Issue link: https://www.e-digitaleditions.com/i/1450659
Pharmaceutical Technology Europe BIO/PHARMA OUTSOURCING INNOVATION eBOOK 2022 35 of the precision of evidence required. For example, in the US, sponsors need to provide scientific rationale and proof of efficacy for the use of an orphan drug. When clinical data or an applicable preclinical model is not available, sponsors may justify using data that include the pathogenesis of the disease, mechanism of action of the drug specific to the dis- ease, and supporting in vitro data. Sponsors may also lever- age data from published literature during the orphan des- ignation application process. In the EU, justification using only in vitro studies and mechanism of action may not be enough to justify 'medical plausibility' and 'significant ben- efit', which is best supported by clinical or preclinical data. PTE: Is it more difficult to gain orphan drug designation in the US versus the EU? Jones: There seems to be an increasing trend for more drugs to be designated as orphan in the US than in the EU, as reported by the Regulatory Affairs Professional Society (RAPS) in March 2021. Between 2019 and 2020, there had been an increase of 41% in the number of requests for or- phan drug designation in the US, bringing the total to 753 requests, whereas in the EU, the numbers remained steady, with 235 requests for orphan drug designation in 2020, com- pared with 233 requests in 2019 (2). A recent commentary called for more alignment between the EU and other big markets' regulatory practices to facilitate the development of medicines for orphan diseases (3). Indeed, there are ongoing efforts to harmonize the approach to assessment of orphan drug designation between FDA and EMA, which one would hope would lead to a more consistent submission package between the different territories. Orphan drug challenges PTE: What are the challenges when developing an orphan drug? Are there different challenges for small-molecule versus large-molecule drugs? Mollan: Clinical trial design is one of the biggest chal- lenges in orphan drug development and can be driven by difficulties in setting the appropriate efficacy endpoints, as well as challenges in patient recruitment, and often, pro- grammes require a wider, global view, compared to more traditional drug development. The challenges in setting appropriate efficacy endpoints stem from the often-in- complete understanding of the disease pathophysiology and natural progression of the disease, which can lead to difficulties in identif ying and validating surrogate bio- markers and critical clinical outcomes. By their nature, the relatively low incidence of orphan diseases makes pa- tient recruitment for clinical trials more challenging. The heterogeneous nature of many genetic orphan diseases further diminishes the pool of patients that are likely to see benefits from a new treatment, with many potential patients being children. PTE: What are the challenges when manufacturing an or- phan drug? What types of manufacturing strategies work best? Mollan: Because of the unmet medical needs, treatments for rare diseases often qualify for an expedited develop- ment programme. With that in mind, a limited API supply, shortened timelines, and uncertain formulation require- ments are some of the challenges in manufacturing orphan drugs. The limited API supply can impact the development activities that can be performed and places pressure to have Phase I formulations continue to late-phase development. Strategic investment in Phase I formulation development and de-risking the process, while adding a unit operation, such as roller compaction, can save time and reduce risks by ensuring the formulation is ready for scale-up to be processed on automated equipment. A risk-based CMC [chemistry, manufacturing, and controls] plan and com- munication of the plan with regulatory agencies can help ensure preparation for any unforeseen challenges. PTE: What are some considerations when performing scale-up of orphan drugs? Mollan: Most orphan drug product will not see the batch sizes or volumes associated with traditional commercial pre- scription products, meaning late-stage clinical-scale equip- ment can often be used for commercial manufacturing of orphan products. While the batch sizes may be smaller, reg- ulatory agencies expect manufacturers to follow regulations and stay in compliance, ensure consistent product supply, and have the product stability data to support expiration dates. The manufacturing formulation and processes should be f lexible to allow developers to respond to any changes in demand for the product, as well as being globally acceptable. Oncology orphan drug products can begin the commercial lifecycle as low volume products, but on occasion can ex- perience increased demand as the treatments are studied in additional patient populations for different indications. The benefits of working with a CDMO PTE: How can a CDMO help a sponsor company develop an orphan drug? What specific services and/or facilities can a contractor provide? "When orphan designated drugs receive approval for expanded indications, this might affect the scale of commercial manufacturing." — Judith Jones, Catalent