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FDA Designations for Rare Disease Products, Part 2: Orphan Drug Designation

This is the second installment in a four-part blog series highlighting FDA designations for products with rare disease indications: orphan drug designation (ODD), rare pediatric disease designation (RPDD), and humanitarian use device (HUD) designation. Part 1 compared these designations, and in Part 2, we provide a detailed explanation of ODD for rare disease drug sponsors.

Many diseases and conditions affect such small numbers of people that a drug or biological product developed to treat these patients generates relatively little return on investment for development costs. Companies developing such products can expect to incur a financial loss and, as a result, the pharmaceutical industry has neglected many rare diseases.

The Orphan Drug Act of 1983 was devised to incentivize pharmaceutical companies to address the unmet needs of patients with rare diseases. The act established the ODD program and has since been amended several times to add clarity and additional incentives.

Criteria for orphan drug designation

  • The product must be intended for use in a rare disease or condition
  • Adequate documentation or prevalence data must demonstrate that the intended condition is rare
  • There must be a scientific rationale establishing a medically plausible basis for the use of the product for the rare condition

A key point to remember is that ODD applies to both the active moiety and the condition, but not necessarily the product formulation. It is also worth noting that esters, salts, and other noncovalent derivatives of a given active moiety are generally considered the same drug when it comes to ODD.

Definition of a rare disease or condition

The Orphan Drug Act defines a rare disease or condition as one (a) that affects fewer than 200,000 persons in the United States or (b) for which there is no reasonable expectation that the cost of developing a drug and making it available in the U.S. will be recovered from sales in the country. Sponsors rarely use the second criterion due to the difficulty of proving unprofitability.

Sometimes, a product intended for use in a subset of an otherwise non-rare disease or condition (known as an “orphan subset”) qualifies for ODD, provided the product cannot be used to treat the broader disease or condition due to some property of the drug (toxicity in some subsets but not others, for instance).

Scientific rationale

The content and format requirements for an ODD request are listed in 21 CFR 316.20. In addition to general information about the drug and rare condition for which the ODD is being requested, the sponsor must provide:

[A] discussion of the scientific rationale to establish a medically plausible basis for the use of the drug for the rare disease or condition, including all relevant data from in vitro laboratory studies, preclinical efficacy studies conducted in an animal model for the human disease or condition, and clinical experience with the drug in the rare disease or condition that are available to the sponsor, whether positive, negative, or inconclusive.

For an ODD request for a previously unapproved drug, extensive clinical data are generally not necessary, and sometimes nonclinical proof-of-concept data may be sufficient to demonstrate a medically plausible basis for use of the drug for the indication. However, if another sponsor has already obtained ODD for the same drug and condition and a marketing application has been approved, the new sponsor has the added requirement of providing a plausible hypothesis as to why the proposed drug may be clinically superior to the first already marketed drug in order to obtain ODD.

Timeline and maintenance for orphan drug designation

ODD requests are submitted to the FDA’s Office of Orphan Products Development at any time during drug development prior to NDA or BLA submission for the desired orphan drug and condition. Since an ODD request is not submitted as an amendment to an IND, a sponsor does not need to have an open IND (or even intend to open an IND) to request ODD.

In its 2017 Orphan Drug Modernization Plan, the FDA committed to a goal of responding to all new ODD requests within 90 days of their receipt.

Once ODD is granted, the sponsor is required to submit orphan annual reports (which are different from IND annual reports) every year until the marketing application is approved.

Benefits of orphan drug designation

A sponsor may be eligible for the following benefits and incentives for a product with ODD:

  • Pre-approval:
    • Potential Pediatric Research Equity Act (PREA) requirements exemption (this exemption may not apply for certain molecularly targeted anticancer agents)
    • Waiver of the marketing application user fee
    • Tax credits and research grants for qualified clinical testing expenses
    • FDA protocol assistance
  • Post-approval: Seven years of orphan drug market exclusivity (this benefit may not be available if the active moiety is already approved or if clinical superiority is not supported with data)

The indication associated with the eventual NDA or BLA must be for the same disease or condition as that associated with the ODD, or the indication must be narrower, for these benefits to apply. For example, if a sponsor obtains ODD for Drug A for Condition 1 but files an NDA for Drug A with an indication for Condition 2, the user fee waiver and market exclusivity does not apply. Likewise, if the NDA is approved for indications in both Condition 1 and Condition 2, the market exclusivity applies only to Condition 1. However, since the NDA includes an indication not covered by the ODD, the user fee still applies.

PREA requirements exemption

PREA requires NDAs and BLAs (or application supplements) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment, unless the applicant has obtained a waiver or deferral.

While some products granted ODD are exempt from PREA requirements for pediatric studies, not all qualify (21 USC 355c(k)(1)). Drugs intended for the treatment of an adult cancer that are directed at a molecular target that is substantially relevant to the growth or progression of a pediatric cancer are not eligible for the exemption. Premier Consulting has frequently coordinated with the FDA’s Oncology Center of Excellence and relevant review divisions to discuss PREA requirements for such products.

Financial incentives

Under Section 736(a)(1)(F) of the FD&C Act, an NDA or BLA for a product to be used in a rare disease or condition granted ODD is not subject to an application fee. The annual program fee also may be waived if certain conditions are met. In addition, sponsors of products with ODD may be eligible for a 25 percent federal tax credit for qualified clinical testing expenses for studies conducted in the U.S. Sponsors also may be eligible for research grants from the OOPD to support clinical studies.

Protocol assistance

Although there are mechanisms in place through which the FDA can provide feedback on protocols for products without ODD, the FD&C Act provides for formal protocol assistance for ODD holders for nonclinical and clinical investigations that must be conducted to support the development of an orphan drug.

Orphan market exclusivity

One of the most significant benefits of obtaining ODD is the seven-year orphan drug market exclusivity following approval of an NDA or BLA. This market exclusivity prevents the FDA from approving another product with the same active moiety for the same disease or condition unless the second product is demonstrated to be clinically superior to the first.

There are three ways a sponsor can move forward when confronted with the market exclusivity of another sponsor’s orphan product:

  • Wait for the market exclusivity to expire
  • Develop the same drug for a different indication
  • Demonstrate that the new product is clinically superior to the already approved product (in this case, the FDA considers the clinically superior product to be a different drug even if the active moiety is the same)

Premier Consulting has a long history of helping sponsors attain ODD for their rare disease products and mapping the most time- and cost-efficient development plan for regulatory and post-marketing success. Contact us to find out how we can support your program.


CFR – Code of Federal Regulations Title 21

The United States Code

Designating an Orphan Product: Drugs and Biological Products

FDA’s Orphan Drug Modernization Plan

Clarification of Orphan Designation of Drugs and Biologics for Pediatric Subpopulations of Common Diseases

User Fee Waivers, Reductions, and Refunds for Drug and Biological Products: Guidance for Industry