In addition to the complexity induced by pathogenetic and clinical heterogeneity, the development of medicines for the treatment of IPF suffers from the hurdles characteristic of rare diseases, where small numbers of patients limit the feasibility of adequately powered trials, the validation of endpoints and biomarkers , and the use of hard endpoints such as mortality. From a regulatory perspective, additional factors complicating the clinical development in IPF include changes over time in case definition and lack of consistency in clinical trial endpoints.
The recent consensus on imaging-based diagnosis  may facilitate the conduct of IPF trials in clearly defined study populations. On the other hand, the great heterogeneity in outcome measures used across clinical trials has largely limited the feasibility to conclusively assess the validity of most of them. Indeed, while slowing the decline of forced vital capacity was accepted as the primary endpoint for the regulatory approval of pirfenidone and nintedanib , there is not yet consensus on its minimal clinically important difference . Mortality, used mostly as a secondary endpoint, has also been measured inconsistently in IPF trials, as all-causes mortality, IPF-specific mortality, time to death, progression-free survival, or survival time . Finally, composite endpoints have been suggested as a way to improve trial efficiency and sensitivity to drug effect ; however, potentially interesting measures in composite endpoints, such as symptoms and clinical worsening, have not been validated in IPF.
A recent consensus group proposing provisional core sets of domains and instruments for clinical trials in connective tissue disease-related ILDs and IPF concluded that none of the proposed endpoints were ideal, or fully validated . Global collaborative work for validation and standardization of endpoints for regulatory use is needed to facilitate the clinical development and the approval of new medicines in IPF. This is warranted by the increasing complexity of clinical trials, where efficacy will now have to be established on top of, or in comparison to, the authorized treatments . The consistent use of standardized endpoints across trials would improve comparability of compounds during pre-licensing clinical development, and provide continuity in the measurement of treatment effects through the whole lifecycle of medicinal products. This would allow the harmonization of the assessment of regulatory, health technology assessment, and payers’ bodies on the therapeutic added value of different products, and increase clarity on the clinical benefit for prescribing physicians and patients.
Ideally, outcome measures would be chosen from among those that can be monitored in patients’ registries, to align measures of natural history of the disease with disease progression parameters measurable in clinical trials. Initiatives are ongoing at EMA to explore the use of registry data in the frame of regulatory procedures , in particular for the establishment of real-life post-approval confirmation of effectiveness. A handful of national IPF registries exist in Europe ; however, a European rather than national dimension would be needed, ideally integrated with the recently proposed initiatives of an IPF clinical trial network . The participation of patients in international disease networks is crucial to the development of patient-reported outcome measures, at present poorly developed in IPF, and in line with current initiatives incorporating patients’ views into the benefit–risk assessment of medicines.
Among the initiatives facilitating the approval of new medicines, early access regulatory pathways, such as the adaptive pathway in pilot phase in Europe , aim to optimize development by balancing the need for timely patient access with the importance of providing adequate, evolving information on a medicine’s benefit and risk, including collection of real-world data post-authorization to complement randomized clinical trials data. IPF appears to be a potential candidate in this respect, because the development of medicines initially developed for IPF could be gradually expanded to other target populations, e.g., ILDs other than IPF, for most of which currently no treatment exists, including pediatric ILDs.