FOP临床试验的特殊注意事项

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Introduction | 简介

孤儿病的临床试验变得越来越普遍，孤儿药疾病认定是增长最快的领域之一。其中一种孤儿病——进行性骨化性纤维发育不良（FOP；MIM#135100），其特征是广泛的异位骨化（HO），即骨骼肌和软组织的异常骨化【1】。FOP 的病程具有累积性，导致功能逐步丧失并影响患者的独立生活能力【2】。此外，FOP中的HO可以自发发生，也可能由创伤或炎症事件在患者一生中诱发【1–4】。虽然HO是FOP最突出的临床特征，但其他系统（如中枢神经系统）也可能受到影响【1, 5】。FOP的独特表型及其高并发症风险为临床护理和试验设计带来了重大挑战，在优化受试者安全性时必须考虑这些因素。本文提出了FOP特有的临床试验设计要点，这些要点已获得国际FOP临床专家的共识。

Clinical manifestations of FOP | FOP的临床表现

FOP（进行性骨化性纤维发育不良）是一种严重致残的遗传性结缔组织疾病，其典型特征包括大脚趾的先天性畸形和进行性异位骨化（HO），后者（HO：进行性异位骨化）会在特定的骨骼外部区域形成同质正常的骨骼【2】。全球的发病率估计为1/1,300,000至1/2,000,000【6】。FOP没有种族、性别、地理或人种上的偏好。患有FOP的儿童出生时通常看起来正常，除大脚趾的先天畸形外无其他显著症状。放射学检查有助于诊断该疾病【7】。在生命的第一个十年中，患者会出现偶发性的软组织疼痛肿胀（即“急性发作”），这些急性发作可自发发生，也可能由软组织损伤、肌肉注射、病毒感染、肌肉拉伸、肌肉疲劳或跌倒引起。每次发作会使骨骼肌、肌腱、韧带、筋膜及腱膜转化为异位骨，逐渐使运动功能丧失。经典的FOP由Activin A受体I型/Activin样激酶2（ACVR1/ALK2）基因中的一种复发性激活突变（c.617G>A; p.R206H）引起，该基因编码的是一种骨形态发生蛋白（BMP）I型受体【8】。少数患者还存在极为罕见的FOP基因变异类型【9】，变异型突变可能表现为经典的表型特征，或者更严重的表型。

FOP的诊断通常可以很容易经过临床评估鉴定，同时也可以通过基因检测确诊。尽管大脚趾的标志性变化明显，但仍存在诊断延误的情况。鉴别诊断较为复杂，但误诊通常包括进行性骨发育异常征（POH）、骨肉瘤、淋巴水肿、软组织肉瘤、硬纤维瘤、侵袭性青少年纤维瘤病、皮肤和肌肉钙化、感染以及非遗传性（获得性）异位骨化。尽管大多数FOP病例为散发性（非遗传性突变），但少数遗传性FOP病例显示出常染色体显性遗传的种系传播模式。

目前，FOP 尚无明确的治疗方法，但在发作后 24 小时内开始使用高剂量的皮质类固醇药物和非甾体抗炎药（NSAIDs）进行为期四天的短期治疗，可能有助于减轻早期阶段的严重炎症和组织水肿【2】。预防性管理主要依赖于预防跌倒、呼吸功能下降和病毒感染的措施。患者的中位预计寿命为 56 岁【10】。大多数患者在20岁末期已需依靠轮椅，通常因胸廓功能不全综合征的并发症而去世【1，10】。

FOP的显著临床表现以及对其发病机制的深入了解，激发了人们对FOP新疗法临床试验的强烈且日益增长的兴趣。这些研究突显了理解FOP独特临床特征的重要性，以及这些特征对临床试验设计和实施的影响。

The International Clinical Council on FOP (ICC) | FOP国际临床理事会（ICC）

ICC FOP分会于2016年成立，旨在为FOP患者的临床护理和临床研究提供统一协调的最佳实践建议。创始成员包括19位国际公认的医生，这些专家在FOP领域拥有丰富的临床经验，并深刻理解患者面临的挑战和需求。ICC的使命包括：

推广FOP患者护理的最佳实践；

为FOP患者的干预试验设计和实施提供建议；

更新FOP临床指南；

倡导建立稳健的数据共享和协作基础设施，以应对FOP社区关注的重要和新兴临床问题；

确定FOP患者护理中的未充分探索领域，并提出可能促进研究的新问题；

分享在经典和变异型FOP患者护理中的宝贵临床经验；

更好地理解FOP的多样性表型及其系统性病理特征。

ICC识别出的关键挑战之一是制定特定于FOP的指南，以支持全球FOP患者安全且具有变革性的治疗方法的开发。ICC旨在为大学实验室、制药公司、生物技术公司和政府机构的研究科学家提供针对FOP患者群体的临床研究试验的专业建议。本文讨论了FOP患者群体在成功开展临床试验方面面临的主要挑战和考量因素。这些考量旨在补充标准的临床试验设计和实施方法，强调特定于FOP患者群体的特殊因素。

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Clinical trials in orphan diseases are becoming increasingly common. Orphan drug disease designations are one of the fastest areas of growth. One such orphan disease, ﬁbrodysplasia ossiﬁcans progressiva (FOP; MIM#135100), is characterized by widespread progressive heterotopic ossiﬁcation (HO) of skeletal muscle and soft connective tissues [1]. The course of FOP is cumulative, leading to progressive loss of function and independence [2]. Furthermore, HO in FOP can be spontaneous or be triggered by trauma and inﬂammatory events throughout life [1–4]. Although HO is by far the most prominent clinical feature in FOP, other organ systems such as the central nervous system can also be affected [1, 5]. The unique phenotypes of FOP, as well as the high risk of complications, pose signiﬁcant challenges for clinical care and clinical trial design that must be considered to optimize subject safety. Here, we propose FOP-speciﬁc clinical trial considerations that are agreed upon by international FOP clinical experts.

FOP is a severely disabling heritable disorder of connective tissue characterized by the classic features of congenital malformations of the great toes and progressive HO that forms qualitatively normal bone in characteristic extra-skeletal sites [2]. The worldwide prevalence is estimated at 1/1 300 000 to 1/2 000 000 [6]. There are no ethnic, racial, gender or geographic predilections to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. Radiological ﬁndings can assist with diagnosis of the disease [7]. During the ﬁrst decade of life, sporadic episodes of painful soft tissue swellings (ʻﬂareupsʼ) occur spontaneously or can be precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, muscular fatigue or falls. These ﬂare-ups transform skeletal muscles, tendons, ligaments, fascia and aponeuroses into heterotopic bone, progressively rendering movement impossible. Classic FOP is caused by a recurrent activating mutation (c.617G>A; p.R206H) in the gene encoding Activin A receptor type I/Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor [8]. There are a few patients with exceedingly rare genetic variant forms of FOP [9] that may show the classical phenotypic presentation, or more severe phenotypes.

The diagnosis of FOP can easily be made by clinical evaluation. Conﬁrmatory genetic testing is available. Delayed diagnosis still occurs, despite the hallmark changes in great toes. Differential diagnoses are varied but often include progressive osseous heteroplasia (POH), osteosarcoma, lymphoedema, soft tissue sarcoma, desmoid tumours, aggressive juvenile ﬁbromatosis, calcinosis of skin and muscles, infection and nonhereditary (acquired) heterotopic ossiﬁcation. Although most cases of FOP are sporadic (non-inherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern.

At present, there are no deﬁnitive treatments for FOP, but a brief, 4-day course of high-dose corticosteroids combined with nonsteroidal anti-inﬂammatory drugs (NSAIDs), started within the ﬁrst 24 h of a ﬂare-up, may help to reduce the intense inﬂammation and tissue oedema seen in the early stages of the disease [2]. Preventative management is based on prophylactic measures against falls, respiratory decline and viral infections. The median estimated lifespan is 56 years [10]. Most patients are wheelchair bound by the end of the second decade of life and commonly die of complications of thoracic insufﬁciency syndrome [1, 10].

The dramatic presentation of FOP and growing understanding of the disease’s pathogenic mechanisms have triggered strong and growing interest in clinical trials for novel treatments in FOP. These studies have highlighted the need for understanding the unique clinical features of FOP and how they affect clinical trial design and execution.

The ICC was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for those who suffer from FOP. The founding members are 19 internationally recognized physicians who are clinical experts in FOP and who have a deep understanding of the challenges and the needs of patients with FOP. The missions of the ICC are:

to educate on best practices for the care of individuals with FOP;

to advise on the design and conduct of interventional trials in patients with FOP;

to update the FOP clinical guidelines;

to advocate for a robust infrastructure for data sharing and collaboration on vital and emerging matters of clinical concern to the FOP community;

to identify less-explored areas of caring for patients with FOP and issues that may drive insight into research;

to share valuable clinical experiences from the care of patients with classic and variant FOP; and

to better understand the variable phenotype of FOP and the systemic nature of FOP pathology.

One of the key challenges identiﬁed by the ICC was the need for FOP-speciﬁc guidelines to support the development of safe and transformative treatments for patients with FOP worldwide. The ICC seeks to provide research scientists at university laboratories, pharmaceutical companies, biotechnology ﬁrms and government agencies with expert advice on clinical research trials tailored to the FOP community. Here, we discuss the major challenges and considerations for successful clinical trials that are speciﬁc to the FOP community. These considerations are meant to complement the standard approaches for clinical trial design and execution by highlighting considerations speciﬁc to the FOP community.

Methods | 方法

我们发现，对于FOP患者群体，急需一个整合的临床试验考量要点，特别是关注安全性和临床试验流程的要点。由八位临床试验和FOP临床护理专家组成的临床试验委员会通过线上会议和面对面会议的方式，进行了长期的圆桌讨论。委员会审查了文献和个人经验中关于FOP的临床过程和管理，当前的治疗指南【1】，美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）对于临床试验设计的建议，并讨论了与FOP患者相关的临床研究个人经验。委员会重点关注了临床试验的四个主要步骤（临床前阶段、试验设计、试验执行和试验后评估），以识别FOP特定考量至关重要的领域，这些考量可能显著影响试验的成功和受试者的安全性。这些主题领域由包括21位FOP临床专家和一位患者代表的ICC全体成员进行了审查。随后，临床试验委员会整合并进一步完善了这些建议，最终由委员会和ICC全体成员共同审核最终的考量要点。

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We identiﬁed an unmet need for a consolidated collection of clinical trial considerations directly relevant to the FOP community, with a particular focus on safety and clinical trial procedures. The Clinical Trials Committee, composed of eight experts in clinical trials and FOP clinical care, met using a longitudinal round-table discussion format via web conferences and in-person meetings. The committee reviewed the clinical course and management of FOP in the literature and in personal experience; the current treatment guidelines [1]; current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations for the design of clinical trials; and discussed personal experiences with clinical studies related to patients with FOP. The committee focused on the four main steps of a clinical trial (preclinical, trial design, trial execution and post-trial evaluation) to identify areas where FOP-speciﬁc considerations were particularly important, as they could substantially affect the success of a trial and the safety of subjects. These topic areas were reviewed by the full ICC, which included 21 clinical experts in FOP and one patient representative. The Clinical Trials Committee then consolidated and further developed the recommendations. The ﬁnal considerations were then reviewed by the committee and by the full ICC.

Results | 结果

ICC临床试验委员会提出的挑战，对研究人员主导和企业资助的研究都非常重要。此外，委员会认识到这些考量并非排他性规定，也并非用于规定具体的临床试验设计或方法，因为这些方面通常因试验药物或地区而异，最适合由试验研究者决定。此外，委员会也认识到，随着对FOP疾病发病机制认识的不断深入，持续进行的临床研究和临床护理改进将揭示出更多FOP特有的考量。因此，临床试验委员会和ICC全体成员力求建立一个关于FOP患者群体的关键考量的共同基础。

Pre-clinical study development | 临床前研究的开发

在早期研究设计阶段，应邀请FOP临床护理领域的资深专家（如ICC成员）作为资源提供支持。建议研究人员和公司将ICC视为顾问资源，以讨论试验设计及其可能的优缺点。ICC不会充当管理机构，也不要求研究必须获得ICC批准，因为主要责任在于首席研究员（PI）和资助方。ICC将设有保密机制以确保信息安全。

在研究设计的早期阶段应与FOP患者群体（包括FOP患者）积极交流。FOP患者在参与研究方面有独特的限制和需求。提前了解这些需求可以有助于最大限度地提高研究的成功率，并确保FOP参与者的安全。

临床研究应基于模型系统中的临床前研究理论。试验的理论基础应由适当的临床前数据支持，并在合适的临床前模型中进行验证。这可能包括在已建立的FOP遗传小鼠模型中证明疗效，并根据需要展示体外信号或生物效应。尽可能地，应评估非异位骨化（HO）的效应，包括但不限于潜在的生殖、神经、心脏、肺、胃肠、成长与发育、口腔/牙齿及血液方面的并发症。

理想情况下，初步研究应在适当的平行人群中对人类进行充分的安全性评估，并确保参与者在年龄和性别上匹配。应优先使用人类的初步数据以最大限度地提高安全性。这些数据应包括来自两个性别的信息，并涵盖与研究及潜在后续研究相关的适当年龄范围。

Trial design | 试验设计

使用最佳的临床试验设计来评估潜在疗法。按照未来监管批准的一致方式进行的正式临床试验，并具备严格的科学性，是确定任何潜在疗法的疗效和安全性的最佳方法。由于FOP患者的数量较少，因此需要精心规划，以确保结果尽可能可靠。

所有研究均应获得伦理委员会的批准。所有临床试验在给受试者施用任何实验性疗法之前，应获得适用的当地伦理委员会的批准，并经过科学验证。

对于儿科试验领域。鼓励包括儿童的试验，只要有适当的安全性数据、适应症和初步数据，并符合当地法规，如欧洲委员会所提议的法规【11】。对于可能已经在儿童群体中用于其他疾病的药物以及可能为仿制药或成本较低的药物，特别感兴趣。

保护弱势群体。FOP患者应被视为残疾人士，因此属于弱势群体。应实施适当的保护措施，以确保同意和数据共享。鉴于FOP患者数量极少且去标识化风险高，尤其是结合成像时，遗传学研究应具有充分的保护措施。所有遗传研究，如DNA测序、RNA测序和微生物组研究，需适当去标识化并获得适当同意。同样，成像数据，特别是全身成像，对于每位受试者都是独特的，可能基于HO模式允许去标识化。

重点是安全。试验设计要以受试者安全为重中之重。我们鼓励所有药厂和研究小组直接与研究者分享安全性试验的主要数据，而不能仅仅是依赖研究者手册中普遍提供的摘要数据。这对研究者发起的研究尤为重要，因为有关的安全信息可能不是那么容易通过FDA或EMA等监管结构的审查。我们认识到其中一些数据可能会是敏感的，因此在项目团队中最好签订双向保密协议。我们还会鼓励调查人员将ICC作为支持和保证试验安全的资源。

FOP特定的健康考虑应包含在试验设计和安全性评估中。下面列出了FOP特定的主要注意事项。应与所有FOP受试者明确讨论这些考虑因素以及特定研究风险。

a. Repeated blood draw/intravenous access complications: 反复抽血/静脉通路并发症

FOP患者要由经验丰富的采血医生进行认真且可耐受的外周采血。以尽可能温和与微创的方式进行处置尤为重要。根据当前的FOP治疗指南，应该尽可能减少止血带的使用时间以及去尝试反复抽血的次数。咨询那些熟悉FOP患者护理的临床医生至关重要。

b. Respiratory complications: 呼吸系统并发症

FOP患者由于胸壁被异位骨包裹、先天性肋椎关节畸形 [1] 以及潜在的肺生理学变化 [12] ，会存在限制性肺病的风险。由于颈椎畸形、颌骨受累和异位骨化 [1, 13]，对FOP患者插管极为困难。临床试验应该考虑这些潜在的风险，并且判断是否需要进行监测。此外，医疗人员应接受标准的操作程序培训，以便在发生过敏反应或呼吸衰竭时对FOP患者进行有效的管理。这些处置方式应该包括FOP特定的气管插管流程，遵循当前的FOP治疗指南 [1]和FOP患者气道管理的最佳实践 [13]。

c. Infection complications: 感染并发症

虽然无法弄清FOP患者是否存在较高的感染风险，但考虑到FOP患者存在呼吸系统损害和缺少免疫接种，呼吸道感染也许尤具破坏性 [1]。合适的管理策略，包括采取通用的预防措施和预防性接触措施，以及奥司他韦（达菲）等预防性药物，这些要酌情纳入研究方案。此外，应特别注意预防治疗过程中的获得性感染。以上最好通过标准操作程序，记录成文档以备团队参考。

d. Gastrointestinal complications: 胃肠道并发症

许多FOP患者的下颌活动能力降低。此外，许多FOP患者报告描述会经常出现恶心或呕吐。这种情况要判断FOP患者的呕吐是否会关系到较高的肺误吸风险。下颌活动受限也可能影响口服药物的给药方式。（即药丸的大小，或对粉末或液体的要求）根据试验设计和药理化合物，可以结合监测最大下颌开口度或者进行唾液流量评估。

e. Neurological considerations: 神经学方面的考虑

无论是在FOP发作期间还是发作之后，患者报告称神经系统问题的发生率较高（包括疼痛） [1, 14]。此外，一些FOP患者存在神经系统的变化，从磁共振成像 (MRI) 所示，如中枢神经系统脱髓鞘 [5]；但这些变化的意义目前尚不清楚。任何临床试验都应包括止痛措施，并为受试者提供合理的临床管理。

f. Potential complications of blood pressure measurements: 测量血压的潜在并发症

据报道，测量血压与FOP急性发作的触发有关，但目前尚未系统地研究与急性发作有明确的相关性。要遵守当前FOP临床指南的操作，尽可能地减少血压的测量。应手动测量血压，用最小的袖带充气，必要时缩短袖带充气的时间。应尽可能地避免重复测量血压。

g. Radiology considerations: 放射学方面的考虑

尽管FOP患者尚未有发生过因辐射暴露而导致发生并发症，但是由于异位骨化和身体锁定，在将患者移动到放射检查地点和适当的成像定位方面将会是极具挑战性的事情。受试者、护理人员和医疗保健人员应该接受有关病人行动限制方面的培训。要向放射科团队提供足够的软垫和安全的转移器具，并以正确的定位对受试者进行拍照。最后，一些受试者会由于关节强直而无法成像。有关临床试验应该在患者入组时和研究期间考虑到这些方面，因为受试者的状态可能会在研究期间发生变化。

h. Mechanism for rapid response to a FOP flare-up: 快速响应FOP急性发作的机制

FOP急性发作会自然发生，并不会有明确的触发事件。所有试验的标准操作方案应该包括快速评估、响应和治疗控制潜在FOP急性发作的机制，以减少异位骨化形成的风险。

i. Travel risks: 旅途风险

由于FOP会影响关节的活动能力，FOP患者在旅行期间的受伤风险将会增加，尤其是在机场等繁忙的交通枢纽。

需要给这些潜在的受试者预留出足够的转移时间，以及预先安排轮椅和交通援助，以及有必要让护理人员与受试者一同随行，并要将其纳入临床研究的标准操作流程。

另外还要再旅途路线的所有环节中考虑到患者身体因疲劳劳损的潜在风险。此外，作为所有试验的必备环节，按常规要在潜在受试者的旅途期间进行安全检查（即长途飞行中呼吸衰竭的风险）。

Considerations for paediatric patients with FOP. | 针对FOP儿童患者的考虑。

涉及儿童的临床试验应由具有FOP儿童护理经验的团队进行。研究程序，如抽血和成像，可能非常困难且令人焦虑。此外，对于非常年轻的儿童而言，通常需要镇静或全身麻醉的某些程序（如影像学检查），在FOP患者中具有更高的风险，因为这些患者可能存在呼吸功能受损、颈部活动受限、下颌运动受限以及麻醉风险（详见上述“FOP特定健康考虑”部分中的呼吸并发症）。临床研究的设计还应考虑儿童的需求，包括预防疲劳、最小化程序、使用最低辐射剂量、减少旅行/时区变化带来的压力，以及尽量减少缺课天数。研究设计中还应纳入对家庭的额外考虑，包括家庭为年幼的兄弟姐妹寻找托儿支持或全家一起旅行的需要。最后，认识到儿童和青少年的特定社会/情感需求（如在决策中赋予权力）对于在该人群中成功开展试验极为重要【15】。

International cooperation. | 国际合作

非常鼓励进行全球多中心联合试验。这种试验对与招募患者极为重要，而且对与传递有关FOP的关键资源和知识也极为重要。尽管根据FOP的治疗指南，在医疗管理上实现了很大程度的标准化，但是FOP并发症的管理可能会因为当地资源的可用性而具有很大的差异。（如移动器械工具，管理策略等）

Limited subject availability. | 有限的受试者

与其他罕见病和孤儿病一样，在设计试验时需要理解和体会到全球的FOP患者的数量非常有限，并且更为有限的是能够成功实施临床试验，且具备多学科临床专业知识的中心。在适当的情况下，应该包括变异型FOP的受试者（非ACVR1 R206H突变的患者）。

Innovative trial design. | 创新的试验设计

安慰剂对照试验对科学实验的完整性非常重要，但是由于这种疾病的罕见性和严重性，对与FOP的家庭来说可能非常具有挑战性，并且一旦觉得药物有点儿效果，那么可能会带来伦理上的挑战。我们鼓励创新型的试验设计，包括将安慰剂组与积极治疗组交叉的随机试验、利用标注的历史对照数据，以及在已经证明其有效的研究中使用积极比较的非劣效性设计。如果药物显现出其效果，我们鼓励在试验设计中，允许受试者在试验结束后继续使用药物（即开放标签阶段或其他的等效方式）。这在资源匮乏的国家尤为重要，在这些国家中，由于成本的问题，试验后能否够获得治疗可能会是一个挑战。由于欧洲和北美有新的儿科立法，现在，由行业赞助的新药临床试验习惯于让资源较少国家和中心参与。

Common study endpoints. | 常见的研究终点

数据，包括那些安慰剂组或正在进行临床观察研究的受试者数据，对其二者都要有评估和测量。应该制定计划，尽可能的共享原始数据（即通过国际FOP鞋柜（IFOPA进行注册））通过授权获得直接结果的比较，这将有助于最大限度地发挥受试者数量少的潜在影响。特别是当没有足够的潜在受试者时，这种方法还可以增加可用虚拟受试组的数量。这些通识评估应该包括以下内容：

a. 应得到一组核心的基线数据，涵盖基线患者的特征（即人口统计学、异位骨化的范围、机体功能的状态、FOP的相关特征、遗传变异和疼痛的评估）以及FOP急性发作的基线水平（即频率、持续时间、位置和突发症状）。

b. 应收集研究药物的基础评估，包括但不限于对急性发作频率的影响、已建立和新发异位骨化的范围、机体功能的评估和相关药物的耐受性以及毒性。

c. 功能评估应包括由医生评估的关节累积受累模拟量表 (CAJIS) [16]。

d. 患者报告的结果应包括日常生活活动和生活质量的评估 [例如：FOP患者独立的日常生活活动 (FOP I-ADL) 问卷或 FOP-身体功能问卷 (FOP-PFQ) 和 EuroQol 5三级量表维度问卷（EQ-5D-3 L）]。

e. 应包含对全身（首选）或低剂量CT进行特定部位新发异位骨化的体积测量。这也会得到骨形成的定量。还有其他有关的评估，例如：PET/CT；但是，采用这种方式在某些医疗机构中可能会受到使用限制。

f. 如果改变评分或测量标准，则需要证明这些评分或测量在效果上至少与推荐的衡量标准相匹配，并且在理想的情况下是要与被推荐的测量标准具有已知明确的相关性。

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The ICC Clinical Trials Committee identiﬁed challenges that were important for both investigator-initiated and industrysponsored studies. In addition, the committee recognized that these considerations are not exclusive, and that the considerations are not meant to be used to dictate speciﬁc clinical trial design or methods, as those considerations are often agent or location speciﬁc and best left to trial investigators. Furthermore, the committee recognized that ongoing clinical studies and improvements in clinical care will continue to reveal more FOP-speciﬁc considerations as our knowledge about FOP disease pathogenesis improves. Thus, the Clinical Trials Committee and the entire ICC sought to establish a common foundation for discussions about critical considerations that are speciﬁc to the FOP community.

Engage established experts in FOP clinical care, such as the members of the ICC, as a resource during early study design. Investigators and companies are encouraged to use the ICC as an advisory resource for discussing trial design and potential strengths/weaknesses of a particular study. The ICC will not serve as a governing body or require ICC approval for a study, as primary responsibility lies with the primary investigators (PIs) and sponsor. The ICC will have mechanisms for maintaining conﬁdentiality.

Engage the FOP community, including patients with FOP, early on in study design. Patients with FOP have unique limitations and requirements for participating in a study. Understanding these requirements early in the study design process can help to maximize the success of a study and safety for FOP participants.

Clinical studies should be based on preclinical rationales in model systems. Trial rationales should be supported by appropriate preclinical data in an appropriate preclinical model. This could include demonstration of efﬁcacy in established genetic mouse models of FOP, with demonstration of in vitro signalling or biological effects, as appropriate. Whenever possible, assessment of non-HO effects should be included, including but not limited to potential reproductive, neurological, cardiac, pulmonary, gastrointestinal, growth and developmental, oral/dental and haematological complications.

Ideally, preliminary studies should include sufficient assessment in humans for safety in an appropriate parallel population with ageand sex-matched subjects. Ideally, human preliminary data should be used to maximize safety. These should include information in both sexes and in an appropriate age range relevant to the study and potential follow-up studies.

Use of the best possible clinical trial designs to assess potential therapies. Formal clinical trials, performed in a way consistent with future regulatory approval and with strong scientiﬁc rigour, are the best way to determine the efﬁcacy and safety of any potential therapy. The small population of patients with FOP necessitates careful planning, to ensure that the results are as robust as possible.

All studies should have ethics committee approvals. All clinical trials should obtain the approval of the applicable local ethics committee and be scientiﬁcally validated before any investigational therapy is given to a subject.

Pediatrics as the battleground. Trials that can include children are encouraged, provided that the appropriate safety data, indications and preliminary data are present and in compliance with local regulations such as those proposed by the European Commission [11]. Trials of medications that may already be used in paediatric populations for other conditions, and drugs that may be generic or of lower cost, are of particular interest.

Protection for a vulnerable population. Patients with FOP are considered disabled and are thus a vulnerable population. Appropriate protections for consenting and data sharing should be implemented. Genetics studies should have adequate protections, given the extremely small population of patients with FOP and the high risk of de-identiﬁcation, particularly when combined with imaging. All genetic studies, such as those including DNA sequencing, RNA sequencing and microbiome studies, need to be appropriately de-identiﬁed and properly consented. Likewise, imaging data, particularly whole-body imaging, are unique to each subject and could allow de-identiﬁcation based on HO patterns.

Emphasis on safety. Trials need to be designed with subject safety as the topmost priority. We encourage all companies and research groups to share primary data from safety trials directly with the investigators, and not rely solely on summary data often presented in investigator brochures. This is particularly important for investigator-initiated studies, as safety information may not be readily available or scrutinized by regulatory agencies, such as the FDA or EMA. We recognize that some of these data may be sensitive, so a two-way nondisclosure agreement is preferable within the project team. We also encourage investigators to use the ICC as a resource to support and maintain safety.

FOP-specific health considerations should be included in trial design and safety assessments. Key considerations unique to FOP are listed below. These considerations, as well as studyspeciﬁc risks, should be clearly discussed with all subjects with FOP.

patients with FOP can tolerate peripheral blood collection when performed carefully by an experienced phlebotomist. It is critical that the procedure be performed in as gentle and minimally invasive manner as possible. Tourniquet time and number of blood draw attempts should be minimized, according to the current FOP treatment guidelines. Consultation with clinicians who are familiar with the care of patients with FOP is critical.

Patients with FOP are at risk of restrictive lung disease because of chest wall HO, congenital malformation of the costovertebral joints [1] and possibly changes in lung physiology [12]. Patients with FOP are also extremely difﬁcult to intubate owing to their cervical spine malformations, jaw involvement and HO [1, 13]. Clinical trials should consider these risks, and whether monitoring is needed. In addition, healthcare providers should be trained with a standard operating procedure for managing patients with FOP in the event of anaphylaxis or respiratory failure. These procedures should include FOP-speciﬁc processes for intubation of the trachea, following the current FOP treatment guidelines [1] and best practices of airway management of patients with FOP [13].

Although patients with FOP are not known to be at higher overall risk for infections, respiratory infections can be especially devastating, given the respiratory compromise present in affected patients with FOP and the lack of immunizations [1]. Appropriate management strategies, including the use of universal precautions and contact precautions, as well as prophylactic medications such as oseltamivir (Tamiﬂu), should be incorporated into study protocols as appropriate. In addition, extra care should be taken to prevent hospitalacquired infections. These are best documented with a standard operating protocol for the team.

Many patients with FOP have decreased mobility of their jaw. In addition, a number of patients with FOP report frequent nausea or vomiting. This should be considered as vomiting in a patient with FOP may be associated with a higher risk of pulmonary aspiration. Limited jaw mobility may also affect choice of how an oral medication is administered (i.e. pill size, or need for powders or liquids). Monitoring of maximal jaw opening, or assessments of salivary ﬂow, may be incorporated depending on the trial design and pharmacological compound.

Patients with FOP have reported a higher incidence of neurological concerns including pain, both during and out of a FOP ﬂare [1, 14]. In addition, some patients with FOP have neurological changes, as seen on magnetic resonance imaging (MRI), such as central nervous system demyelination [5]; however, the signiﬁcance of these changes is unclear. Pain measures should be included in any clinical trials, with appropriate clinical management available for subjects.

Blood pressure measurements have been anecdotally reported to be associated with the triggering of FOP ﬂares but clear correlation with ﬂares has not been studied systematically. Blood pressures should be taken as infrequently as possible, in a manner that follows the current FOP clinical guidelines [1]. Blood pressure should be taken manually, with minimal cuff inﬂation, and with as short of a duration of cuff inﬂation as necessary. Repeated blood pressure measurements should be avoided whenever possible.

Although patients with FOP have no known increase in complications from radiation exposure, transportation to a radiology site and positioning for the appropriate imaging can be extremely challenging because of the HO and body positioning. Subjects, care givers and healthcare staff should be trained about the limitations of mobility. Adequate soft padding and safe transfer equipment should be provided to the radiology team to position a subject properly for imaging. Finally, some subjects will not be able to be imaged owing to their ankylosed joints. Clinical trials should consider this at the time of enrolment and during the study, as a subject’s status may change over the duration of a study.

FOP ﬂares can occur spontaneously, with no clear triggering event. The standard operating protocol of all trials should include mechanisms for rapid assessment, response and treatment of potential FOP ﬂare-ups to decrease the risk of HO formation.

As FOP affects joint mobility, patients with FOP are at increased risk of injury during travel, particularly in busy transportation hubs such as airports. Sufﬁcient times for transfers, as well as pre-arrangements for wheelchairs and transport assistance, and the need for caregivers to travel with subjects, should be discussed with any potential subject and incorporated into the standard operating protocols for clinical studies. Potential risks for physical strain should also be considered at all steps along a travel route. In addition, the screening of potential subjects for safety during travel (i.e. the risk of respiratory failure during a long ﬂight) should be performed routinely as part of any trial.

Considerations for paediatric patients with FOP. Clinical trials involving children should utilize a team with experience in caring for paediatric patients with FOP. Study procedures, such as phlebotomy and imaging, can be very difﬁcult and anxiety-provoking. In addition, some procedures that are normally conducted with sedation or general anaesthesia, such as imaging studies in very young children, are associated with much higher risks in children with FOP because of respiratory compromise, restricted neck movement, restricted jaw movement and anaesthesia risks in patients with FOP (see respiratory complications in the ‘FOPspeciﬁc health considerations’ section above). Clinical studies should also be designed to consider the needs of children, including prevention of fatigue, minimization of procedures, using the lowest radiation doses possible, minimizing the stresses of travel/time zone changes and keeping days missed from school to a minimum. Additional considerations for the families, including the need for families to identify childcare support for younger siblings or for the family to travel together, should be incorporated into the study design. Finally, recognition of the speciﬁc social/emotional needs of children and adolescents (such as empowerment in decision making) can be extremely valuable for successful trial execution in this subject population [15].

Multinational trials are strongly encouraged. This is important for recruitment but also for spreading key resources and knowledge about FOP. Although medical management is largely standardized according to the FOP treatment guidelines [1], management of FOP complications can vary signiﬁcantly, based on the availability of local resources (i.e. mobility devices, management strategies and so forth).

As with other rare and orphan diseases, trials need to be designed with an understanding and appreciation of the very limited number of patients with FOP in the world, as well as the even more limited number of centres with the multidisciplinary clinical expertise for successfully executing trials. Where and when appropriate, subjects with non-ACVR1 R206H variants of FOP should be included.

Placebo-controlled trials are important for scientiﬁc integrity but can be challenging for FOP families because of the rarity and severity of the disease, and is likely to present ethical challenges once even partially effective medications become available. We encourage innovative trial designs, including randomized trials with a crossover of the placebo group to active treatment, use of annotated historical control data, and non-inferiority designs using active comparators in studies where efﬁcacy has already been proven. We encourage trial designs that allow subjects to continue on the medications after the trial ends (i.e. open-label phase or other equivalent system) if the medications show evidence of efﬁcacy. This is especially important in less-resourced countries where post-trial access to therapy may be a challenge because of cost. As a result of new paediatric legislation in Europe and North America, it is now customary for industry-sponsored clinical trials with new medications to involve centres in less-resourced countries [11].

Common study endpoints. Data, including those derived from subjects who receive placebo or are in observational studies, should have common assessments and outcome measures. Plans should be established for the raw data to be shared whenever possible [i.e. via the International FOP Association (IFOPA) registry]. This will help to maximize the impact from the small number of subjects by allowing for direct comparisons of outcomes. It will also increase the number of subjects that could be used as a virtual control arm, particularly as treatment-naive subjects become less common. These common assessments should include the following:

a. A core set of baseline data should be obtained, covering baseline patient characteristics (i.e. demographics, extent of HO, functional status, associated FOP features, genetic variants, and pain assessments) and baseline ﬂare-up activity (i.e. frequency, duration, locations and ﬂare symptoms).

b. Common assessments of the investigational agent should be collected, including but not limited to the effect on frequency of ﬂares, extent of established and new HO, functional assessments and tolerability/toxicity of the agent concerned.

c. Functional assessment should include the cumulative analogue joint involvement scale (CAJIS) [16], assessed by a physician.

d. Patient-reported outcomes should include activities of daily living and quality of life assessments [such as the FOP Independent Activity of Daily Living (FOP I-ADL) Questionnaire or FOP-Physical Function Questionnaire (FOP-PFQ) and EuroQol 5 dimensions questionnaire with a three-level scale (EQ-5D-3 L)].

e. Volumetric measurements of ossification via total body (preferred) or site-speciﬁc new HO by low-dose computed tomography (CT) should be included. This will also allow quantitation of bone formation. Other related assessments, such as 18 F sodium ﬂuoride positron emission tomography (PET)/CT can also be considered [17, 18]; however, availability may be limited in some institutions.

f. Where alternate scores or measures are used, these need to be demonstrated to be at least equivalent in performance to the recommended measures, and ideally have known and close correlation with the recommended measures.

Clinical trial execution | 临床试验执行

应该为研究的执行分配充足的资源。受到FOP影响的个体有其独特的需求，并且由于他们较高的护理需求而常常无法远行。此外，遵循国际和当地的医学和伦理标准，为所有研究提供充足的资源，以提供可靠的程序说明、一致性和高质量的数据，这对与所有的研究都很重要。我们建议与FOP专家中心、ICC和FOP社区密切协商，以确保评估出实用、安全且可以产生有效的数据。

旅行注意事项

运送FOP患者涉及许多因素。试验前评估可能需要与当地医生和FOP专家进行密切协调，特别是当有呼吸功能受损的风险时，因为FOP患者在缺氧、受伤和疲劳方面的并发症风险较高【1, 19】。应在现场配备适当的医疗管理团队，以协助处理潜在的并发症。应允许适当的照护人员随同受试者前往现场（通常为一到两名照护人员），以便在旅行中提供日常协助及预防受伤。以下讨论了具体的旅行考虑因素。

a. 旅行座椅：FOP患者的运动范围有限，四肢固定在不适当的位置，并可能有异位骨骼突出。航空公司、火车或其他交通工具的座位应提供足够的垫子、舒适性和支持，以适应这些需求，包括为FOP患者定制或当前使用的座椅。此外，应提供休息间隔，以最小化发展压疮和深静脉血栓形成的风险。尽可能安排患者使用自己的轮椅进行运输，因为这通常能提供最佳支持，以减少疲劳和受伤的风险。

b. 酒店和住宿必须符合《美国残疾人法案》（ADA）：虽然一些酒店被视为符合ADA标准，但可能并不完全适合电动轮椅或FOP患者（例如，位于山顶或无法容纳四肢严重畸形的患者）。对设施进行预筛选，并询问受试者的具体需求，对于访问计划非常有帮助。

c. 试验访问：疲劳是FOP患者的主要问题。防止受试者疲劳的考虑（如通过减少旅行或安排半天的评估并提供足够的休息）对于减少与试验访问相关的伤害或急性发作非常重要。

d. FOP患者的抽血：由于静脉通路差、挛缩和不寻常的体位，FOP患者的抽血可能会很困难。一个经验丰富的抽血团队对于成功至关重要，这包括任何门诊或家庭护理中的抽血。使用静脉探测器/超声波可以非常有帮助。记录之前尝试和成功的抽血部位，以及与抽血相关的任何并发症，有助于最大程度地提高安全性。此外，制定减少抽血和创伤的既定协议也至关重要（包括建议的止血带时间少于1分钟，以降低缺氧的风险）。

e. 针对FOP儿童的考虑：禁食抽血非常困难且容易引起焦虑。应尽可能寻求儿童生活服务的支持，并考虑在经验丰富的专业人员指导下进行针头脱敏训练【20】。由于所有儿童群体的风险，使用电离辐射进行成像应尽量减少【21】。应谨慎规划或尽量减少那些使FOP儿童面临额外风险的程序（例如，影像学检查使用全身麻醉，或长时间的门诊访问或多次连续评估导致的疲劳增加）。

f. MRI、CT和PET/CT扫描选择：由于挛缩和异位骨骼的存在，这些扫描选项可能会受到限制。可能需要小心和创造性的体位调整（例如，分别扫描头部和尾部）。根据挛缩或不动的性质，可能无法进行MRI。我们建议在到达之前考虑获取受试者的照片进行筛查，以便事先评估成像方式的体位或适宜性。成像设施应制定安全转移受试者到成像台的计划（如使用升降设备或专用升降团队）。

受试者和随行的护理人员应该具有充分的旅途和健康保险。

受试者及其随行护理人员应拥有足够的健康和旅行保险。这一点至关重要，因为FOP患者在交通运输中面临因受伤而导致并发症的高风险，并且由于旅行受伤或疲劳可能加重急性发作。应提供在整个旅行过程中有效的适当医疗保险，并能够覆盖既往病症（即与FOP相关的病症）。这一点应明确告知潜在的受试者。国际患者尤其脆弱，因为他们在东道国的保险覆盖范围可能存在差异，并且旅行要求可能更长或更具挑战性。

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Sufficient resources should be allocated for execution of the study. People affected by FOP have unique needs and often do not travel frequently owing to their high care needs. In addition, sufﬁcient resources for robust documentation, consistency and high data quality are important for all studies, following international and local medical and ethical standards. We recommend close consultation with FOP expert centres, the ICC and the FOP community, to make sure that assessments are practical, safe and will yield usable data.

Travel considerations. The transportation of a patient with FOP involves many factors. Pretrial assessment may require close coordination with the local physicians and FOP experts, particularly if there is a risk of respiratory compromise, as patients with FOP are at increased risk of complications from hypoxia, injury and fatigue [1, 19]. Appropriate medical management teams should be available on site to assist with potential complications. Appropriate caregivers should be allowed to travel with the subjects on site (usually one or two caregivers) for routine assistance, as well as injury prevention during travel. Speciﬁc travel considerations are discussed below.

a. Travel seating: Patients with FOP have a limited range of motion, limbs ﬁxed in awkward positions and areas of heterotopic bone that may be protruding. Seating in aircraft, trains or other vehicles should accommodate these by providing sufﬁcient padding, comfort and support, including those customized for or currently used by the FOP subject. In addition, rest breaks should be provided, to minimize the risks of developing pressure sores and deep vein thrombosis. Whenever possible, transport in the patients’ own wheelchair should be accommodated, as this often has the best support to minimize fatigue and injury.

b. Hotels and lodging must be Americans with Disabilities Act (ADA) accessible: Although some hotels are considered ADA accessible, they may not be fully compatible with motorized wheelchairs or patients with FOP (i.e. located at the top of a hill or unable to accommodate subjects with signiﬁcant physical deformities such as outstretched extremities). Prescreening of facilities and asking the subjects for details about their needs can be very helpful for visit planning.

c. Trial visits: Fatigue is a major issue for patients with FOP. Consideration for preventing subject fatigue (i.e. by minimizing travel or by scheduling half-day assessments with sufﬁcient rest) are important for reducing injuries or ﬂares related to the trial visit.

d. Blood draws in patients with FOP can be difficult owing to poor venous access, contractures and unusual positioning. A consistent, experienced phlebotomy team experienced with patients with FOP is critical for success. This includes any outpatient or home care blood draws. Use of a vein ﬁnder/ultrasound can be extremely helpful. Documentation of prior attempted and successful phlebotomy sites, and any complications related to blood draws, is beneﬁcial for maximizing safety. In addition, established protocols for minimizing phlebotomy and trauma are critical (including a recommended tourniquet time of less than 1 min to minimize risks of hypoxia).

e. Considerations for children with FOP: Fasting blood draws are extremely difﬁcult and anxiety provoking. Child Life Services should be engaged whenever possible, and needle desensitization training [20] under the care of an experienced professional should be considered if available. Imaging with ionizing radiation should be kept to a minimum owing to risks in all paediatric populations [21]. Procedures that place children with FOP at additional risk (such as the use of general anaesthesia for imaging, or increased risk of fatigue from long clinic visits or multiple sequential assessments) should be carefully planned or minimized whenever possible.

f. MRI, CT and PET/CT scanning options may be limited owing to contractures and HO. Careful and creative positioning may be needed (i.e. scanning cranial and caudal portions separately). MRIs may not be possible, depending on the nature of the contractures or immobility. We recommend considering obtaining subject photographs prior to arrival and screening, so that the positioning or suitability of an imaging modality can be assessed beforehand. Imaging facilities should have plans in place for safe transfer of subjects onto the imaging table (lifts or dedicated lift teams).

Subjects and accompanying care providers should have adequate health and travel insurance. This is critical, as subjects with FOP are at high risk of complications from any injury with transportation, and of a worsening of any ﬂares due to travel injuries or fatigue. Appropriate medical insurance that is effective at all points along the travel route should be provided, with the ability to cover pre-existing conditions (i.e. those related to FOP). This should be explicitly described to the potential subject. International patients are particularly vulnerable, given differences in coverage in their host country, as well as longer or more challenging travel requirements.

Post-clinical trial | 临床后试验

及时发布数据和结果。试验应有计划快速公开数据，包括积极和消极结果。这对于患者的安全和该领域的科学完整性至关重要。所有临床试验都应包括快速不良事件记录和尽可能分享研究发现的机制。

为患者的利益而合作。我们强烈鼓励公司和所有研究人员尽可能高程度地相互合作，包括共享基线数据、评估工具和患者护理经验，因为可用于试验的受试者数量极为有限，并且任何重大的不良事件（即死亡或残疾）都将对FOP领域的所有试验产生重大负面影响。

共享公共数据元素。临床试验应设计为支持辅助观察性试验（例如基线数据），尽可能收集相应数据。试验应假设所收集的数据和研究发现将得到最大程度的共享。鼓励共享公共数据元素和终点，例如异位骨总量的量化、功能评估（例如CAJIS评分）和血清生物标志物。此外，强烈建议遵循公共指南的共享数据元素，例如通过美国国立卫生研究院（NIH）公共数据元素倡议（NIH CDE）或与IFOPA患者登记处共享的元素。

试验结束时的数据存放。我们鼓励与IFOPA讨论，以利用全球患者登记作为数据共享的潜在平台，特别是对理解疾病自然历史至关重要的安慰剂或基线结果。我们还鼓励根据大型公共机构（如NIH）共享政策的指南，公开原始数据（如测序数据），并使用公共存储库。这应在出版时进行，以便该领域受益并可能减少FOP患者的风险。

应对所有药物进行上市后/试验后监测。许多国家已经要求孤儿药进行上市后研究。然而，在研究者主导和产业赞助的试验中测试的所有疗法，都应设有长期的上市后或试验后随访程序，以确保治疗的长期安全性和有效性。重要的是要展示功能性活动能力在长期内的变化，因为在药物批准过程中使用的短期研究中，可能无法轻易检测到差异。这些纵向评估应纳入长期上市后评估中。

如果可能且合适，应开发对有效实验药物的长期获取机制。应尽可能开发通过同情用药计划或后续研究获得有效实验药物的机制。应考虑将资源较少国家的需求纳入临床试验后的计划中。

应尽可能共享剩余的生物样本。临床试验提供了一个罕见的机会，可以将大量FOP患者聚集在一起进行研究。应尽可能提供带有适当注释（但去标识化）的剩余生物样本，以供其他研究人员使用。这应纳入知情同意的过程。

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Timely publication/data release. Trials should have a plan for rapid public release of data, both positive and negative. This is critical for the safety of patients and for the scientiﬁc integrity of the ﬁeld. All clinical trials should include rapid adverse event recording and the sharing of ﬁndings whenever possible.

Cooperation for the benefit of the patients. We strongly encourage companies and all researchers to work with each other to the highest extent possible, including the sharing of baseline data, assessment tools and patient care experiences, as the number of subjects available for trials is extremely limited, and also because any major adverse event (i.e. death or disability) will have a major negative impact on all trials in the FOP arena.

Shared common data elements. Clinical trials should be designed to support ancillary observational trials, whenever possible (i.e. of baseline data). Trials should be performed with the assumption that the data collected and ﬁndings made will be maximally shared. Shared common data elements and endpoints are encouraged, such as quantitation of total HO, functional assessments (e.g. CAJIS score) and serum biomarkers. In addition, common data elements following public guidelines, such as through the National Institutes of Health (NIH) Common Data Element Initiative (https://www.nlm.nih.gov/cde/glossary.html) or shared elements with the IFOPA patient registry, are strongly encouraged.

Data deposition at end of trial. We encourage discussion with the IFOPA to leverage the global patient registry as a potential point for data sharing, particularly of placebo or baseline results that will be important for understanding the natural history of the disease. We also encourage public release of the raw data (such as sequencing data) following guidelines of large public agencies such as the NIH (https://grants.nih. gov/policy/sharing.htm) and using public repositories. This should be done at the time of publication, so that the ﬁeld can beneﬁt and potentially decrease risk to the patients with FOP.

Postmarketing/post-trial surveillance should be conducted for all agents. Many countries already require postmarketing studies for orphan drugs. However, all therapies tested in both investigator-initiated and industry-sponsored studies should have a procedure for long-term postmarketing or post-trial follow-up, to ensure the long-term safety and efﬁcacy of the treatments. It is important to show how functional mobility changes over the long term since differences may not be readily detected in the shorter studies used for drug approvals. These longitudinal assessments should be implemented into the long-term postmarketing assessments.

Long-term access to effective experimental medications should be developed if possible and appropriate. Mechanisms for access to an effective experimental medication via a compassionate use programme or follow-up studies should be developed whenever possible. Consideration for lessresourced countries should be incorporated into the postclinical trial plan.

Leftover biospecimens should be shared whenever possible. Clinical trials provide a rare opportunity to study large numbers of patients with FOP together. Whenever possible, leftover biospecimens with appropriate annotations (but deidentiﬁed) should be made available for other researchers. This should be included in the consenting process.

Discussion | 讨论

近期对FOP（进行性骨化性纤维发育不良）的新治疗临床试验的关注，是针对这种稀有但极其严重疾病的一项令人振奋的发展。在过去的几年中，这种关注促使人们认识到，必须更好地理解FOP患者在临床试验中面临的独特挑战。了解每个患者群体的社会、情感和疾病背景有助于改善试验设计和安全性。这种全球化的视角与世界卫生组织的《国际功能、残疾和健康分类》框架相似。在这里，我们确定了FOP临床试验的主要考虑因素，包括特定于疾病的因素，如因创伤导致的伤害风险和运输的独特要求，以及FOP的稀有性质如何影响临床试验的设计和执行。与所有临床研究一样，受试者安全是首要任务，必须包括一个完整的知情同意过程，以允许自愿参与而不受胁迫。

我们与21位FOP临床专家及一位家庭代表的讨论结果，使我们能够制定出一份强有力的共识声明，阐明FOP临床试验的关键考虑因素。ICC识别的一个主要挑战是，拥有经验丰富的临床医生来照顾大量FOP患者的数量较少。这一资源瓶颈导致许多研究者可能与其在临床试验中的工作存在利益冲突，但他们在顾问角色方面则非常合格。这一点与其他稀有疾病研究领域类似。ICC认为，提前、公开地声明这些潜在的利益冲突，并避免匿名咨询（即通过第三方数据收集公司，潜在利益冲突无法识别），是促进FOP相关临床研究知识和安全性的最佳策略。ICC内部成立了一个伦理委员会以支持这一开放策略。

ICC识别的另一个主要挑战是研究者主导和产业赞助临床试验之间的差异——这一领域在许多学科中都有探讨。尽管旨在支持药物批准或申请过程的试验必须遵循既定的监管指南，但其他较小或探索性试验的范围和资源可能更为有限。我们的委员会认识到，各种类型的试验都有其优缺点，但研究者主导的试验也应努力在数据质量和受试者安全方面达到与大型试验或产业赞助试验相似的标准。同样，所有涉及FOP患者的临床试验都应考虑到为安全和成功招募FOP受试者所需的额外资源和努力。最后，我们坚信，学术界、产业、临床医生和患者支持团体之间的紧密合作对开发有效的治疗方法至关重要。

这些指南并不排他或全面。它们并不旨在规定具体的临床试验设计或方法论——这些问题通常是药物或地点特定的，最好留给试验研究者。ICC旨在建立一个共同的基础，以便就特定于FOP社区的关键考虑因素展开讨论，主要关注点是患者安全。我们相信，这些FOP特定的考虑因素，加上建立稳健和安全的临床试验流程，将有助于提高FOP受试者的安全性，并最大化整个FOP社区的临床试验结果产出。

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The recent interest in clinical trials for novel treatments for FOP is an exciting development for this rare but extremely severe disease. During the past few years, this interest has led to recognition that there needs to be a better understanding of the unique challenges that patients with FOP face in clinical trials. Understanding the social, emotional and disease context of each patient group can help to improve trial design and safety. This global approach is similar to the World Health Organization’s International Classiﬁcation of Functioning, Disability and Health framework [22]. Here, we identiﬁed the major considerations for clinical trials in FOP, including disease-speciﬁc factors such as risks of injury from trauma and unique requirements for transportation, as well as how the rare nature of FOP affects clinical trial design and execution. As in all clinical studies, subject safety takes utmost priority and should include a full consent process that allows for voluntary participation without coercion.

The results of our discussion among 21 clinical experts in FOP and one family representative allowed us to develop a strong consensus statement with key considerations for effective clinical trials in FOP. One major challenge that the ICC identiﬁed was the small number of clinicians with experience of caring for signiﬁcant numbers of patients with FOP. This resource bottleneck meant that many investigators may have conﬂicts of interest related to their work in clinical trials, but would otherwise be highly qualiﬁed to serve in advisory roles. This is similar to other areas of rare-disease research. The ICC felt that open, early and public declaration of these potential conﬂicts, and the avoidance of anonymous consultations (i.e. via third-party data gathering companies, where potential conﬂicts cannot be identiﬁed), was the best strategy for promoting knowledge and safety in FOP-related clinical studies. An ethics committee within the ICC was constituted to support this open strategy.

Another major challenge that the ICC identiﬁed was the difference between investigator-initiated and industrysponsored clinical trials – an area that has been explored in many disciplines [23]. Although trials that are designed to support a drug approval or application process must also follow established regulatory guidelines, other trials that are smaller or exploratory may be more limited in scope and resources. Our committee recognized that there are strengths and limitations in all formats of trials [24], but that investigator-initiated trials should also strive to meet similar standards for data quality and subject safety to larger trials or those sponsored by industry. Likewise, all clinical trials involving patients with FOP should take into account the increased resources and effort needed for safe and successful enrollment of subjects with FOP. Finally, we ﬁrmly believe that strong cooperation between academics, industry, clinicians and patient support groups is absolutely critical for developing effective therapies for this devastating disease.

These guidelines are not exclusive or comprehensive. They are not meant to be used to dictate speciﬁc clinical trial design or methodology – those types of concerns are often agent- or location-speciﬁc and best left to trial investigators. Rather, the ICC seeks to establish a common foundation for discussions about critical considerations that are speciﬁc to the FOP community, with the main focus being patient safety. Together, we believe that these FOP-speciﬁc considerations, along with established processes for robust and safe clinical trials, will help to enhance FOP subject safety and maximize clinical trial result yield for the entire FOP community.

Nomenclature of targets and ligands | 靶标和配体的命名

本文章中关键的蛋白质靶点和配体都超链接至http://www.guidetopharmacology.org，该网站是IUPHAR/BPS药理学指南的数据共享平台 [25]，同时这些数据也永久归档于2017/18年《药理学简明指南》中[26].

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Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www. guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY [25], and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 [26].

References | 参考文献

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