RWE Decision Alert
SOHONOS, the First Drug for Fibrodysplasia Ossificans Progressiva, Receives US FDA Approval with Real-World Evidence as External Control
The Food and Drug Administration (FDA) approved SOHONOS (palovarotene),2 for the treatment of fibrodysplasia ossificans progressive (FOP), on August 16, 2023. The approval was based on a single-arm trial utilizing real-world evidence (RWE) from a natural history study as an external control. FDA’s approval contrasts with the European Medicines Agency (EMA)3,4 decision to refuse marketing authorization for SOHONOS (May 2023). Our expert team has reviewed the decision process and shared its highlights.1,2
SOHONOS, manufactured by Ipsen Biopharmaceuticals,5 Inc., is a retinoid indicated for the reduction in volume of new heterotopic ossification in adults and pediatric patients aged eight years and older for females and ten years and older for males FOP. SOHONOS is the first and only treatment approved by the FDA for FOP. SOHONOS received a priority review, fast-track designation, and breakthrough therapy designation for this indication. FOP is an ultra-rare, severely disabling, genetic disease that begins in childhood and eventually leads to complete immobilization and decreased life expectancy. In FOP, the muscle and connective tissue are replaced by bone, causing extra-skeletal or heterotopic bone formation. This results in pain, inflammation, and swelling (flare-ups), often triggered by minor injuries.6
The FDA approval was based on two main studies. The Phase III MOVE trial (NCT03312634, Study PVO-1A-301) enrolled 107 subjects treated with SOHONOS. The Clementia’s FOP natural history study (NCT02322255, Study PVO-1A-001), used as an external control, enrolled 114 subjects not treated with SOHONOS and receiving standard of care.
Additionally, the clinical program included two dose-finding studies: a Phase II study (Study PVO-1A-201) to evaluate the efficacy and safety of episodic treatment with SOHONOS at the time of a flare-up in adult and pediatric subjects with FOP, and a Phase II open-label extension study (Study PVO-1A-202) to evaluate the efficacy and safety study of SOHONOS in the treatment of pre-osseous flare-ups in subjects with FOP.
In an eighteen-month interim analysis, including 97 MOVE and 101 natural history study individuals, the mean annualized new heterotopic ossification was 9.4 cm3/year in subjects receiving SOHONOS, and 20.3 cm3/year in untreated subjects from the natural history study, based on a linear mixed effect model. The treatment effect was about 10.9 cm3/year with 95% confidence interval (-21.2 cm3/year, -0.6 cm3/year). The mean annualized new heterotopic ossification volume was 60% lower in MOVE versus the natural history study. The post hoc analyses showed evidence for efficacy of SOHONOS in reducing new heterotopic ossification in FOP, but high risk of premature physeal closure in skeletally immature patients.
The FDA´s decision was based on the study results demonstrating that SOHONOS effectively reduced the annualized heterotopic ossification volume compared with no treatment beyond standard of care, and that SOHONOS has a well-characterized safety profile, with adverse events consistent with the systemic retinoid class. The FDA did not publish a clinical review report on SOHONOS, therefore limited information is available about the appraisal process.
The EMA´s opinion on refusal of marketing authorization was based on the limited long-term clinical data available that did not support SOHONOS’ efficacy3,4. The EMA criticized the application, stating that the quality, safety, and efficacy of SOHONOS had not been sufficiently demonstrated and that the benefits of SOHONOS did not outweigh its risks. Specifically, the EMA highlighted that the Clementia study had broad inclusion criteria which contrasted with the stringent inclusion and exclusion criteria of the MOVE single-arm trial, therefore the two populations were not comparable. Additionally, the lack of randomization is a known source of bias.
The EMA also stated that the clinical relevance and statistical significance of the SONONOS treatment effect were not demonstrated due to multiple methodological issues compromising the interpretability and robustness of the study results. The efficacy results were considered post-hoc due to the timing and selection of statistical methods, contributing to a lack of confidence in the results.
The use of a natural history control group in a study presents challenges, including unclear causal conclusions, limited covariates, selection bias, differences in subject characteristics, methods of outcome assessment, and background standards of care. For example, there were differences at baseline heterotopic ossification between the cohorts that could indicate more active disease in the Clementia study. Moreover, differences in flare-up reporting and whole body computed tomography (WBCT) scan frequency hindered endpoint comparison. Also, the study was interrupted early, resulting in less data collected for efficacy analyses, making the available heterotopic ossification data unreliable, especially regarding longer-term disease course.
Finally, due to the single-arm open-label study design, the EMA found it challenging to assess the safety profile of SOHONOS at the intended dosing regimen in the target population. The risk minimization measures for premature physeal closure in subjects with an immature skeleton proposed by the applicant were not considered adequate and feasible.
The EMA concluded that due to differences in the baseline characteristics of the populations between the single-arm trial and the control group, differences in primary endpoint assessment, lack of pre-specification of the statistical analyses, and overall lack of methodological robustness, it was not possible to demonstrate the clinical efficacy and safety of SOHONOS.
SOHONOS demonstrates that two key regulatory agencies can make highly divergent decisions based on similar data packages for a disease of high unmet need. The situation highlights the complexity and diversity in the healthcare decision-making process, especially for cases with some degree of uncertainty where products are tested in single-arm trials with external control arms derived from real-world data (RWD).
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RWE Decision Alerts provide subscribers with timely analyses of published reports from HAS, AEMPS, NICE, EMA, and the FDA where RWE is used to support HTA and regulatory decision-making. We identify if a submission included RWE and assess the value of the RWE submitted.
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