The Food and Drug Administration (FDA) recently published a Federal Register notice announcing proposed amendments to the agency’s 1992 orphan drug regulations.1 The proposed changes, which address a variety of issues related to orphan drug designation and exclusive approval, are intended to clarify existing regulatory provisions. Interested pharmaceutical companies and other stakeholders have until January 17, 2012, to submit comments on the proposed changes.

Demonstrating a “Medically Plausible” Orphan Subset

By law, the FDA will designate a product as an orphan drug if the sponsor demonstrates, among other things, that the drug is intended for a rare disease or condition that affects fewer than 200,000 people per year in the United States.2 In some cases, however, the FDA will grant orphan designation for a “non-rare” disease or condition (i.e. one that affects more the 200,000 people annually). To obtain orphan designation for a non-rare disease or condition the sponsor must demonstrate that the drug will treat only a subset of persons with the particular disease or condition. The patient subset group must fall under the orphan prevalence limit of 200,000 people annually, and the sponsor must have a “medically plausible” reason for limiting treatment to the subset.3

The current orphan drug regulations do not define the term “medically plausible” and, according to the FDA, the term has been misinterpreted as referring to any clinically distinguishable subset of persons. To address this confusion, the FDA proposes to remove “medically plausible” from the regulations and instead provide a description of how sponsors should identify an appropriate orphan subset. The proposed amendment requires that the subset must not be arbitrarily chosen merely to reduce the disease prevalence for purposes of obtaining orphan designation. Rather, the product sponsor must develop a reasonable scientific or medical rationale for limiting the drug investigation to a specific subset.  

The FDA explains that the drug’s pharmacological properties or prior clinical experience with the drug might provide an appropriate basis for an orphan subset. For example, a cancer-fighting antibody product might have the pharmacological property of attacking a specific antigen type. In such a case, it would be appropriate to identify an orphan subset based on the subtypes of tumors that possess the specific antigen and to exclude from the prevalence calculation patients with tumors that lack the antigen. Similarly, if existing clinical data (from a completed trial or from published literature) show that a cancer-fighting drug is only effective against a certain subset of tumors, an orphan subset may be identified accordingly.  

In the proposed rule, the FDA suggests that sponsors ask two practical questions to “test” whether a patient sub-group may appropriately be treated as an orphan subset:

  1. Is the intended subset artificially restricted in any way?
  2. Given that the drug may potentially benefit a particular patient subset, is there a reasonable scientific or medical basis for believing that the drug will also benefit the remaining population with the disease or condition? If not, why not?  

If the subset is not artificially restricted, and there is medical or scientific basis to explain why the drug will not benefit the patients excluded from the subset, then it is likely that a valid and “medically plausible” orphan subset has been identified.  

Obtaining Orphan Designation When FDA Already Approved Same Drug for Orphan Indication

Under the current orphan drug regulations, a sponsor of a subsequent drug that is the same as an “approved orphan drug” may not obtain orphan designation for the same indication as the existing drug, unless the sponsor can demonstrate that the subsequent drug is clinically superior.4 The FDA proposes to delete the word “orphan” from the phrase “approved orphan drug” in sections 316.3(b)(3), 316.20(a) and 316.20(b)(5) of the regulations to clarify that this non-designation rule applies whether or not the existing drug has orphan exclusivity for the indication in question. That is, the agency will not grant orphan designation to a drug that is the same as (and not clinically superior to) an already approved drug for the orphan indication, regardless of whether the approved drug has orphan exclusivity.

Eligibility for Multiple Orphan Exclusive Approvals

The FDA proposes to add additional language to section 316.31 of the orphan drug regulations to clarify that the scope of orphan exclusivity is limited to the approved indication or use, even if the underlying orphan designation is broader. For example, a drug might have orphan designation for treatment of T-cell non- Hodgkin’s lymphoma; however, the data submitted for product approval might only support treatment of cutaneous manifestations of the disease. In this example, the sponsor would receive orphan exclusivity only for the narrow indication of treatment in patients with cutaneous manifestations of T-cell non-Hodgkin’s lymphoma. The orphan exclusivity would not cover other subsets of T-cell non-Hodgkin’s lymphoma. The proposed approach of limiting the orphan exclusivity to the approved indication means that, in some cases, multiple orphan drug approvals with exclusivity could exist for the same underlying disease or condition. This approach has important implications both for the initial orphan drug sponsor and subsequent sponsors of the same drug. Returning to the lymphoma example, if the initial sponsor, or a subsequent sponsor with orphan drug designation, later submits data and obtains approval for treatment of another subset of T-cell non-Hodgkin’s lymphoma (e.g., treatment of anaplastic large cell lymphoma), the sponsor will be eligible for orphan exclusivity for the new indication, effective on the date of approval.  

The FDA believes this approach is consistent with the Orphan Drug Act, because it “provides an important incentive to one or more sponsors to develop, or continue to develop, a potentially promising drug for use in all persons affected by a rare disease or condition.”5  

Demonstrating Clinical Superiority

As noted above, a drug sponsor must demonstrate clinical superiority to obtain orphan designation for a drug that is the same as a drug already approved for the orphan indication.6 The current regulations specify that, if a sponsor is unable to demonstrate greater safety or effectiveness, the FDA may still consider the drug “clinically superior” if it makes a major contribution to patient care.7 The FDA is proposing additions to the definition of “clinically superior” to clarify that a major contribution to patient care is only meaningful in cases where the drug can at least demonstrate safety and effectiveness comparable to the approved drug.

For example, a sponsor might wish to demonstrate clinical superiority by showing that a drug has made a major contribution to patient care through a new formulation or route of administration. The FDA will also require the sponsor to show that this change does not render the drug less safe or effective than the approved drug.  

FDA Recognition of Orphan Drug Exclusivity

Drug sponsors that demonstrate clinical superiority for purposes of obtaining orphan drug designation must also be able to demonstrate clinical superiority at the time of product approval to be eligible for orphan drug exclusivity. The FDA will not grant orphan exclusivity to a drug that is the same as an already approved drug if the sponsor fails to substantiate in the marketing application the clinical superiority hypothesis that was the original basis for orphan drug designation. To clarify this existing policy, the FDA proposes to add the following language to section 316.34 of the regulations:

If a drug is otherwise the same as a previously approved drug, FDA will not recognize orphan-drug exclusive approval if the sponsor fails to substantiate, at the time of marketing approval, the hypothesis of clinical superiority over the approved drug that formed the basis for designation.8

Timing of Request for Orphan Drug Designation

The FDA proposes to revise section 316.23(a) of the orphan drug regulations to clarify that a sponsor may request orphan drug designation at any time in the drug development process. According to the FDA, the existing timing provisions have caused confusion and the agency intends to clarify that a sponsor may not submit an orphan drug designation request after it has submitted a marketing application for the drug for that use. Other sponsors, however, may still submit orphan designation requests for the same drug while the initial sponsor’s marketing application is pending. The FDA explains that “there is no certainty that the [initial sponsor’s] marketing application will be approved promptly, if at all” and allowing additional requests for orphan designation is consistent with the Orphan Drug Act’s purpose of incentivizing the development of drugs that treat rare diseases or conditions.9  

Providing Pertinent Data in Request for Orphan Drug Designation

The FDA has observed that many requests for orphan designation exclude required information, such as the identity of the active moiety or a description of the drug’s principal molecular features. In other cases, sponsors provide the wrong type of information to support the use of the drug in the rare disease or condition. Some sponsors provide only theoretical support without data, while other sponsors include all available data about the drug rather than the pertinent data to support the use of the drug in the rare disease or condition. The FDA notes that “pertinent” data include in vitro data, preclinical efficacy data from studies conducted in a relevant animal model for the human disease or condition, and clinical data. Animal toxicology studies are generally not relevant to a request for orphan designation. The FDA proposes to revise section 315.20(b)(4) of the orphan drug regulations to ensure that sponsors submit appropriate data with their requests for designation.

Responding to Deficiency Letter on Orphan Designation Request

The current regulations do not address when sponsors must respond to a deficiency letter from the FDA regarding a request for orphan designation. The agency has observed that response times vary widely, taking up to several years in some cases. The FDA explains that, when several years elapse between the date of the deficiency letter and the sponsor’s response, the basis for the original orphan designation request may no longer hold. For example, the prevalence of the disease or condition in question may have grown to surpass the 200,000 patient prevalence limit.

To address this issue, the FDA proposes to require that sponsors respond to deficiency letters within one year. The FDA will grant reasonable written requests for an extension of the one-year period.10 According to the agency, “some deficiencies are less suitable to extension requests that others.”11 The FDA generally expects that deficiencies involving an inaccurate or incomplete prevalence estimate will be resolved in the one-year period. Other deficiencies may require the sponsor to conduct research or develop additional data, and the FDA acknowledges that this can take several years or more. The FDA anticipates granting extension requests in cases where sponsors need to develop supporting data (e.g., data to support the scientific rationale for a designation request for only a subset of persons with a particular disease).  

In the event that a sponsor does not respond or request an extension within one year, the proposed rule specifies that the FDA may treat the designation request as voluntarily withdrawn. The FDA may also consider a request voluntarily withdrawn if it denies the sponsor’s request for an extension.  

Publication of Orphan Drug Designations

Pursuant to existing regulations, the FDA publishes a monthly updated list of orphan-designated drugs. The FDA also makes available a cumulative list of all orphan-designated drugs on its website.12 A drug’s presence on the designation list does not necessarily indicate that the drug’s sponsors are actively developing the drug for an orphan indication. The FDA believes that information about the status of development for orphandesignated drugs could be useful for patients, medical practitioners, and the drug development community. Accordingly, the FDA is currently seeking public comment on whether it would be useful to make public information about whether sponsors of orphan-designated drugs have submitted annual reports. The agency does not plan to disclose the contents of the annual reports, but believes that information about whether such reports have been submitted might indicate whether the drug is still under active development.  

Other Updates to the Regulations

The Federal Register notice announces several ministerial and administrative updates relevant to orphan drug sponsors. The FDA plans to revise the regulations to allow sponsors to submit requests for designation that include the chemical name or a meaningful descriptive name of the drug in cases where a generic name or trade name is not available. The agency proposes to remove the requirement that requests for orphan drug designation include a statement of whether the party submitting the request is the real party in interest for the drug. The FDA has found that this requirement causes confusion and notes that the information has not been useful to the agency. The FDA also provides an updated address for all submissions related to orphan drugs.  


The FDA’s proposals intend to help clarify and further explain the agency’s approach to orphan drug designation and exclusivity. For companies seeking orphan designation or orphan exclusive approval, the notice provides information about the proposed new circumstances under which the FDA will grant such benefits, and also highlights potential pitfalls that might not have been readily apparent in the existing regulations. The FDA will accept comments on its proposed regulatory updates until January 17, 2012, and interested sponsors should consider using this opportunity to voice any questions or concerns about the topics addressed in the notice.