Patient involvement and access
The identification of the classic FOP gene mutation (
ALK2/ACVR1R206H) and the dysregulated BMP signaling pathway was a key milestone in the history of FOP [
2]. The discovery identified druggable targets for treatments and fueled international interest in research and development (R&D) in FOP [
2,
14]. This recent drive in R&D has resulted in several promising treatments for FOP reaching clinical trial stage [
43]. Patients played a pivotal role in the discovery of the FOP gene and continue to be instrumental in advancing FOP research by being actively involved in online surveys and participating in advisory panels for industry, clinical trials, non-interventional studies, the “Tooth Ferry” Program, and the IFOPA’s FOP Registry and FOP Biobank [
44‐
46].
Patients are often keen to participate in clinical trials, but opportunities can be limited (particularly in the Global South). Pharmaceutical companies often rely on existing patient networks, created and maintained through a patient organization or specialist clinicians, to increase awareness of an upcoming trial and to identify participants. The lack of an established, local patient network can, therefore, be a major barrier to initiating a clinical trial in a certain geographical region. Other barriers to establishing clinical trials in underserved areas include cumbersome country-specific legal regulations that cause delays or roadblocks, a very low number of known diagnosed patients, lack of local supportive infrastructure for clinical trials and inadequate research training, and prioritization of local sites for trials of treatments for more prevalent infectious diseases.
As there is an increased drive to expand clinical trials into new regions and increase participation for underserved patient groups, there are important ethical concerns to be considered. It is crucial that the relevant risks and benefits of a clinical trial are clearly communicated, taking into account cultural context; the message should convey that clinical trials are experiments, not proven treatments [
14,
47]. There are also ethical considerations around access to post-trial care and/or treatments for participants following a clinical trial. This is especially important if the treatment provided during the trial resulted in a meaningful clinical benefit for the participant [
48].
Guidance for clinical trials in FOP have recently been developed by the Clinical Trials Committee of the ICC [
47]. These guidelines emphasize the responsibility of pharmaceutical companies to engage with patients and their families during all stages of clinical trial development. The patient perspective should be reflected in the practicalities of the trial (e.g. need for onsite visits, imaging, etc.), but also to provide insight into the FOP-specific safety considerations that are necessary to include in the trial design, and the assessment of measurable outcomes that are meaningful to patients [
47]. Ensuring that the voice of the patient is heard and incorporated into research studies and clinical trial design is essential to maintaining a positive relationship between the FOP community and the pharmaceutical industry.
Maintaining patient-friendly communication with the FOP community throughout a clinical trial or research study is important, even when there is no new information to provide. The IFOPA provides educational resources to explain the drug development process and how clinical studies and trials are conducted to enable individuals to accurately interpret research results and understand how these findings may be relevant to themselves or their family members. Although there are many possible avenues to communicate research outcomes, some of the most accessible and well-known to the FOP community are the Annual Reports of the FOP Collaborative Research Project at the University of Pennsylvania [
46], lay summaries provided by IFOPA for research projects that they fund, and the IFOPA’s FOP Family Gathering. In addition, the FOP Drug Development Forum organized by the IFOPA brings together academic researchers, clinical care specialists and patients to discuss and plan future research with the patient voice central to these discussions. However, there is a need for all stakeholders to go beyond the proactive communication of research to actively sharing non-proprietary research information with the FOP community to build knowledge and limit the duplication of research. As such, the IFOPA, in collaboration with the ICC, has developed guidelines for data-sharing specific to various research activities. This “Open Science” approach to data sharing and collaboration has been identified as particularly important within the rare disease community to reduce the time to diagnosis and treatment [
49].
National patient organizations and networks also play an important role in communicating research updates and information to individuals within a given country or region (Additional file
1: Table S2). For example, the national FOP organization for Argentina (Fundación FOP) connects the Spanish-speaking patients and families throughout Latin America with the international FOP community. However, there are still regions that are not directly supported by a patient organization, which can be very isolating for patients and their families [
4].
To improve access to care, reliable information, and clinical studies and trials for all individuals with FOP, there have been several recent initiatives to increase regional representation and expand the reach of the international FOP community. For example, the FOP Registry, launched in 2015 by the IFOPA, is a centralized, international registry for patients with FOP that captures demographic data and has facilitated longitudinal studies of patient health and quality of life [
50]. As of December 2020, the Registry had 323 enrolled patients from 69 countries, approximately 36% of the world’s known FOP population. In addition to providing valuable research information, it is hoped that the Registry will increase the known patient base for this ultra-rare disease and improve clinical care by increasing the speed of development of novel treatments [
44]. It is important to note that language (the Registry is currently available in seven languages), educational level and/or limited access to the internet/enabled devices may be barriers to participation in the FOP Registry for some individuals. Addressing these issues that limit regional representation and ethnic diversity are crucial to ensure that patients, regardless of their location, receive appropriate care and treatment, access to clinical trials and up-to-date information and support.
Gaps in research
Despite many crucial advancements arising from FOP research from over 60 institutions worldwide, such as the discovery of the genetic mutation underlying FOP [
2], there is still much to understand about disease progression. The natural course and co-morbidities of FOP in poorly resourced areas remain particularly understudied. Future research should also prioritize the identification of biomarkers that can be used to predict flare-up and HO status, and evaluate treatment efficacy. In addition, as FOP shares similarities with other inflammatory diseases, understanding the role of inflammation in the context of FOP could provide valuable insight and new avenues to treatments. Finally, although FOP is often categorized as a “new bone” disease, it is also a disease of the joints [
51,
52]. As such, further research on the joint manifestations of FOP is warranted.
Natural history studies of FOP are important to understand disease progression and to identify clinically meaningful outcome measures to assess in short-term (typically 1–2 years) clinical trials [
6]. However, conducting these studies in ultra-rare diseases can be fraught with challenges, including small numbers of geographically-dispersed patients and a lack of established biomarkers, validated measurement tools, and clinically-meaningful disease progression endpoints. A recent 3-year, global natural history study of FOP (NCT02322255; sponsored by Ipsen) provided valuable information on the baseline, cross-sectional disease phenotypes of 114 individuals with FOP [
52‐
54] and additional longitudinal data are forthcoming. These studies will be crucial to better understand the natural history of FOP and identify common secondary health issues. In addition, the increased use of FOP-specific assessments, such as the Cumulative Analogue Joint Involvement Scale (CAIJS), will help to better understand the disease progression of FOP [
55]. An initial clinical staging system for FOP has also been proposed [
56], which is currently being validated using data from a longitudinal natural history study on FOP and the FOP Registry. Further expansion of the FOP Registry will continue to yield valuable data on the longitudinal natural history of FOP for patients globally, and can also be used in the future to facilitate post-marketing surveillance of new therapies/treatments [
50].