Explore Our Blog

Orphan Drug Products and the FDA

An orphan drug is a pharmaceutical agent that is developed specifically to treat a rare disease or medical condition. There are many key factors, as well as, FDA rules and regulations to be aware of when developing an orphan drug.

1) Summary of the Orphan Drug Act

The Orphan Drug Act of 1982 was designed to promote the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.  The Orphan Drug Act defines a disease or condition as “rare” if it affects fewer than 200,000 people in the US, or if the cost of developing a drug and making it available in the United States for such diseases or conditions will exceed any profits from its sale in the United States.  The resulting Orphan Drug Regulations (21 CFR Part 316) outline the procedures and requirements for submitting requests for designation of a drug for a rare disease or condition.

2) Incentives for Developing Orphan Products

  • 7-year marketing exclusivity to sponsors of approved orphan products, with an additional 6 months for a pediatric indication.
  • 50% federal tax credit for expenses incurred in conducting clinical research within the US (tax credits may be applied to prior year or applied over as many as 20 years to future taxes).
  • Waiver of PDUFA (Prescription Drug User Fee Act) fees for orphan drugs.
  • Qualify to compete for research grants from the OOPD (Office of Orphan Products Development) to support clinical studies for developing orphan drugs.
  • Eligible to receive regulatory assistance and guidance from the FDA in the design of an overall drug development plan.

3) Eligibility of a product for orphan drug designation

Product must have a sponsor (ie, company, individual, institution, government agency). A sponsor may request orphan drug designation of a previously unapproved drug, or of a new orphan indication for an already marketed drug.

A sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.

>More than one sponsor may receive orphan drug designation of the same drug for the same rare disease or condition, but each sponsor seeking orphan drug designation must file a complete request for designation.Sponsor’s product cannot have approval under a New Drug application (NDA), Biologic License Application (BLA) or Premarket Approval (PMA) application for the disease or condition for which orphan status is requested. A marketing application for the product has not been filed prior to filing the orphan designation application.

4) Content of a Request for Orphan-Drug Designation

  • A statement that the sponsor requests orphan drug designation for a rare disease or condition, which shall be identified with specificity.
  • The name and address of the sponsor; the name of the sponsor’s primary contact person and/or resident agent including title, address, and telephone number; the generic and trade name, if any, of the drug or drug product; and the name and address of the source of the drug if it is not manufactured by the sponsor.
  • A description of the rare disease or condition for which the drug is being or will be investigated, the proposed indication or indications for use of the drug, and the reasons why such therapy is needed.
  • A description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition, including all data from nonclinical laboratory studies, clinical investigations, and other relevant data that are available to the sponsor, whether positive, negative, or inconclusive. Copies of pertinent unpublished and published papers are also required.
  • Where the sponsor of a drug that is otherwise the same drug as an already approved orphan drug seeks orphan drug designation for the subsequent drug for the same rare disease or condition, an explanation of why the proposed variation may be clinically superior to the first drug.
  • Where a drug is under development for only a subset of persons with a particular disease or condition, a demonstration that the subset is medically plausible.
  • A summary of the regulatory status and marketing history of the drug in the United States and in foreign countries, e.g., IND and marketing application status and dispositions, what uses are under investigation and in what countries; for what indication is the drug approved in foreign countries; what adverse regulatory actions have been taken against the drug in any country.
  • Documentation, with appended authoritative references, to demonstrate that:
    • The disease or condition for which the drug is intended affects fewer than 200,000 people in the United States or, if the drug is a vaccine, diagnostic drug, or preventive drug, the persons to whom the drug will be administered in the United States are fewer than 200,000 per year as specified in § 316.21(b), or
    • For a drug intended for diseases or conditions affecting 200,000 or more people, or for a vaccine, diagnostic drug, or preventive drug to be administered to 200,000 or more persons per year in the United States, there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the United States as specified in § 316.21(c).
  • A statement as to whether the sponsor submitting the request is the real party in interest of the development and the intended or actual production and sales of the product.

5) Proposed Amendments to Orphan Drug Regulations

The FDA issued 13 proposed amendments to the Orphan Drug Regulations on October 19, 2011, intended to clarify some of the regulatory provisions and address issues that have arisen since implementation.  Public comments about the proposed amendments were collected through January 17, 2012, and 12 comments were provided by pharmaceutical companies, trade associations, attorneys, health care organizations, and individuals.  These amendments and the public comments are currently under review by the FDA.

The Specific Issues Addressed by the Proposed Amendments:
  • Clarification of a “medically plausible” subset of persons with a particular disease or condition, renaming the subset an “orphan subset”. Sponsors are asked to provide a reasonable scientific or medical rationale for limiting the investigational and potential use of the drug to only the subset of interest, using the following “practical questions” to determine the appropriateness of the subset:
    • Is the intended subset artificially restricted in any way with respect to the use of the drug to treat the disease or condition?
    • Is there a reasonable scientific or medical basis for believing that the drug would also potentially benefit the remaining population with the non-rare disease or condition or a larger subset of that population?
  • Eligibility for orphan-drug designation of a drug that is otherwise the same drug for the same orphan indication as a previously approved drug. The current regulations indicate that a drug may be eligible for orphan designation if the Sponsor can present a plausible hypothesis that the subsequent drug may be clinically superior to the approved orphan drug. However, the previously approved drug does not have to be designated as an orphan drug-clinical superiority would need to be demonstrated over any previously approved drug.
  • Eligibility for multiple orphan-drug exclusive approvals when a designated orphan drug is separately approved for use in different subsets of the rare disease or condition. The uses for which an orphan drug is approved might be limited to further subsets of the orphan population for which there is adequate data and information to support approval. The scope of orphan exclusive approval is limited to the approved indication, even if the underlying orphan designation was broader. If the orphan subset if further subdivided into multiple approved indications, Because orphan designation can be
  • Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval.
  • Requirement for submitting the name of the drug in an orphan-drug designation request. Generic and trade names, if any, are currently required. The neither is available, the FDA proposes requiring a chemical name or a meaningful descriptive name be included.
  • Required drug description and scientific rationale in a designation request. In order to review the scientific rationale of the drug, the FDA proposes requiring identification of the active moiety or principal molecular structural features of the proposed drug.
  • Required information in a designation request relating to the sponsor’s interest in the drug. FDA proposes to remove the last section of the requirements for submission for Orphan Drug Designation (316.20(b)(9) as it has proven to be of marginal if any utility in applications.
  • Timing of a request for orphan drug designation. While sponsors can request orphan-drug designation at any time prior to submission of a marketing application for the rare condition/disease.
  • Responding to a deficiency letter from FDA on an orphan-drug designation request. Sponsors would be required to respond to a deficiency letter within 1 year after issuance of the letter, unless within that timeframe, the sponsor requests in writing an extension of time to respond.
  • FDA publication of information regarding designated orphan drugs. The Agency is considering ways to make available to the public information about the status of development for designated orphan drugs, including whether to provide information to the public on whether a sponsor has submitted the required annual reports.
  • FDA recognition of orphan-drug exclusive approval. To clarify existing practice, the FDA would add language to 316.34(c) that specifies that orphan-drug exclusive approval is not granted if upon submission of the NDA, the sponsor fails to substantiate clinical superiority over the previously approved drug.
  • Miscellaneous terminology changes.
  • An address change for submissions.

6) Hints, Advice, & Precautions

The FDA indicates that the most critically reviewed areas of the application concern the scientific rationale (Item 4), and the population prevalence (Item 8). These sections should be well-researched, and key information should be concisely summarized, presented, and referenced in full so the reviewers can easily follow and check the points being made.

Providing a thorough and objective listing of prevalence estimates for the orphan condition is critical for a successful application. While the FDA does not spell out how the prevalence argument should be structured, the EMA has provided a very helpful guidance outlining points that should be addressed in this section of the application (link to EMA prevalence guidance). The research into prevalence estimates should be systematic and efforts should be made to show that all available data has been reviewed and considered. The methods used to evaluate and combine all the available references should be spelled out, as well as any calculations used. If certain references are thought to be inaccurate or skewed, evidence must be presented to support your position (the reference should not be ignored!).

An increasingly complicated issue embedded within the prevalence estimate concerns the “medical plausibility” of the subset of the population being treated/diagnosed by the potential orphan product (now referred to as the “orphan subset”). In fact, this topic was the #1 item listed in the proposed amendments to the Orphan Drug Regulations in October 2011. Along these lines, the “FDA recommends that the following practical questions be asked when assessing whether a subset of a non-rare disease or condition is an appropriate orphan subset:

  • Is the intended subset artificially restricted in any way with respect to the use of the drug to treat the disease or condition?
  • Given that the drug may potentially benefit this particular subset of persons, is there a reasonable scientific or medical basis for believing that the drug would also potentially benefit the remaining population with the non-rare disease or condition or a larger subset of that population? If not, why not?”

While the amendments are still under review, they highlight the FDA’s current thinking on the topic, and we have seen comments on applications returned from the FDA asking similar questions.


Sources

Back