Managing the Risks Associated with Orphan Drug Development and Manufacturing

The Advanced Therapeutics Issue Feature: Inside the World of Orphan Drugs

Developments in Orphan Drugs: Part 2

Orphan drugs present numerous development and manufacturing challenges. Clinical trials can be difficult to set up due to the limited number of possible participants and their disparate locations. Production of novel small APIs and drug products create process design challenges. Manufacture of high-value, low-volume products also requires special considerations. 

Technical Challenges

Rare diseases that affect limited patient populations and have not been extensively studied can pose significant research and development challenges for companies looking to identify new drugs to treat them. 

In a recent Tufts Center for the Study of Drug Development survey,1 rare drug developers indicated that they must overcome many different types of challenges owing to the lack of knowledge about disease mechanisms. In addition to an incomplete understanding of the biology underlying these diseases, researchers often do not have information about their natural history and are uncertain how to translate what information has been gathered into useful knowledge for drug development. In addition, they may have to choose between multiple potential disease pathways and establish endpoints and outcome measures without sufficient knowledge or access to biomarkers and animal models.2 Rare diseases can also present differently in men and women and in children and adults.

Long Development Times

The Tufts study also found that, for orphan drugs approved by the FDA between 1999 and 2012, it took 18% longer on average to go from first patent filing to product launch than it did for all new drugs.2 A separate analysis of FDA data from 2015 to 2017 revealed that an orphan drug designation does not contribute to accelerated approvals.3

Another study found that it can take 10 or more years — and sometimes more than 20 — from receipt of orphan drug designation to marketing approval, with four to eight years the most common timeframe.4 From 2010 to 2017, the average time from orphan designation to FDA approval was 5.3 years, and the likelihood of FDA approval for an orphan indication was 0.25.5

Rare diseases that affect limited patient populations and have not been extensively studied can pose significant research and development challenges for companies looking to identify new drugs to treat them.

Unique Development Approaches Required

In addition to often limited knowledge, another key factor contributing to the longer development times associated with orphan drugs is the difficulty in establishing clinical trials for very small patient populations. It takes time to recruit patients, and those that do participate are often highly geographically dispersed, so managing the trials can be complex.6

Modeling and simulation can help address many of these issues by enabling quantification of drug–disease trial and exposure–response models, providing insight into biomarkers and endpoints and facilitating dose selection and identification of pediatric treatment options. Both are also encouraged by regulators.7

Movement away from the traditional requirements for clinical trials is also necessary. Potential patient pools are too small to conduct large randomized controlled trials, let alone two or more pivotal confirmatory studies.6 A common trial design for international multi-center trials would allow regulatory approval in multiple countries. Approvals based on less comprehensive but sufficient supporting evidence would also enable orphan drugs to reach patients more quickly. While such decisions can be made under specific but infrequent circumstances today, adoption of a clear pathway for orphan drugs that considers the risk/benefit balance in combination with requirements for appropriate postmarketing studies would be a more practical approach.

In a 2017 draft guidance for pediatric orphan drug development, the FDA outlined a new approach involving controlled, multi-arm, multi-company clinical trials, which would allow several products to be tested in a more time-efficient manner and reduce the number of patients needed to receive a placebo.8

Manufacturing Hurdles

Orphan drugs are in many cases formulated at high concentrations and administered to limited patient populations, leading to the need, even for commercial products, to manufacture much smaller quantities than have been traditionally required. The drug substances are also often highly complex, requiring novel and sophisticated synthetic routes and production methods (e.g., low temperatures or high pressures), including new types of equipment that can be implemented under GMP conditions.9 Similarly, flexibility in manufacturing scale is essential for the production of sterile biologic drugs (typically injectables).

The high value and limited quantity of these materials (drug substance and drug product) also pose challenges for analytical method development and validation. Quality-by-design (QbD) and design of experiment (DoE) approaches are increasingly implemented to help ensure the development of robust processes and methods.9

The Role of CDMOs

Contract development and manufacturing organizations (CDMOs) have key roles to play in overcoming the manufacturing challenges posed by small-volume orphan drugs. 

CDMOs that have adopted QbD and DoE approaches and have established expertise in continuous manufacturing, particularly using modular systems that can be readily replicated, are best suited to support orphan drug projects. They provide lower costs of production and enable in-country manufacturing at multiple locations, leading to more cost-effective and secure supply chains.10

CDMOs are also ideal partners for small and emerging pharma companies that are focused on niche, targeted therapies. These firms have limited resources and benefit from tailored, customized support offered by CDMOs with integrated services including process and formulation development, validation, analytical method development, regulatory compliance support and manufacturing activities.11 Outsourcing partners with the right complements of technical capabilities and experience can accelerate drug development and reduce costs for their clients.

Large pharma companies developing orphan drugs can also benefit from strategic partnerships with smaller CDMOs that are flexible and have experience with both small- and large-volume manufacturing.12 These CDMOs are adept at designing cost-effective routes to drug substances and formulated products, as well as managing multiple small-volume projects simultaneously, including candidates with accelerated approval designations. They are flexible enough to scale with projects as they move through the development cycle and are capable of producing larger volumes if necessary. 

Read Part 1: An Expanding Orphan Drug Market
Read Part 3: Navigating the Road to Successful
Orphan Drug Commercialization and Launch



  1. Redfearn, Suz. “Tufts: Facing Many Challenges, Orphan Drugs Take 18% Longer to Develop,” Center Watch Weekly. 14 May 2018. Web.
  2. Van Arnum, Patricia. “What is Trending: Orphan Drugs.” DCAT Value Chain Insights. 14 Nov. 2018. Web.
  3. Barham, Leela. “Does Being an Orphan Speed Up FDA Approval?” Pharmaceutical Executive. 12 Oct. 2018. Web.
  4. “Engaged for 20 years: an orphan drug designation from 1995 just got approved in 2018.” Draceana Consulting. 3 Jan. 2019. Web.
  5. Love, James. “Orphan Drugs Designations and Approvals have Something to Say about Risks.” Harvard Law Bill of Health. 25 Sep. 2017. Web.
  6. Tsang, Lincoln. “Orphan drug development and the urgent need for a new approach.” PharmaTimes. 5 Dec. 2018. Web.
  7. “Orphan Drugs: Unique Challenges Require Unique Development Approaches.” Certara. n.d. Web.
  8. “FDA In Brief: FDA recommends new, more efficient approach to drug development for rare pediatric diseases.” FDA in Brief. 6 Dec. 2017. Web.
  9. Challener, Cynthia. “Small Volumes, Big Challenges.” Pharmaceutical Technology. 42: 22–24 (2018).
  10. Ciurczak, Emil W. “Orphan Drug Development & Production: Turning Lemons into Lemonade.” Contract Pharma. 26 Jan. 2017. Web.
  11. Senft, Kristine K. “In-depth Process and Product Expertise — This is Key to CDMO Support of Orphan Drug and Breakthrough Therapy Development and Commercialization.” Pharma’s Almanac. 1 Oct. 2015.
  12. Price, Ed. “Growth of targeted therapies gives rise to need for flexible manufacturing of smaller API quantities.” PCI Synthesis Blog. 20 Jul. 2018. Web.

David Alvaro, Ph.D.

David is Scientific Editor in Chief of the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content, in addition to serving as Scientific Research Director for That's Nice. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University in 1999 and a Ph.D. in Genetics and Development from Columbia University in 2008.