Jeff Antos, Weinberg Group

		Small biopharma companies are often interested in obtaining the advantages of an orphan designation and subsequent approval. This can lower the cost of approval and potentially reduce development costs. While most understand the major benefits of orphan approval, such as seven-year market exclusivity, there are a number of misconceptions about orphans. The following is a list of the most common.

1. The orphan designation is part of the approval process

		Submitting an orphan designation request is unrelated to the drug approval process. In fact, the orphan application can be filed anytime in the drug development process before NDA/BLA submission, even prior to IND filing.

2. There can be only one orphan designation per indication

		Not only can there be multiple orphan designations per indication; more than one sponsor can receive an orphan designation for the same drug/indication. However, only the first drug to be approved for a given indication will enjoy the benefits of orphan approval. A product with a different active moiety can also receive orphan approval for an already approved orphan indication. Additionally, a second sponsor may gain orphan approval for a previously approved orphan drug/indication if the second sponsor’s product demonstrates increased clinical benefit, e.g. oral administration instead of intravenous.

3. A drug must be proven safe and effective in order to get orphan designation

		The safety and efficacy bar is fairly low for an orphan designation. The applicant is asked to provide a “scientific rationale” for the use of the drug. The applicant may provide clinical data, animal studies or in vitro data to make the case. If sufficient information exists in published literature, that may suffice.

4. The orphan application process is arduous

		Actually, the orphan application process is quite simple. In the US, the argument hinges on disease prevalence of under 200,000. If the number can be established and there is a “scientific rationale” for the use of the drug, it will most likely achieve orphan status. Unlike most other FDA submissions, we often urge our clients to file rather than continuing a lengthy internal debate. If FDA rejects the submission, FDA will explain why and the submission may be reworked and refiled as many times as necessary. Additionally, there is no FDA fee for the orphan designation request.

5. The same designation criteria are used for US and EU applications

		There are a number of differences between the US and EU applications. For example, in the EU:

			Prevalence is defined as less than 5 out of 10,000 people

			The disease must be life threatening or chronically debilitating

			No treatment can exist or if there is an existing treatment, the new must show significant benefit over the old.

6. Scrutiny of orphan designations has not changed over time

		The orphan field is becoming crowded. Since the beginning of the program in 1984, there have been more than 3,000 orphan designations with nearly 500 approvals. As more companies pursue rare diseases there is a tendency to slice disease states into sub-indications in an attempt to gain orphan status. While some of these sub-indications might be considered improper and therefore will receive increased scrutiny, improved diagnostic techniques have enabled sponsors to match treatments with specific therapies. For example, there is an orphan designation for skin testing of victims of fire ant stings to confirm fire ant sensitivity, and if positive, for use as immunotherapy for the prevention of IgE-mediated anaphylactic reactions.

7. Seven-year exclusivity is the sole benefit of the orphan approval

		Although post-approval benefits are significant, many early-stage companies apply for orphan designation when approvals are in the distant future. The successful application becomes public when the designation occurs, thereby broadcasting the young company’s intention and opening the category to anyone. Therefore, there must be another reason for these early filings. There is. Orphan designations are newsworthy and small companies often use the designation to put themselves on the map and to gain the interest of the investment community. Other benefits of orphan designation include:

			Tax credits of 50% of the clinical drug testing cost awarded upon approval

			Research grants—FDA awarded approximately 75 grants in 2013

			Waiver of NDA/BLA application fee—this is a $2.2 million value

		Jeff Antos is vice president at the Weinberg Group (Washington, DC; www.weinberggroup.com). For more than 30 years, The Weinberg Group has served the global pharma industry, providing companies of every size with regulatory and compliance support.  A new retainer-based service, Outsourced Regulatory Affairs, enables clients to put selected ongoing regulatory affairs responsibilities on the company.

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