Issue link: https://www.e-digitaleditions.com/i/1467950
30 BioPharm International May 2022 eBook www.biopharminternational.com Agency] do not fundamentally differ, they do vary in terms of the precision of evidence required. For example, in the US, sponsors need to provide sci- entific rationale and proof of efficacy for the use of an orphan drug. When clinical data or an applicable preclin- ical model is not available, sponsors may justify using data that include the pathogenesis of the disease, mecha- nism of action of the drug specific to the disease, and supporting in vitro data. Sponsors may also leverage data from published literature during the orphan designation application pro- cess. In the EU, justif ication using only in vitro studies and mechanism of action may not be enough to justify 'medical plausibility' and 'signif icant benef it', which is best supported by clinical or preclinical data. BioPharm: Is it more difficult to gain orphan drug designation in the US versus the EU? Jone s: T here seems to be a n i nc re a si ng t rend for more d r u g s to be designated as orphan in the US than in the EU, as reported by the Regulator y Affairs Professional S oc iet y (R A PS) in Ma rc h 2 021. Bet ween 2019 and 2020, there had been an increase of 41% in the num- ber of requests for orphan drug des- ignation in the US, bringing the total to 753 requests, whereas in the EU, the numbers remained steady, with 235 requests for orphan drug desig- nation in 2020, compared with 233 requests in 2019 (2). A recent com- mentar y called for more alignment between the EU and other big mar- kets' reg ulator y practices to facili- tate 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 BioPharm: What are the challenges when developing an orphan drug? Are there different challenges for small-mol- ecule versus large-molecule drugs? Mollan: Clinical trial design is one of the biggest challenges in orphan drug development and can be driven by diff iculties in setting the appro- priate eff icacy endpoints, as well as challenges in patient recruitment, and often, programs require a wider, global view, compared to more traditional dr ug development. The cha llenges in setting appropriate eff icacy end- points stem from the often-incomplete understanding of the disease patho- physiology and natural progression of the disease, which can lead to difficul- ties in identifying and validating sur- rogate biomarkers and critical clinical outcomes. By their nature, the rela- tively low incidence of orphan diseases makes patient recruitment for clinical trials more challenging. The heteroge- neous nature of many genetic orphan diseases further diminishes the pool of patients that are likely to see bene- fits from a new treatment, with many potential patients being children. BioPharm: What are the challenges when manufacturing an orphan drug? What types of manufacturing strate- gies work best? Mollan: Because of the unmet med- ical needs, treatments for rare diseases often qualify for an expedited develop- ment program. With that in mind, a limited API supply, shortened timelines, and uncertain formulation requirements are some of the challenges in manu- facturing orphan drugs. The limited API supply can impact the develop- ment activities that can be performed and places pressure to have Phase I for- mulations continue to late-phase devel- opment. Strategic investment in Phase I formulation development and de-risking the process, while adding a unit oper- ation, 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, manu- facturing, and controls] plan and com- munication of the plan with regulatory agencies can help ensure preparation for any unforeseen challenges. BioPharm: What are some consid- erations when performing scale-up of orphan drugs? Mollan: Most orphan drug product will not see the batch sizes or volumes associated with traditional commer- cial prescription products, meaning late-stage clinical-scale equipment can often be used for commercial manufac- turing of orphan products. While the batch sizes may be smaller, regulatory agencies expect manufacturers to fol- low regulations and stay in compli- ance, ensure consistent product supply, and have the product stability data to Partnerships for Outsourcing Quality/Regulations "Clinical trial design is one of the biggest challenges in orphan drug development." — Matthew Mollan, Catalent "There seems to be an increasing trend for more drugs to be designated as orphan in the US than in the EU ..." —Judith Jones, Catalent