Fostering Orphan Drugs

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology, BioPharma Outsourcing Innovation, February 2022,
Pages: s26–s29

CDMOs offer expertise and customization options for sponsors of orphan drugs.

To foster the development of treatments for undertreated and rare conditions, FDA grants orphan drug designation to drugs and biologics that treat, prevent, or diagnose diseases that affect fewer than 200,000 people in the United States or drugs that meet certain cost recovery provisions (1). This designation comes with incentives such as tax credits, user fee exemptions, and market exclusivity. To receive such designation, sponsors must submit requests and present data to support the request.

Pharmaceutical Technology asked Judith Jones, FRSC, Director Regulatory Affairs, Global Regulatory Affairs, Catalent, and Matthew Mollan, RPh, PhD, Regional Head of Operations, Early Phase Development North America, Catalent, about the specific ways contract development and manufacturing organizations (CDMOs) can assist sponsors in developing, applying for, and manufacturing orphan drugs.

Regulatory requirements

PharmTech: What are the criteria for receiving orphan drug designation in the US compared to the European Union?

Jones: In the US, to be designated as an orphan drug, sponsors need to show that the disease or condition that the drug is intended to treat has a prevalence of 7.5 or less for every 10,000 individuals, as opposed to five in every 10,000 individuals in the European Union. If this criterion is not met, orphan drug designation could still be granted in both the US and EU if sponsors can demonstrate that there would be insufficient return on investment to cover the cost of development when commercializing the drug in the respective markets. Another additional criterion in the EU is that there is no satisfactory method of diagnosis authorized in the EU for the prevention or treatment of the disease or condition in question.

PharmTech: How are the processes different in the US versus the EU to receive orphan drug designation?

Jones: While the process of orphan drug designation requirements for FDA and the EMA [European Medicines 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 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 disease, and supporting in vitro data. Sponsors may also leverage data from published literature during the orphan designation 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 benefit’, which is best supported by clinical or preclinical data.

PharmTech: 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 orphan 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, compared 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

PharmTech: 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 challenges 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, programs require a wider, global view, compared to more traditional drug development. The challenges in setting appropriate efficacy endpoints stem from the often-incomplete understanding of the disease pathophysiology and natural progression of the disease, which can lead to difficulties in identifying and validating surrogate biomarkers and critical clinical outcomes. By their nature, the relatively low incidence of orphan diseases makes patient 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.

PharmTech: What are the challenges when manufacturing an orphan drug? What types of manufacturing strategies work best?


Mollan: Because of the unmet medical needs, treatments for rare diseases often qualify for an expedited development program. With that in mind, a limited API supply, shortened timelines, and uncertain formulation requirements 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 communication of the plan with regulatory agencies can help ensure preparation for any unforeseen challenges.

PharmTech: 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 prescription products, meaning late-stage clinical-scale equipment can often be used for commercial manufacturing of orphan products. While the batch sizes may be smaller, regulatory 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 flexible 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 experience increased demand as the treatments are studied in additional patient populations for different indications.

The benefits of working with a CDMO

PharmTech: How can a CDMO help a sponsor company develop an orphan drug? What specific services and/or facilities can a contractor provide?

Jones: Typically, the manufacturing of an orphan medicine is undertaken at a considerably smaller scale than traditional commercial manufacturing, because of the very limited patient population. When orphan designated drugs receive approval for expanded indications, this might affect the scale of commercial manufacturing. Therefore, a CDMO with the experience of manufacturing at customized scales, as well as the flexibility to respond to changes in the types of products being sold, the volume of sales, and the facilities and equipment needed for production, may be better able to help a sponsor company overcome barriers in terms of cost and timeline during an orphan drug development.

PharmTech: How can a CDMO help a sponsor obtain regulatory approval for an orphan drug? What specific services and/or facilities can a contractor provide?

Jones: When information is needed on specific technologies, or processes that require alteration, the CDMO’s regulatory team can respond quickly with minimal risk of error. A CDMO is also able to offer sponsors a global network of regulatory affairs experts that have local knowledge, to facilitate successful agency interactions. In addition, CMC activities could be easily and quickly prioritized to ensure that they do not present as bottlenecks to the execution of the orphan development program and submission of application to regulatory agencies. A CDMO should already be intimately familiar with its dosage form(s), which can be customized to potentially address a specific orphan medicine’s need. They are then able to provide complete advice and provide support on the formulation, development, and manufacturing intricacies. Leveraging a CDMO to obtain regulatory approval for an orphan drug may also result in overall improvement of efficiency in orphan drug product development time and accelerate product approval.

PharmTech: How can a CDMO help a sponsor control the costs, specifically, of the development and manufacture of an orphan drug?

Mollan: A major global CDMO could provide access to an international network of technical expertise and state-of-the-art facilities. An integrated CDMO can save costs by accelerating timelines, reducing program risks, and ensuring a smooth transition between early and late-phase manufacturing sites. These benefits are achieved by harmonizing equipment, processes, pharmaceutical excipient vendors, collaboration tools, and project management structure between sites.

PharmTech: Can a CDMO help a sponsor company determine which medical needs might warrant the development of an orphan drug?

Mollan: For the most part, CDMOs do not determine which diseases to target, but can help refine the target product profile and ensure that the final product meets the needs of the target patient population. Developing a formulation and process that can accommodate a very wide range of potential drug loading is a key decision that can significantly de-risk changes in drug loading requirements as more information becomes known. Many factors drive the development of the target product profile, and these include the physicochemical and pharmacokinetic properties of the API, patient considerations such as age and co-morbidities, and manufacturability of the drug product used in the treatment.


  1. FDA, Developing Products for Rare Diseases & Conditions,, accessed Jan. 26, 2022.
  2. M.E. Schneider, “Orphan Product Designation Requests Climb in the US, Remain Steady in the EU,” Regulatory Affairs Professionals Society, March 11, 2021.
  3. D. Horgan et al., “Time for Change? The Why, What and How of Promoting Innovation to Tackle Rare Diseases – Is It Time to Update the EU’s Orphan Regulation? And if so, What Should be Changed?” Biomed Hub 2020;5:1-11. doi: 10.1159/0005

Article Details

Pharmaceutical Technology
Supplement: Bio/Pharma Outsourcing Innovation 2022
February 2022
Pages: s26–s29


When referring to this article, please cite it as S. Haigney, “Fostering Orphan Drugs,” Bio/Pharma Outsourcing Innovation 2022, Supplement to Pharmaceutical Technology (February 2022).