Navigating orphan drug designation for breakthrough cell and gene therapies

Understanding orphan drug designation and accelerated pathways 

Orphan drug designation is a status granted by regulatory agencies like the FDA and EMA to encourage the development of treatments for rare diseases, defined as conditions affecting fewer than 200,000 people in the US or fewer than 5 in 10,000 in the EU. This designation provides incentives such as tax credits, grant funding and market exclusivity.

There are various accelerated approval pathways available, including Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. These pathways aim to expedite the development and review of drugs that address unmet medical needs or offer significant improvements over existing treatments.

Comparing orphan drug designation to other accelerated pathways

Although orphan drug designation provides specific benefits such as market exclusivity and grants, other accelerated pathways offer different advantages. For instance, Fast Track and Breakthrough Therapy designations facilitate more frequent interactions with regulatory agencies, potentially speeding up the development process. The choice between these pathways depends on several factors:

• Nature of the disease: rare diseases might benefit more from orphan drug designation, while therapies for serious conditions with unmet needs might be better suited for Breakthrough Therapy or Fast Track designations.
• Development stage: early-stage therapies might benefit from the intensive guidance of Breakthrough Therapy designation, while later-stage therapies might leverage Accelerated Approval to expedite market entry.
• Business strategy: smaller companies might prioritise pathways offering financial incentives, while larger companies might focus on pathways that provide a competitive edge through faster market access.

By understanding these pathways and their strategic implications, companies can make informed decisions that align with their development goals and commercial strategies.

Some examples of strategic pathway choices include:

• Spinraza (nusinersen): approved for the treatment of spinal muscular atrophy (SMA). Spinraza received orphan drug designation, benefiting from market exclusivity and financial incentives that supported its development and commercialisation.
• Kymriah (tisagenlecleucel): the original CAR-T cell therapy for certain types of leukaemia, Kymriah received Fast Track designation. This facilitated frequent interactions with the FDA, allowing for more frequent meetings and written communications to discuss the drug’s development plan and ensure collection of appropriate data needed to support approval. It also allowed for rolling reviews, permitting the submission of completed sections of the New Drug Application (NDA) or Biologics License Application (BLA) as they are ready, rather than waiting until every section is completed before the entire application can be reviewed.
• Luxturna (voretigene neparvovec): a gene therapy for a rare form of inherited vision loss, Luxturna received Breakthrough Therapy designation. This helped accelerate its development and approval by providing intensive FDA guidance on an efficient drug development programme, beginning as early as Phase 1. Furthermore, it requires organisational commitment from senior managers within the FDA in a proactive and collaborative review process.
• Zolgensma (onasemnogene abeparvovec): approved for SMA, Zolgensma received Accelerated Approval. This was based on surrogate endpoints that are reasonably likely to predict clinical benefit, rather than waiting for direct evidence of clinical benefit. As such, it required post-market confirmatory trials to verify the anticipated clinical benefit.
• Keytruda (pembrolizumab): an immunotherapy for various cancers, Keytruda received Priority Review, which significantly shortened its time to market. Reducing the FDA review period from the standard ten months to six months. This route is typically granted to therapies that offer significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The commercial considerations of accelerated regulatory pathways

Despite the incentives, the number of orphan drugs remains limited. As of 2023, only about 700 orphan drugs have been approved by the FDA out of over 6,000 applications. This scarcity underscores the significant challenges in developing treatments for rare diseases, including high costs, limited patient populations for clinical trials and scientific complexities.

Choosing to pursue orphan drug designation or other accelerated pathways is often driven more by commercial considerations than regulatory ones. For large pharmaceutical companies, the cost savings from incentives like tax credits (approximately £11 million) are relatively minor compared to their overall R&D budgets. However, for smaller biotech firms, these savings can be crucial, influencing their decision to pursue these pathways.

Conversely, the nature of orphan drugs means they are for small patient populations, therefore the commercial upside for potential investors will be limited. While orphan drug designation offers financial incentives, the overall cost savings, as well as the potential upside, may not be substantial enough to offset the high costs of developing and marketing these therapies.

Additionally, the high prices of orphan drugs, often reaching millions per dose, raise questions about their accessibility and whether they truly serve the intended patient populations. This pricing strategy can limit access to treatments for those who need them most, potentially undermining the goal of addressing unmet medical needs.

While cost savings are a notable benefit, another advantage of these regulatory pathways is a faster time to market, with the potential to be first to market, which can provide a competitive edge. These pathways can also enhance the credibility and visibility of a novel therapy class, attracting further investment and partnerships.

Conclusion

Navigating the regulatory landscape for cell and gene therapies involves balancing both commercial and regulatory considerations. While orphan drug designation and accelerated pathways offer significant benefits, they also present challenges that must be carefully managed. Ultimately, the goal is to bring innovative therapies to market efficiently and ensure they reach the patients who need them most.

By understanding the intricacies of these regulatory pathways, stakeholders can make informed decisions that align with both their commercial objectives and the broader goal of advancing medical innovation.