Guest Column | December 29, 2017

Best Practices In FDA Orphan Drug Submissions

By Greg Dombal, COO, Halloran Consulting Group

Approval Pills

Since 1983, pharmaceutical developers have been incentivized by the FDA via an Orphan Drug Designation (ODD) program to develop products to treat rare diseases and/or conditions. The program awards orphan status to drugs that show likelihood of benefitting an afflicted population that might not otherwise be the focus of targeted development efforts. To meet the FDA’s specific requirements, sponsors have found specificity matters. Though other steps in a drug’s life cycle require a wider scope, when it comes to defining the orphan population and making a case for the drug’s potential efficacy in that population, a razor-focused effort is key.

A common misperception in the industry is that an orphan designation is one of the easier regulatory milestones to reach. The guidance the FDA has issued on obtaining an orphan designation is relatively straightforward, perhaps so much so that it is easy to overlook some of its key elements. Understanding how the FDA views orphan applications and structuring a development program to deliver the data and rationale to satisfy the FDA can substantially reduce the review period.

An orphan population is defined as one of fewer than 200,000 U.S. residents. However, the FDA has been clear that simply falling under this numerical cap does not mean a population is medically plausible. Companies can (and do) “slice” a patient population based on age or other factors to define an orphan population in an application. However, if such a slice does not reflect how patients are treated or managed by healthcare practitioners, it is not considered medically plausible by the agency. It is inherent upon the sponsor to clearly define the orphan population. References from peer-reviewed journals or other bona fide data sources are required.

In the rare cases that such references or public data sets are not available, the sponsor can propose a specific set of support to define the orphan population prior to submission. Such a package of information might include certifications of the medical plausibility of the orphan population by five key opinion leaders in the therapeutic area and non-peer-reviewed summaries from patient advocacy groups. The Office of Orphan Drugs is quite responsive to such proposals and very helpful in determining prior to submission if a proposed rationale for total prevalence or medical plausibility of the population will be sufficient. This will decrease review questions and ensure the FDA receives a dossier they can act on in the first review cycle and therefore grant ODD more quickly.

Once a medically plausible population is defined, be sure the focus on that specific population informs the orphan application. In most other situations (fundraising, scientific presentations to physicians or academia, partnering conversations, internal company presentations, etc.), it is important (and common) to explore a drug’s potential applications. The appeal of a product to investors or interest from physicians is at least partially driven by an understanding that the more lives impacted by a treatment, the better. Investors or partners may be interested in commercial potential, so presentations that describe “orphan population and all other possible indications” may increase the attractiveness of an asset. However, when writing the orphan application, be cautious of unnecessarily expanding your target. The FDA is mainly concerned with the likelihood of a drug’s impact on the defined population, so including all other possible indications will only detract from the goal of an approvable orphan application.

Focus is also critical when it comes to scientific rationale of the ODD application. As the application does not require clinical data, it can be tempting to cast a wide net of supportive data. Successful applications demonstrate the compound may benefit the defined orphan population, yet leave out data that, while important to understanding other indications, is not germane to the potential effect in the orphan population. It should be clearly proven that the science has a reasonable likelihood to positively impact an orphan population. An animal efficacy model may be sufficient. Prior human data in other indications can act as support, but only if a case can be made for why the data has crossover potential. Any other mechanism data is not essential for the submission. Maintaining a focus on the essential scientific data can reduce the size of the orphan application and thereby the review period.

Keeping focused on the specific needs of the ODD application will help drive the whole process when it gets to the FDA. Ultimately the time spent refocusing the application, rejecting what is redundant or nonspecific, and tailoring data to the particular case is key for successfully securing ODD.

About The Author:

Greg Dombal joined Halloran Consulting Group in 2007. He helps emerging companies navigate challenges in product development while establishing appropriate clinical, regulatory, and compliance structures. Dombal pairs over 25 years of experience in worldwide regulatory affairs, quality assurance, and clinical development with a willingness to challenge conventional, conservative approaches.

Before joining Halloran, Dombal was responsible for the regulatory, quality assurance, and clinical groups at ArQule. At its peak, the programs he was responsible for encompassed 17 clinical studies with annual budgets in excess of $25 million. Over his career, Dombal has successfully filed over 45 clinical trial applications (IND, IDE, or equivalent), attended over 75 regulatory agency meetings, presented to multiple advisory committees, and helped companies respond to warning letters, 522 orders, and clinical hold notices. He has obtained Orphan Drug and/or Fast Track designations for 15 individual products, has successfully negotiated multiple Special Protocol Agreements, and has extensive involvement with NDA/MAA submissions resulting in multiple product approvals.

Dombal has a B.S. in biology from the University of North Carolina at Chapel Hill. He is also a certified PROSCI change management professional from Colorado State University.