On June 12, 2013, the Food and Drug Administration (FDA) issued a Final Rule amending the Orphan Drug regulations (21 C.F.R. Part 316) issued to implement the Orphan Drug Act. The amendments clarify regulatory provisions and address issues that have arisen since those regulations were issued.1 The Final Rule largely mirrors a proposed rule that FDA issued on the same topic in October 2011.2

This bulletin highlights some of the major points described in the Final Rule.

  1. Substantive Issues
  1. Does the "Orphan Subset" Qualify for Designation?

Previously, if a sponsor developed an orphan use for a drug that otherwise was effective in groups larger than 200,000 people, the sponsor needed to demonstrate that the "subset of persons with a particular disease or condition" was "medically plausible."3 Now, the sponsor needs to demonstrate that "use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug, for example, drug toxicity, mechanism of action, or previous clinical experience with the drug."4

FDA provides the following factors to determine if an appropriate orphan subset exists:

  • the drug’s toxicity,
  • mechanism of action of the drug (e.g., antibody-specific or biomarker-based drug);
  • previous clinical experience with the drug,
  • clinical trial eligibility,
  • the sponsor’s plan to study the drug for a select indication,
  • particular disease grade or stage, and
  • price.5
  1. When to Request Orphan Designation

Previously, the regulations stated that "[a] sponsor may request orphan-drug designation at any time in the drug development process prior to the submission of a marketing application for the drug product for the orphan indication."6 The amended rule now reads "[a] sponsor may request orphan-drug designation at any time in its drug development process prior to the time that sponsor submits a marketing application for the same rare disease or condition."7 This change was needed because it was not clear in the earlier regulation that one sponsor’s marketing application would not prevent a different sponsor from submitting a request for orphan drug designation for the same drug for the same orphan use without also submitting a plausible hypothesis of clinical superiority.8

  1. What Must the Designation Request Include?

Sponsors should now submit the sponsor’s email address with the request, as well as the drug’s chemical name or a "meaningful descriptive name" (i.e., "one that would be meaningful to the public") if a generic or trade name is not available.9 Further, the description of the drug should now specifically contain "the identity of the active moiety if it is a drug composed of small molecules, or of the principal molecular structural features if it is composed of macromolecules; [and] its physical and chemical properties, if these characteristics can be determined."10

The Final Rule requires the scientific rationale discussion to establish a "medically plausible basis." Previously, the scientific rationale discussion needed to include "all data from nonclinical laboratory studies, clinical investigations, and other relevant data."11 Now, the discussion must include "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. . . . Animal toxicology studies are generally not relevant to a request for orphan-drug designation."12 The FDA replaced "clinical investigations" with "clinical experience" to reflect the agency’s willingness to consider clinical data from sources other than clinical investigations, such as well-documented case histories.13

Finally, the request no longer must contain "[a] statement as to whether the sponsor . . . is the real party in interest of the development and the intended or actual production and sales of the product."14

  1. Demonstrating Clinical Superiority

Timing: As both the current regulations and Final Rule state, for a sponsor to obtain orphan-drug designation when the drug is otherwise the same as a previously approved drug, it must demonstrate a plausible hypothesis of clinical superiority.15 For a sponsor to obtain orphan-drug exclusivity, it must submit affirmative evidence to demonstrate this clinical superiority.16 Also to obtain orphan-drug exclusivity, sponsors must demonstrate clinical superiority at the approval stage, if in the interim between obtaining orphan-drug designation and marketing approval, the same drug is approved for the same orphan use or indication by another sponsor.17 This would be the case even if the sponsor did not need to demonstrate clinical superiority when initially obtaining orphan-drug designation, because the same drug had not yet been approved for the same orphan use.

Substantiation of a Specific Hypothesis: "FDA will recognize orphan-drug exclusivity as long as clinical superiority to the previously approved drug is demonstrated, regardless of whether the sponsor substantiates the particular hypothesis of clinical superiority upon which the designation was based (e.g., the drug may in fact be safer for a different reason than that hypothesized at the designation stage)."18

Major Contribution to Patient Care Factors: One way of demonstrating clinical superiority is to show that "a drug makes a major contribution to patient care." The following factors should be considering in demonstrating clinical superiority in this manner:

  • convenient treatment location,
  • duration of treatment,
  • patient comfort,
  • reduced treatment burden,
  • advances in ease and comfort of drug administration,
  • longer periods between doses, and
  • potential for self-administration.19
  1. Refusals to Grant the Designation

One of the reasons FDA previously refused to grant requests for orphan-drug designation was if "[a] drug . . . is otherwise the same drug as one that already has orphan-drug exclusive approval for the same rare disease or condition and the sponsor has not submitted a medically plausible hypothesis for the possible clinical superiority of the subsequent drug."20 Now, FDA may still refuse to grant the request for this reason, and also if the "drug is otherwise the same drug as an already approved drug for the same rare disease or condition" and has not received orphan-drug exclusive approval.21

  1. Scope of Orphan-Drug Exclusive Approval

In accordance with FDA’s longstanding practice, an orphan-designated drug will receive orphan-drug exclusivity upon approval only if the same drug has not been previously approved for the same use or indication.22

FDA made explicit in the Final Rule another longstanding practice regarding one of the means by which a new marketing application may be approved before the seven years of exclusivity for an approved orphan drug expire. If FDA’s approval is limited to only particular indication(s) within the rare disease or condition for which the drug was designated, FDA may later grant a new exclusive approval of the drug for an additional indication within the rare disease or condition but which is not protected by the exclusive approval. In other words, FDA may grant orphan-drug exclusivity for a second indication, and that exclusivity is effective from the date of the second indication’s approval.23

The scope of orphan-drug exclusivity is limited to the indication(s) or use(s) for which the drug is approved for marketing, even if the orphan-drug designation for the drug is broader.24 FDA designates orphan drugs for use by all people with the rare disease or condition, but FDA can only approve a drug for an indication or use if there are adequate data in the marketing application to support approval.25 However, if the agency approves the drug for additional indications in which the drug is already orphan-designated, the sponsor does not need to submit additional designation requests because they would fall within the original designation.26

  1. Procedural Issues

FDA also addressed the following additional issues.

  1. Address for Submissions

The Final Rule provides updated addresses to submit orphan drug correspondence.27

  1. Permanent-Resident Agent for Foreign Sponsors

Prior to the Final Rule, every foreign sponsor was to name an agent for communications to be made on behalf of the sponsor, but only the name of the agent was required.28 Now, foreign sponsors must also submit the agent’s address, telephone number, and email address.29

  1. Deficiency Letters

In addition to the notification that FDA already sends to the sponsor when the agency grants the sponsor’s request for orphan-drug designation, FDA is now required to send to the sponsor a deficiency letter if the request for designation contains inaccurate information or is otherwise incomplete.30

  1. Requesting an Extension of Time to Respond

FDA may consider a designation request voluntarily withdrawn if the sponsor fails to respond to the deficiency letter within one year from the date FDA issues the letter, unless within this year the sponsor requests an extension of time to respond. This request must be in writing and include the reason(s) for the requested extension and the length of time of the requested extension. If FDA denies the request, it may consider the designation request voluntarily withdrawn, and will notify the sponsor in writing.31

  1. Requests for Withdrawal

Although the Final Rule codifies an existing practice, it clarifies that sponsors may voluntarily withdraw a designation request or designation at any time, by submitting a written request for withdrawal to FDA.32 FDA will acknowledge the withdrawal in a letter to the sponsor, and the designation benefits (e.g., exclusivity) will end on the date of this letter.33 Benefits that have already vested (e.g., tax credits or user fee exemptions) would not be affected.34

  1. Public Posting

FDA’s public listing of all orphan-designated drugs will now include whether a drug loses its designation, and if so, as of what date.35 Previously, this information had been deducible from FDA’s publication of hard copy quarterly lists, but it was no longer deducible once FDA switched to Internet publication.36 However, the public posting will not specify the reason that the drug lost its designation or whether a designation request was withdrawn.37 FDA will no longer list the manufacturer’s name and address and only that of the sponsor. FDA will also now list the chemical name or a "meaningful descriptive name of the drug" if neither the generic name nor trade name is available.

The Final Rule takes effect August 12, 2013.