It is an unfortunate reality that many diseases and conditions affect such small numbers of patients that, when a sponsor develops a drug or biological product to treat them, relatively little return on investment is generated to offset the high development costs. As a result, the pharmaceutical industry has neglected many rare diseases in the past.

However, the Orphan Drug Act of 1983 created the orphan drug designation (ODD) program to incentivize pharmaceutical companies to address the unmet needs of patients with rare diseases. ODD qualifies sponsors for tax credits, waivers from NDA and BLA user fees, and an appealing seven-year market exclusivity period after approval. To be considered orphan, a drug or biological product must be intended for the prevention, diagnosis, or treatment of a disease or condition affecting fewer than 200,000 people in the US.

Securing orphan drug designation

Sponsors may submit a request for ODD to the FDA at any time during product development – an IND is not required. The request should accomplish three primary objectives:

1. Explain the disease or condition (the mechanism of action, pathophysiology, etiology, treatment, and prognosis)
2. Provide a strong scientific rationale for use of the product in the proposed population, including nonclinical and/or clinical supporting data
3. Estimate the patient population to demonstrate that the disease or condition affects fewer than 200,000 individuals

It is crucial that the population to benefit from the proposed orphan product be well-defined. When a disease or condition affects a very small number of people, this is a fairly simple matter. Conversely, in some particular (and more complicated) cases, a product intended for a non-rare disease or condition may not be suitable to treat all affected persons, and the targeted population is thus narrowed down. In these cases, requesting ODD to treat an orphan subset of the non-rare disease population may be appropriate.

Defining orphan subsets

The agency has a history of rigorous scrutiny when reviewing ODD requests for orphan subsets of non-rare diseases, so the requests are frequently denied. Sponsors seeking ODD in this situation must explain to the Office of Orphan Products Development (OOPD) precisely why the product in question can never be used in the broader disease or condition.

The chances of success correlate with the adequacy of the scientific data supporting the justification of the orphan subset. That justification should not be based on a sponsor’s plan to study the product for a select indication, the cost of the product, its clinical trial eligibility, an unmet need, or the disease grade or stage. To appropriately define an orphan subset of a non-rare disease, the sponsor much provide the following information:

1. Scientific justification explaining why the proposed product is not appropriate for use in all individuals affected by a disease or condition
   1. Highly toxic drugs: Patients who are refractory to or intolerant of other drugs may be considered an appropriate orphan subset to support ODD for a highly toxic product.
   2. Inherent properties of a drug: The pharmacologic or biopharmaceutical characteristics of a product may provide a reasonable basis upon which to justify limiting treatment to a subset of patients.
   3. Previous clinical experience: The product may have characteristics that have been demonstrated through previous clinical experiences and can be used to identify appropriate orphan subsets.
2. Estimate of the target population (must be fewer than 200,000 persons)

The request must contain information on the prevalence of the disease or condition in the orphan subset. Incidence is only recommended for acute diseases with a duration of less than one year that are curable and do not recur. The sponsor is expected to make a good faith effort to find the most recent US prevalence data.

---

Since ODD is often denied in cases of orphan subsets, it is important that a sponsor to approach the agency with a thorough understanding of its expectations and requirements. Premier Consulting has a long history of helping sponsors apply for and attain ODD for their rare disease products, including those for orphan subsets. Our expertise gives us the ability to develop customized and tailored strategic plans, mitigate regulatory risks, and optimize marketing success. Contact us to find out how we can support your program.