，用于评估对治疗的反应。 这些领域包括以下内容：

 1.   A disease activity index (DAI) (e.g., European Consensus Lupus Activity Measure (ECLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Systemic Lupus Erythematosus Activity Measure (SLAM), British Isles Lupus Assessment Group (BILAG), or other DAI deemed appropriate for clinical trials)

1. 疾病活动指数（DAI）（如欧洲红斑狼疮活动指数（ECLAM）、系统性红斑狼疮疾病活动指数（SLEDAI）、系统性红斑狼疮活动指数（SLAM）、不列颠群岛红斑狼疮评估小组（BILAG）或其他被认为适合临床试验的疾病活动指数）。

  2.   Renal function (24-hour proteinuria)

2. 肾功能（24 小时蛋白尿）

 3.   Parent’s global 3. 家长全球

 4.   Physician’s global 4. 全球医生

 5.   Health status (Child Health Questionnaire physical summary score)

5. 健康状况（儿童健康问卷体格总分）

 Evaluation of response in these five domains can be considered for exploratory use in pediatric SLE trials.  Future research will help to establish the degree of change in these domains that      represents a clinically important benefit to establish efficacy in clinical trials.  Sponsors should discuss the design of pediatric SLE trials with the review division before beginning such trials.

可以考虑在儿科系统性红斑狼疮试验中探索性地评估这五个方面的反应。 未来的研究将有助于确定这些领域的变化程度，这些变化程度代表了临床上重要的获益，从而在临床试验中确定疗效。 申办者在开始儿科系统性红斑狼疮试验前，应与审查部门讨论此类试验的设计。

 8.        Primary Efficacy Endpoints

8. 主要疗效终点

 Sponsors should consider designing clinical trials for medical products to address one or more of the following primary endpoints, as discussed in detail below.

申办者在设计医疗产品的临床试验时，应考虑针对以下一个或多个主要终点（详见下文）。

 a.         Reduction in disease activity

a. 减少疾病活动

 The primary endpoint for a trial evaluating reduction in signs and symptoms of SLE disease activity can be determined using a DAI that has documented evidence of validity, reliability, and ability to detect change in the targeted clinical trial setting.  Disease activity scores allow inclusion of patients whose disease affects different organ systems by providing an overall severity score.

评估系统性红斑狼疮疾病活动性体征和症状减少情况的试验的主要终点，可以使用一种 DAI 来确定，这种 DAI 有文件证明其有效性、可靠性和在目标临床试验环境中检测变化的能力。 疾病活动性评分通过提供总体严重程度评分，可将疾病影响不同器官系统的患者纳入试验范围。

 Disease activity should be measured at the beginning and end of the trial as well as over the course of the trial.  To meet the primary endpoint of the trial, the change in DAI between the outset and the end of the trial should show a statistically significant difference between the treatment groups.  It is also important to determine that an improvement in DAI score is not accompanied by a worsening of other disease manifestations.  (See also section III.B.14., Risk- Benefit Considerations.)

应在试验开始和结束时以及试验过程中测量疾病活动度。 为了达到试验的主要终点，试验开始和结束时的 DAI 变化应显示治疗组之间存在统计学意义上的显著差异。 同样重要的是，要确定 DAI 评分的改善不会伴随其他疾病表现的恶化。 (另请参阅第 III.B.14 节 "风险-效益考虑因素"）。

 Several indices exist that mirror the assessment of experienced clinicians and are sensitive to   changes in disease activity.  The BILAG is the preferred index to study reduction in disease     activity in clinical trials.  The BILAG scores patients based on the need for therapy; therefore, the clinical interpretation of a change in score is apparent.

有几种指数可以反映经验丰富的临床医生的评估结果，并且对疾病活动性的变化非常敏感。 在临床试验中，BILAG 是研究疾病活动性降低的首选指标。 BILAG 根据治疗需求对患者进行评分；因此，评分变化的临床解释是显而易见的。

 Other DAIs include the SLEDAI and Safety of Estrogen in Lupus Erythematosus National Assessment Trial (SELENA)-SLEDAI, the SLAM, and the ECLAM.  Updated versions of the    BILAG, SLAM, and SLEDAI have been released (BILAG2004, SELENA-SLEDAI/SLEDAI     2K, and SLAM-R).  These indices have been shown to be valid in some treatment settings based on the concordance of scores with expert opinion, acceptable interobserver variability among trained evaluators, correlation between individual patient scores on different indices, and correlation between increases in scores and clinical decisions to increase therapy.  They also have been shown in cohort studies to be sensitive to changes in disease activity, and can be used in clinical trials if the instrument measurement properties are adequate for the specific clinical trial setting.7

其他 DAI 包括 SLEDAI 和红斑狼疮雌激素安全性国家评估试验 (SELENA)-SLEDAI、SLAM 和 ECLAM。 BILAG、SLAM 和 SLEDAI 的更新版本已经发布（BILAG2004、SELENA-SLEDAI/SLEDAI 2K 和 SLAM-R）。 根据评分与专家意见的一致性、训练有素的评估者之间可接受的观察者间变异性、患者在不同指数上的个体评分之间的相关性以及评分增加与临床决定增加治疗之间的相关性，这些指数已被证明在某些治疗环境中是有效的。 队列研究也表明，这些指标对疾病活动性的变化很敏感，如果测量工具的测量特性足以满足特定临床试验环境的需要，则可用于临床试验。

 It is important to ensure that the selected DAIs accurately assess disease activity over time. Some DAIs allot points for a new disease manifestation and no points for a stable manifestation. Thus, a disease manifestation that is present at screening and that is stable during the trial can contribute points to the baseline score but no points to subsequent scores leading to an artifactual reduction in the overall disease activity score.  The DAIs should also address disease manifestations not caused by SLE and how they will be scored (e.g., hematuria and/or pyuria caused by a urinary tract infection versus lupus nephritis).

必须确保所选的 DAI 能准确评估疾病在一段时间内的活动性。有些 DAI 对新出现的疾病表现给分，而对稳定的疾病表现不给分。因此，筛查时就存在且在试验期间保持稳定的疾病表现可能会为基线得分加分，但不会为后续得分加分，从而导致疾病活动性总分的人为降低。 DAIs 还应涉及非系统性红斑狼疮引起的疾病表现及其评分方法（例如，由尿路感染引起的血尿和/或脓尿与狼疮肾炎）。

 If using the BILAG in a 1-year SLE trial, sponsors should conduct an assessment of disease activity at both 6 months and 12 months, as well as at other time points (e.g., monthly) to assess the time course of response.  The timing of the primary efficacy analysis, at either 6 or 12 months, depends upon the time it takes for the new medical product to achieve optimal activity.  If 12 months is chosen as the primary endpoint, BILAG should show a statistically significant     improvement at 12 months that has been sustained at a minimum for 2 months.  Alternatively, if the primary endpoint is set at 6 months, clinical benefit should be assessed at 12 months as a secondary endpoint.

如果在为期 1 年的系统性红斑狼疮试验中使用 BILAG，申办者应在 6 个月和 12 个月以及其他时间点（如每月一次）进行疾病活动性评估，以评估反应的时间进程。 主要疗效分析的时间是 6 个月还是 12 个月，取决于新医疗产品达到最佳活性所需的时间。 如果选择 12 个月作为主要终点，则 BILAG 在 12 个月时应显示出统计学意义上的显著改善，并至少持续 2 个月。 或者，如果将主要终点设定为 6 个月，则应将 12 个月的临床疗效作为次要终点进行评估。

 In patients with active disease at baseline (defined as one or more BILAG A or two or more BILAG B scores), the primary efficacy analysis using a clinically meaningful benefit can be based on the outcome of major clinical response (MCR) or partial clinical response (PCR),   showing a greater frequency in drug-treated patients than in control-treated patients.

对于基线时疾病处于活动期（定义为一个或多个 BILAG A 或两个或多个 BILAG B 评分）的患者，使用有临床意义的获益进行主要疗效分析时，可根据主要临床反应（MCR）或部分临床反应（PCR）的结果进行分析。

 An example of the definition of MCR or PCR is presented here.  In the example of PCR, flare is defined as the presence of one or more new BILAG A scores or two or more new BILAG B scores.  BILAG C scores do not affect the definition of flare, since, by definition, they are not judged to be serious enough to require treatment. An adjudication committee should be employed to determine which patients meet the predefined outcome.  The following factors can be used to define MCR and PCR:

这里举例说明 MCR 或 PCR 的定义。 在 PCR 的例子中，复发的定义是出现一个或多个新的 BILAG A 评分或两个或多个新的 BILAG B 评分。 BILAG C 评分不影响复发的定义，因为根据定义，这些评分不会被判定为严重到需要治疗的程度。应成立评审委员会来确定哪些患者符合预设结果。 以下因素可用于定义 MCR 和 PCR：

 Major Clinical Response 主要临床反应

 A patient with BILAG C scores or better at 6 months with no new BILAG A or BILAG B scores AND maintenance of response with no new BILAG A or B     scores between 6 and 12 months.

患者在 6 个月时 BILAG C 评分或更高，且没有出现新的 BILAG A 或 BILAG B 评分，并在 6 至 12 个月期间保持应答，没有出现新的 BILAG A 或 B 评分。

 Partial Clinical Response

部分临床反应

 A patient with BILAG C scores or better at 6 months with no new BILAG A or BILAG B scores and maintenance of response without a flare for 4 months.

患者在 6 个月时 BILAG C 评分或更高，且没有出现新的 BILAG A 或 BILAG B 评分，并在 4 个月内保持反应而没有复发。

  OR

 A patient with a maximum of 1 BILAG B score or better at 6 months AND maintenance of response without a flare out to 1 year.

患者在 6 个月时最多获得 1 个 BILAG B 评分或更好的评分，并在 1 年内保持反应而不复发。

  OR

 A patient with very high disease activity (as defined below) who achieves a maximum of 2 BILAG B scores at 6 months AND maintenance of this response without developing a flare out to 1 year.   Very high disease activity is defined as the presence of one of the following conditions:

疾病活动度非常高的患者（定义如下），在 6 个月时最多达到 2 个 BILAG B 评分，并在 1 年内保持这种反应而不复发。 极高的疾病活动度是指出现以下情况之一：

 •   ≥ 2 BILAG A scores (regardless of the number of BILAG B scores)

- ≥ 2 个 BILAG A 级评分（与 BILAG B 级评分的数量无关）

 OR

 •    1 BILAG A score and ≥ 2 BILAG B scores

- 1 个 BILAG A 分数和 ≥ 2 个 BILAG B 分数

 OR

 •   ≥ 4 BILAG B scores (with no BILAG A scores)

- ≥ 4 个 BILAG B 级评分（无 BILAG A 级评分）

A trial of a new medical product’s ability to induce response in patients with active disease can  also be conducted using a DAI, such as BILAG.  In this case, the primary endpoint would be an increase in the proportion of patients with a category C score or better at the end of induction (e.g., 3 or 6 months).  Response should be confirmed by repeat measurement at least 1 month later.  It is also important that a new medical product not only demonstrate early activity, but also not worsen long-term outcome.  Therefore, the maintenance of response also should be assessed   as a secondary endpoint at 1 year.

也可以使用 DAI（如 BILAG）对新医疗产品诱导活动性疾病患者产生反应的能力进行试验。 在这种情况下，主要终点是在诱导治疗结束时（如 3 个月或 6 个月），C 类评分或更好的患者比例有所增加。 至少应在 1 个月后通过重复测量确认反应。 同样重要的是，新的医疗产品不仅要显示出早期活性，而且不能恶化长期预后。 因此，反应的维持情况也应在 1 年后作为次要终点进行评估。

 Some treatments may target a biologic mechanism that leads to only certain disease manifestations, or to only disease manifestations related to a single organ system.  In these situations, it would usually be preferable to use an organ-specific measure of disease activity as the primary endpoint as opposed to an overall disease activity measure.

有些治疗方法可能只针对导致某些疾病表现的生物机制，或只针对与单一器官系统相关的疾病表现。 在这种情况下，通常最好使用器官特异性疾病活动性指标作为主要终点，而不是整体疾病活动性指标。

 The interpretation of a clinical trial using the organ-specific approach can be problematic, however, if improvement in the organ system selected is counterbalanced by worsening manifestations of disease occurring in other organ systems.  In addition, results from organ- specific trials may be confounded if changes in treatment regimens are made, such as an increase in immunosuppressive agents (see section III.B.5., Concomitant Medications).  Therefore, organ- specific trials should also assess overall disease activity as a secondary endpoint, because the safety information should betaken into consideration in determining the overall risk-benefit assessment of the medical product.

然而，如果所选器官系统的病情好转被其他器官系统的病情恶化所抵消，那么采用器官特异性方法对临床试验的解释就会出现问题。 此外，如果改变治疗方案，如增加免疫抑制剂（见第 III.B.5 节 "伴随用药"），器官特异性试验的结果可能会被混淆。 因此，器官特异性试验也应将总体疾病活动性作为次要终点进行评估，因为在确定医疗产品的总体风险-效益评估时应考虑安全性信息。

 b.         Complete clinical response or remission

b. 完全临床反应或缓解

 The primary endpoint for a trial evaluating complete clinical response or remission is defined by  the complete absence of disease activity, using a DAI (as described above).  The term response is used if the patients continue to receive SLE-directed therapies, whereas remission is used if patients do not continue to receive ongoing therapy for SLE.

评估完全临床应答或缓解的试验的主要终点是指完全没有疾病活动，使用 DAI（如上所述）。 如果患者继续接受系统性红斑狼疮定向疗法，则使用应答一词，如果患者不再继续接受系统性红斑狼疮治疗，则使用缓解一词。

 The evaluation of efficacy should be based on the proportion of patients who achieve a BILAG level D score, or zero if using the SLEDAI, in all organ systems for at least 6 consecutive months.

疗效评估应基于至少连续 6 个月所有器官系统的 BILAG 评分达到 D 级（如果使用 SLEDAI，则为零分）的患者比例。

 c.         Reduction in flare/increase in time to flare

c. 减少爆燃/增加爆燃时间

 The primary endpoint for a trial evaluating flares can be a reduction in flares or an increase in the time to flare for the new medical product compared to the control group.  If time to flare is evaluated as the primary endpoint, the trial should be at least 1 year in duration to evaluate whether the flares are suppressed or only delayed in occurrence.  A critical secondary endpoint should be comparison of flare rates or proportion of patients flare-free at an appropriate time    point.

评估复发试验的主要终点可以是与对照组相比，新医疗产品的复发减少或复发时间延长。 如果将复发时间作为主要终点进行评估，试验时间至少应为一年，以评估复发是被抑制了还是只是推迟了。 一个重要的次要终点应该是在适当的时间点比较复发率或无复发患者的比例。

 A trial assessing flares should randomize patients with quiescent disease (e.g., BILAG C score or better in all organ systems) and assess flares in the group receiving the new medical product compared to the control group.

评估复发的试验应随机抽取疾病处于静止状态的患者（如所有器官系统的 BILAG C 评分或更高），并评估接受新医疗产品组与对照组的复发情况。

 The definition of flare should be specified in the protocol and should reflect an episode of increased disease activity that correlates with the need for an increase in or change in treatment  on clinical grounds.  All possible flares should be adjudicated by a data monitoring board that is blinded to treatment.

复发的定义应在治疗方案中明确规定，应反映疾病活动性增加的情况，并与临床需要增加或改变治疗相关联。 所有可能出现的病情复发都应由数据监测委员会裁定，该委员会对治疗过程不设盲区。

 An index used to measure flare should measure disease activity over a month’s period, rather than at fixed time points, in order not to miss any intercurrent flares and to allow full characterization of activity of the medical product over the course of the trial.  Acceptable flare   indices for clinical trials include the BILAG and SELENA-SLEDAI flare indexes.  For example, the BILAG identifies flares as A for severe flare and B for mild to moderate flare.  A worsening  from an E,D, or C to two or more B scores or one or more A score in any body or organ system  during the 1-year trial period can be used to define the occurrence of flare.  Time to flare should  be the number of days since randomization to occurrence of flare based on BILAG A or B scores.

用于测量病情发作的指数应测量一个月内的疾病活动情况，而不是固定的时间点，这样才不会遗漏任何间歇性的病情发作，并能全面描述试验过程中医疗产品的活动情况。 可接受的临床试验复发指数包括 BILAG 和 SELENA-SLEDAI 复发指数。 例如，BILAG 将严重复发确定为 A，将轻度至中度复发确定为 B。 在为期 1 年的试验期间，任何身体或器官系统从 E、D 或 C 级恶化为两个或两个以上 B 级或一个或一个以上 A 级，均可定义为发生复发。 根据 BILAG A 或 B 评分，复发时间应为自随机分配到复发的天数。

 A trial evaluating maintenance of response can also be considered for a new medical product once active disease (i.e., flares) is in remission (defined as BILAG C or better).  Such trials can be a continuation of an induction trial of the new medical product.  Patients with active disease who achieve quiescence following induction with a new medical product can be further randomized to switch to placebo or continue the new medical product for the duration of the trial.  Alternatively, the induction regimen can consist of a standard-of-care regimen whereby     patients are randomized to continue standard of care or are switched to the new medical product for maintenance.  The primary endpoint for a trial evaluating maintenance of response can be     met by demonstrating an increase (compared to standard of care) in the proportion of patients     maintaining a BILAG C score or better at 1 year.  If the endpoint is assessed at 6 months, then    clinical benefit should also be assessed at 1 year as a secondary endpoint.

一旦活动性疾病（即复发）处于缓解期（定义为 BILAG C 或更好），也可考虑对新医疗产品进行评估反应维持情况的试验。 此类试验可以是新医疗产品诱导试验的延续。 使用新医疗产品诱导后达到静止状态的活动性疾病患者可进一步随机转为使用安慰剂或在试验期间继续使用新医疗产品。 或者，诱导治疗方案可以由标准治疗方案组成，患者被随机分配继续接受标准治疗或改用新医疗产品进行维持治疗。 评估反应维持情况的试验的主要终点可以通过证明在 1 年时保持 BILAG C 评分或更高的患者比例有所增加（与标准护理相比）来实现。 如果终点在 6 个月时进行评估，则还应在 1 年时评估临床疗效，作为次要终点。

 d.         Reduction in concomitant steroids

d. 减少同时使用类固醇

 Reducing corticosteroid use is an important goal in treatment of patients with SLE if it occurs in the context of a treatment that effectively controls disease activity.  Therefore, for a medical product to be labeled as reducing corticosteroid usage, it should also demonstrate another clinical benefit, such as reduction in disease activity as the primary endpoint.

减少皮质类固醇的使用量是治疗系统性红斑狼疮患者的一个重要目标，如果它是在有效控制疾病活动的治疗过程中发生的话。 因此，医疗产品若要标示为减少皮质类固醇用量，还应该证明另一种临床益处，例如以减少疾病活动为主要终点。

 In an add-on trial to test the steroid-sparing potential of a new medical product, patients should   be enrolled during a flare and randomized to the addition of the new medical product or placebo to induction doses of corticosteroids.  In both study arms, when patients achieve quiescent disease, the corticosteroid dose should be tapered to a maintenance dose that is not usually associated with major toxicities while still maintaining quiescence.  The induction steroid dosage and duration of induction therapy and taper schedule should be based on the severity of disease    activity in the dominant organ system involved.8

在测试新医疗产品节省类固醇潜力的附加试验中，患者应在疾病发作期间入组，并随机决定在皮质类固醇诱导剂量的基础上添加新医疗产品或安慰剂。 在这两个研究组中，当患者的疾病达到静止状态时，皮质类固醇的剂量应逐渐减少到通常不会引起主要毒性反应的维持剂量，同时仍保持静止状态。 诱导类固醇的剂量、诱导治疗的持续时间和减量计划应根据所涉及的主要器官系统疾病活动的严重程度而定。

 The evaluation of efficacy should be based on the proportion of patients in treatment and control groups that achieve a reduction in steroid dose to less than or equal to 10 mg per day of prednisone or equivalent, with quiescent disease and no flares (see definition above) for at least 3 consecutive months during a 1-year clinical trial.  For a result to be clinically meaningful, the patient population should be on moderate to high doses of steroids at baseline.  Trials should also assess the occurrence of clinically significant steroid toxicities.

疗效评估应基于治疗组和对照组中将类固醇剂量减至小于或等于每天 10 毫克泼尼松或同等剂量，且在为期 1 年的临床试验中至少连续 3 个月疾病静止且未复发（见上文定义）的患者比例。 要使结果具有临床意义，患者群体在基线时应使用中等至高剂量的类固醇。 试验还应评估是否出现了具有临床意义的类固醇毒性反应。

 e.         Treatment of serious acute manifestations

e. 严重急性表现的治疗

 Treatment of serious acute manifestations of SLE can be considered a special case of induction therapy for treatment of SLE emergencies (e.g., acute confusional state, acute transverse myelitis, or acute lupus pneumonitis).  The primary endpoints for a trial evaluating treatment of serious acute manifestations should reflect the proportion of patients with improvement after administration of a new medical product or placebo.  The improvement should be measured as a lower score in the organ system score on a DAI of the involved organ(s), such that there is no     longer a threat to that organ.

治疗系统性红斑狼疮的严重急性表现可被视为治疗系统性红斑狼疮急症（如急性意识障碍、急性横贯性脊髓炎或急性狼疮性肺炎）的诱导疗法的一种特殊情况。 评估治疗严重急性表现的试验的主要终点应反映患者在服用新医疗产品或安慰剂后病情得到改善的比例。 病情改善的衡量标准应该是受累器官在 DAI 中的器官系统评分降低，从而不再对该器官构成威胁。

 As stated in section III.B.3., Study Duration, studies investigating treatment of serious acute manifestations of SLE are considered a special case of induction therapy.  Therefore, therapy with the investigational medical product can be of relatively short duration depending on the nature of the manifestation.  It is understood that in many cases maintenance therapy will involve a different regimen than the study drug used for induction.  Assessment of the durability of response and safety should be obtained after the patient is switched to maintenance therapy for a total of at least 1-year duration.

如第 III.B.3 节 "研究持续时间 "所述，调查系统性红斑狼疮严重急性表现的治疗研究被认为是一种特殊的诱导治疗。 因此，研究用医药产品的治疗时间可以相对较短，这取决于表现的性质。 不言而喻，在许多情况下，维持治疗将采用与诱导治疗所用研究药物不同的方案。 应在患者转为接受至少为期 1 年的维持治疗后，对反应的持久性和安全性进行评估。

 Trials investigating treatments for serious acute manifestations of SLE can include the following secondary endpoints:  time to resolution of the acute manifestation, mortality, need for re- treatment, use of corticosteroids, and overall disease activity as measured by a DAI, such as the SLEDAI or BILAG.

研究系统性红斑狼疮严重急性表现治疗方法的试验可包括以下次要终点：急性表现缓解的时间、死亡率、再次治疗的需要、皮质类固醇激素的使用，以及通过DAI（如SLEDAI或BILAG）测量的总体疾病活动性。

 Study designs investigating therapies for serious acute manifestations of SLE should be discussed with the review division before beginning trials.

研究设计调查系统性红斑狼疮严重急性表现的疗法时，应在试验开始前与审查部门进行讨论。

 9.        Patient-Reported Outcomes

9. 患者报告的结果

 We recognize that improvements in clinical outcome measures (e.g., lab tests, clinical evaluation) inpatients with SLE may not always translate to improvements in how patients feel    or function.  Therefore, we encourage the use of patient-reported outcome (PRO) instruments to   measure all relevant and important SLE symptoms and patient-perceived abilities to function and perform daily activities.  PRO instrument development should be based upon qualitative research conducted in the target patient population to ensure the content validity of the measure.

我们认识到，系统性红斑狼疮患者的临床结果指标（如实验室检查、临床评估）的改善并不总能转化为患者感觉或功能的改善。 因此，我们鼓励使用患者报告结果（PRO）工具来测量所有相关和重要的系统性红斑狼疮症状以及患者感知的功能和日常活动能力。 PRO工具的开发应基于在目标患者群体中进行的定性研究，以确保测量内容的有效性。

 Most experts agree that fatigue is an important symptom in SLE.  However, experts and patients define fatigue differently.  Measurement of fatigue in SLE should include the following:  (1) a    clear definition of fatigue as it relates to patients with SLE; (2) a clear conceptual framework describing fatigue in SLE including physical and mental components, as appropriate; and (3) methods for measuring fatigue symptoms and effect in the presence of comorbid factors (e.g., depression and medication effects).  We have not identified an existing PRO instrument optimal  for measurement of fatigue symptom complex inpatients with SLE to support labeling claims.     Therefore, an exploratory endpoint measure consisting of the use of an existing fatigue measure   as well as an open-ended item that asks patients to identify their symptoms could be useful in the development of future instruments for measuring fatigue in SLE.

大多数专家都认为，疲劳是系统性红斑狼疮的一个重要症状。 然而，专家和患者对疲劳的定义各不相同。 对系统性红斑狼疮患者疲劳的测量应包括以下内容： (1) 与系统性红斑狼疮患者有关的疲劳的明确定义；(2) 描述系统性红斑狼疮疲劳的明确概念框架，包括适当的生理和心理因素；(3) 在存在合并因素（如抑郁和药物影响）的情况下测量疲劳症状和效果的方法。 我们还没有找到最适合测量系统性红斑狼疮患者疲劳症状复合体的现有 PRO 工具来支持标签声明。 因此，一种探索性终点测量方法，包括使用现有的疲劳测量方法以及要求患者识别其症状的开放式项目，可能会对未来开发系统性红斑狼疮疲劳测量工具有所帮助。

 PRO instruments should be used as key secondary endpoints in all SLE trials.  PRO instruments  that are intended as key trial endpoints should be demonstrated to be well-defined and reliable in the SLE trial population.  We encourage development of new PRO instruments where appropriate.  Additional information on how the FDA reviews PRO instruments used to support medical product labeling can be found in the guidance for industry Patient-Reported Outcome    Measures:  Use in Medical Product Development to Support Labeling Claims.

在所有系统性红斑狼疮试验中，PRO 工具应作为关键的次要终点。 作为关键试验终点的PRO工具应在系统性红斑狼疮试验人群中证明其定义明确且可靠。 我们鼓励在适当的情况下开发新的 PRO 工具。 有关 FDA 如何审查用于支持医疗产品标签的 PRO 工具的更多信息，请参阅 "患者报告的结果测量 "行业指南： 在医疗产品开发中用于支持标签声明。

 10.       Other Endpoints

10. 其他终点

 Endpoints other than those discussed above for consideration in particular SLE trials are discussed here.

这里讨论的终点不包括上文讨论过的在特定系统性红斑狼疮试验中需要考虑的终点。

 a.         Damage a. 损坏

 An assessment of damage caused by manifestations of SLE disease should be considered for inclusion in SLE trials of at least 1-year duration.

在进行至少为期一年的系统性红斑狼疮试验时，应考虑纳入对系统性红斑狼疮疾病表现所造成损害的评估。

 Use of the SLICC/ACR Damage Index measures irreversible organ system damage caused by SLE disease that has been present for at least 6 months.  The SLICC/ACR Damage Index assesses damage that accrues over time in the renal, pulmonary, cardiovascular, and other organ systems.  It can be used in clinical trials to measure the rate of progression of damage caused by  the disease, or its treatment, but is not sensitive to change unless the time interval for observation is at least 1 year in duration.

使用 SLICC/ACR 损伤指数可以测量系统性红斑狼疮疾病至少持续 6 个月所造成的不可逆转的器官系统损伤。 SLICC/ACR损伤指数可评估肾脏、肺部、心血管和其他器官系统随着时间推移而累积的损伤。 它可用于临床试验，测量疾病或其治疗所造成的损害的进展速度，但除非观察时间间隔至少为一年，否则对变化不敏感。

 An assessment of damage during a trial also can be complicated if a new therapy is associated with toxicities not measured by the Damage Index (e.g., in organs not associated with SLE disease).  Therefore, we recommend discussing use of the SLICC/ACR Damage Index or other instrument to assess damage with the review division before beginning trials.

如果一种新疗法伴有损害指数无法测量的毒性（例如，与系统性红斑狼疮疾病无关的器官），那么试验期间的损害评估也会变得复杂。 因此，我们建议在试验开始前与审查部门讨论使用 SLICC/ACR 损伤指数或其他工具来评估损伤。

 b.         Biomarkers b. 生物标志物

 A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.  In some cases, biomarkers can assist in the development and evaluation of therapies for SLE by supporting a hypothesized mechanism of action or by suggesting an appropriate dose or duration of action.

生物标志物是一种客观测量和评估的特征，是正常生物过程、致病过程或对治疗干预的药理反应的指标。 在某些情况下，生物标志物可以通过支持假设的作用机制或提示适当的剂量或作用持续时间来帮助开发和评估系统性红斑狼疮的疗法。

 Surrogate endpoints are a subset of biomarkers that are expected to predict clinical benefit (or   harm or lack of benefit) and are intended to substitute for a clinical endpoint.9    Currently, none of the known biomarkers (e.g., anti-dsDNA levels, complement levels) in SLE has been validated as a surrogate endpoint, and therefore no biomarker can substitute for a direct assessment of clinical benefit in clinical trials.

9 目前，系统性红斑狼疮的已知生物标志物（如抗dsDNA水平、补体水平）都没有被验证为替代终点，因此没有生物标志物可以替代临床试验中对临床获益的直接评估。

 In some cases, biomarkers are used to define risk or identify potential responders to a treatment. Sponsors should consult the appropriate FDA center to determine whether a biomarker used to   select patients or monitor response in clinical trials can be used in prescribing the medical product if it is approved (e.g., for selection of patients or for monitoring safety or

在某些情况下，生物标志物用于确定风险或识别治疗的潜在反应者。申办者应咨询相应的 FDA 中心，以确定在临床试验中用于选择患者或监测反应的生物标记物在医疗产品获得批准后是否可用于处方（例如，用于选择患者或监测安全性或疗效）。

 effectiveness).10 有效性）。

 11.       Study Procedures and Timing of Assessments

11. 研究程序和评估时间

 In SLE trials using reduction in disease activity as an endpoint, it is important that the protocol    specify procedures to ensure that the scoring of the DAI specifically reflects SLE-related organ    dysfunction.  The interpretation of score changes can be confounded if organ system dysfunction caused by a disease or condition other than SLE is present or organ dysfunction caused by the treatment occurs.  Investigators should be appropriately trained to ensure uniform scoring, as   variability can decrease study power.  In some cases, it may be helpful to have an adjudication committee confirm assessment based on DAIs (e.g., flares or quiescence of disease).

在以疾病活动度下降作为终点的系统性红斑狼疮试验中，试验方案必须明确规定程序，以确保 DAI 的评分能具体反映与系统性红斑狼疮相关的器官功能障碍。 如果存在由系统性红斑狼疮以外的疾病或病症引起的器官系统功能障碍，或出现由治疗引起的器官功能障碍，那么对评分变化的解释就会受到干扰。 研究人员应接受适当的培训，以确保统一评分，因为评分的变化会降低研究的有效性。 在某些情况下，由评审委员会根据 DAIs（如疾病发作或静止）来确认评估结果可能会有所帮助。

 12.       Statistical Considerations

12. 统计方面的考虑

 The particular statistical analysis used can differ depending on the endpoints and outcomes of interest.  To assess a reduction in disease activity or flare, induction of response, treatment of   serious acute manifestations, or maintenance of response, the statistical test usually should evaluate the difference between the treatment and control groups in the proportion of patients meeting a predefined outcome, although measures of continuous variety also can be useful. These outcomes can be summarized as binary or ordinal for the purpose of the primary analysis.   Although outcomes at the end of the trial are usually the primary focus, outcomes also should be  evaluated at multiple times during the trial.  To assess the time to flare inpatients with quiescent  disease, the statistical test usually would evaluate the difference in the time-to-event curves using an appropriate test.  This analysis also should be supported by an analysis comparing the proportion of flare-free patients at the end of the trial.  Analysis considerations of primary endpoints for organ-specific disease should be similar to those for SLE.

所使用的特定统计分析方法可能因关注的终点和结果而异。 为了评估疾病活动或复发的减少、诱导反应、严重急性表现的治疗或反应的维持，统计检验通常应评估治疗组和对照组之间在达到预定结果的患者比例上的差异，尽管连续性的各种测量也可能有用。为了进行主要分析，这些结果可以归纳为二元或序数结果。 虽然试验结束时的结果通常是主要关注点，但在试验过程中也应多次评估结果。 为了评估疾病静止期住院患者的复发时间，统计检验通常会使用适当的检验方法来评估事件发生时间曲线的差异。 这一分析还应辅之以比较试验结束时无复发患者比例的分析。 器官特异性疾病主要终点的分析考虑因素应与系统性红斑狼疮相似。

 In addition to the primary assessments of disease activity, other aspects of the disease process may be important in fully elucidating the effect of the treatment on patients.  The overall probability of a false positive finding for a completely ineffective treatment should be controlled by prespecifying a single primary analysis or several analyses with appropriate adjustment for     multiplicity.  Secondary analyses also should be adjusted to avoid error and the protocol should   describe the plan for controlling such errors.

除了对疾病活动性的主要评估外，疾病过程的其他方面对于全面阐明治疗对患者的影响可能也很重要。 对于完全无效的治疗，出现假阳性结果的总体概率应通过预设一项主要分析或多项分析并对多重性进行适当调整来加以控制。 二次分析也应进行调整以避免误差，方案中应说明控制此类误差的计划。

 We recommend prespecifying in the protocol statistical approaches (e.g., regarding dropouts or missing data) (see ICH E9).

我们建议在方案中预先规定统计方法（例如，关于辍学或数据缺失）（见 ICH E9）。

 13.      Accelerated Approval Considerations for Human Drugs and Therapeutic Biological Products (Subpart Hand SubpartE)

13. 加速审批人用药品和治疗性生物制品的考虑因素（Hand 分部分 E 分部分）

 For serious or life-threatening conditions, a new human drug (21 CFR part 314, subpartH) or therapeutic biological product (21 CFR part 601, subpartE) can be approved on the basis of adequate and well-controlled clinical trials that establish that the human drug or therapeutic biological product has an effect on a “surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit” (21 CFR 314.510 and 21 CFR 601.40).  Full approval would be contingent on required postmarketing clinical trials to verify the clinical benefit.

对于严重或危及生命的病症，可根据充分和对照良好的临床试验批准新的人用药物（21 CFR part 314，subpartH）或治疗性生物制品（21 CFR part 601，subpartE），这些临床试验证明该人用药物或治疗性生物制品对 "替代终点 "有影响，而 "替代终点 "根据流行病学、治疗学、病理生理学或其他证据，有合理的可能预测临床益处（21 CFR 314.510 和 21 CFR 601.40）。 全面批准将取决于所需的上市后临床试验，以验证临床益处。

 No surrogate marker has been reliably shown to predict clinical benefit inpatients with SLE and there has been no Subpart H or Subpart E approval of medical products for SLE.  Sponsors should be very cautious about selecting a potential surrogate marker intended to support accelerated approval until there is confidence regarding its predictive value.

目前还没有代用标志物能可靠地预测系统性红斑狼疮患者的临床获益，也没有针对系统性红斑狼疮的医疗产品获得 H 类或 E 类批准。 在对其预测价值有信心之前，申办者在选择支持加速审批的潜在替代标志物时应非常谨慎。

 14.      Risk-Benefit Considerations

14. 风险-效益考虑因素

 Assessment of risks and benefits involves an appraisal of the effect of the medical product on all aspects of the disease process, including disease activity, irreversible damage caused by the disease or its treatment, and health-related quality of life.11    The primary efficacy analysis should show a statistically significant result and the measured clinical effect of the medical product should be clinically meaningful.  Toxicities related to the pharmacologic effects of the medical  product (e.g., immunosuppression) also should be considered as part of this overall risk-benefit assessment of the medical product.

对风险和效益的评估包括评价医疗产品对疾病过程各个方面的影响，包括疾病活动、疾病或其治疗造成的不可逆转的损害以及与健康相关的生活质量。 与医疗产品药理作用相关的毒性（如免疫抑制）也应作为医疗产品整体风险-效益评估的一部分加以考虑。

 It is important that the size of the safety database for human drugs and therapeutic biological products at approval be consistent with the recommendations made in the ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions.  Particular attention should be     paid to the assessment of known toxicities, or to pharmacologic and biological effects that might be suspected to imply delayed toxicities.  It is important to consider these toxicities in formulating the clinical development program.  This information may influence the size of the safety database.

重要的是，人类药物和治疗性生物制品在批准时的安全数据库规模应符合 ICH 行业指导 E1A《评估临床安全性的人群暴露程度》中提出的建议：中提出的建议。 应特别注意评估已知的毒性或可能被怀疑意味着延迟毒性的药理和生物效应。 在制定临床开发计划时必须考虑这些毒性。 这些信息可能会影响安全性数据库的规模。

 A smaller safety database may be appropriate to support approval of medical products designed to treat aspects of SLE that represent orphan indications or for the treatment of serious acute manifestations, because it may be impossible or impractical to study a large number of patients with these conditions.12    Sponsors may wish to discuss these issues with the appropriate review division early in the development of a new treatment.

对于治疗系统性红斑狼疮某些方面的孤儿适应症或治疗严重急性表现的医疗产品，较小的安全性数据库可能适合于支持其获得批准，因为对这些疾病的大量患者进行研究可能是不可能或不切实际的12 。

 Finally, if there is concern about rare but serious adverse events (e.g., from the mechanism of action or experience with similar human drugs and therapeutic biological products), a postmarketing study or clinical trial may be needed to gather additional safety information.

最后，如果担心出现罕见但严重的不良事件（例如，从作用机制或类似人类药物和治疗性生物制品的经验来看），可能需要进行上市后研究或临床试验，以收集更多的安全性信息。