FDA Issues Final Orphan Drug Regulations

By Michelle L. Butler –

On June 12th, the final rule to amend FDA’s 1992 orphan drug regulations was published in the Federal Register.  78 Fed. Reg. 35117 (June 12, 2013).  This final rule, which largely finalizes the revisions as proposed in October 2011, will be effective August 12, 2013.  We previously posted on the details of the proposed rule, as well as litigation that is still ongoing concerning some of the issues discussed by FDA in the proposed and final rules.   

The main changes from the proposed rule are as follows:

(1) Added a definition of “orphan subset” that is consistent with the explanation of orphan subset in the proposed rule (21 C.F.R. § 316.3(b)(13));

(2) Added clarifying language consistent with “FDA’s long-standing practice that a designated drug is eligible for orphan exclusive approval only if the same drug has not already been approved for the same use or indication” (21 C.F.R. §§ 316.3(b)(12), 316.31(a), and 316.34(a));

(3) Removed language regarding the demonstration of a “major contribution to patient care” that stated that the drug must provide “safety and effectiveness comparable to the approved drug” because the language incorrectly implied that FDA would require direct proof of comparability (e.g., through non-inferiority trials) (21 C.F.R. § 316.3(b)(3)(iii));

(4) Clarified that a designation request need only include “relevant” in vitro laboratory data and data from “clinical experience” with the drug (21 C.F.R. § 316.20(b)(2));

(5) Clarified that FDA will notify the sponsor in writing whenever FDA considers a designation request voluntarily withdrawn (21 C.F.R. § 316.24(a));

(6) Clarified that the reasons for denying a designation request identified in 21 C.F.R. § 316.25 are not exhaustive and that FDA can refuse to grant a designation request if the drug is otherwise ineligible for designation under Part 316;

(7) Stated that, if a drug loses designation after the effective date of this final rule (either because the sponsor voluntarily withdrew designation or because FDA revoked designation), FDA’s publicly available posting of designated drugs will include identification of the fact that the drug is no longer designated and the date it lost designation (21 C.F.R. § 316.28);

(8) Clarified that the scope of orphan drug exclusivity is limited to the indications or uses for which the designated drug is approved (21 C.F.R. § 316.31(a) and (b)); and

(9) Clarified that a designated drug that is otherwise the same as a previously approved drug will receive orphan drug exclusivity upon approval only if the sponsor demonstrates that its drug is clinically superior to the previously approved drug.

Below we discuss some of the preamble statements in the final rule that we think merit special attention.

Demonstration of an “Orphan Subset” of a Non-Rare Disease or Condition.  FDA stated that it carefully considered whether to retain “medically plausible” in the discussion of the “orphan subset” concept.  Because of confusion over the term medically plausible and the fact that FDA believes that misinterpretation of medically plausible “could permit a non-rare disease or condition to be artificially subdivided into smaller groups for establishing subsets that are under the prevalence limit for designation,” FDA decided to finalize the description of orphan subset as proposed.  78 Fed. Reg. at 35119.  FDA also reiterated that the description of orphan subset “is consistent with how FDA has long interpreted ‘medically plausible’ in the context of orphan subsets” and “is intended to make clear to sponsors that an orphan subset is a regulatory concept specific to the Orphan Drug regulations [and] does not simply mean any medically recognizable or clinically distinguishable subset of persons with a  particular disease or condition (as the term ‘medically plausible’ in this context may have been erroneously interpreted to imply).”  Id.

For clarity, FDA also decided to add the concept to the definitions section as follows: “Orphan subset of a non-rare disease or condition (‘orphan subset’) means 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.”  21 C.F.R. § 316.3(b)(13). 

The preamble identified the following items as examples of factors that may inform whether an appropriate orphan subset exists:

• Toxicity of the Drug:  The toxicity profile of the drug may render it appropriate for use in only a subset of persons with a non-rare disease or condition.  For example, patients with the disease or condition who can be treated with other, less toxic therapies may not be appropriate candidates for the drug; however, a subset of patients with the disease or condition who are refractory to, or intolerant of, other less toxic drugs may exist and may be the only appropriate candidates for treatment with the more toxic drug.
• Mechanism of Action of the Drug (e.g., antibody-specific or biomarker-based drug):  The mechanism of action of a drug may limit use of a drug to only a subset of patients with a non-rare disease or condition.  For example, use of a certain targeted therapy (e.g., antibody-specific or biomarker-based drug) may be appropriate in only a subset of patients with a non-rare disease or condition owing to its targeting mechanism (e.g., only in patients with the subtypes of tumors that possess the specific antigen targeted or only those patients with the specific biomarker targeted).
• Previous Clinical Experience With the Drug:  Information on the drug’s activity available from completed clinical trials or published in clinical literature may be used to establish an orphan subset.  For example, if relevant data show that the drug has no significant activity in the remaining subset of patients with high grade tumors or with a certain biomarker, respectively, then patients with low grade tumors or without that biomarker may constitute an orphan subset within a given disease or condition.

78 Fed. Reg. at 35120.

The preamble also reiterated certain examples of factors that were addressed in the proposed rule that FDA believes may not inform whether an orphan subset exists: clinical trial eligibility; the sponsor’s plan to study the drug for a select indication; a particular disease grade or stage; and price.  Id.

FDA also discussed what constitutes a distinct “disease or condition” for the purpose of orphan drug designation.  According to the preamble, since FDA considers the prevalence for each disease or condition when determining whether to grant orphan drug designation, “[a] drug that shows promise in multiple different rare diseases or conditions may be eligible for multiple designations.”  Id.  “Whether a given medical condition constitutes a distinct ‘disease or condition’ for the purpose of orphan-drug designation depends on a number of factors, assessed cumulatively, including:  Pathogenesis of the disease or condition; course of the disease or condition; prognosis of the disease or condition; and resistance to treatment.”  Id.  In explaining these concepts, FDA provided the following examples:

• One drug may be eligible for three separate designations – e.g., for the treatment of ovarian cancer, for the treatment of multiple myeloma, and for the treatment of Kaposi’s sarcoma – even if the cumulative prevalence of all three diseases or conditions would exceed 200,000.
• FDA currently considers pneumonia in cystic fibrosis to be a different “disease or condition” than community-acquired pneumonia “based on a cumulative assessment” of the factors described above.  Id.  Therefore, assuming the prevalence of pneumonia in cystic fibrosis patients is under 200,000, but the pool of all pneumonia cases exceeds 200,000, a sponsor seeking designation for a drug to treat pneumonia in cystic fibrosis patients would not need to establish an orphan subset from the larger pool of all pneumonia patients and would not need to provide a rationale for why only cystic fibrosis patients with pneumonia would be appropriate candidates for the drug.  
• FDA currently considers stage 1 breast cancer to be the same “disease or condition” as stage 4 breast cancer.  Since the prevalence of breast cancer currently exceeds 200,000, a sponsor seeking designation for a breast cancer drug would need to demonstrate why only a subset of patients with breast cancer (e.g., patients with stage 4 breast cancer) would be appropriate candidates for the drug.

Eligibility for Orphan Drug Designation of a Drug That Was Previously Approved for the Same Use or Indication.  FDA decided to finalize its proposal to amend 21 C.F.R. §§ 316.3(b) and 316.20(a) and (b)(5) to delete the word “orphan” in the phrase “approved orphan drug” and to revise 21 C.F.R. § 316.25(a)(3) to read “already approved drug for the same disease or condition” in place of “[a drug] that already has orphan-drug exclusive approval for the same disease or condition.”  The purpose of these changes was to clarify, consistent with FDA’s long-standing practice, that a designation request is required to include a plausible hypothesis of clinical superiority if the drug is the same as an already-approved drug, regardless of whether the already-approved drug was designated as an orphan drug or has orphan drug exclusivity.  78 Fed. Reg. at 35121-22.

In the preamble, FDA addressed comments that opposed this change, including comments that interpreted the Orphan Drug Act “to mandate orphan-drug designation of any drug for a rare disease or condition, even those that are the same as a previously approved drug, regardless of clinical superiority, as long as the designation request for the drug is submitted before submission of the marketing application.  At the same time, these comments acknowledge that, in order for the drug to receive and/or break orphan exclusivity under [the statute], clinical superiority would need to be demonstrated upon approval if the drug is otherwise the same as a previously approved drug for the same use or indication.”  Id. at 35121.  According to FDA, the comments argued that more liberal granting of orphan drug designation, even if orphan drug exclusivity is not even theoretically possible, would expand the universe of drugs for rare diseases or conditions eligible for other benefits that inure to orphan-designated drugs, such as Federal tax credits, prescription drug user fee waivers, exclusion from the branded pharmaceutical fee, and exclusion from the requirement to offer discounted prices to certain covered entities under the 340B program.  According to the preamble, certain of the comments identified plasma protein therapies, which are macromolecules, as deprived of these benefits because “‘various drugs within each therapeutic class of products are considered to have the same principal molecular structures and would not be considered different under the regulations without a showing of clinical superiority, despite the fact that each therapy is a unique, non-interchangeable biological product.’”  Id. at 35121-22.  In response, FDA stated that, while it “appreciates this perspective from industry about the impact that obtaining – or not obtaining—orphan-drug designation” may have under other statutes, “FDA continues to believe that the current framework is the best means for giving effect to the intent of the Orphan Drug Act, to provide incentives for sponsors to develop promising drugs for diseases and conditions that would not otherwise be developed and approved, including drugs that are potentially safer or more effective than already approved drugs.”  Id. at 35122.

FDA stated that it is, however, “considering the feasibility of issuing a draft guidance document on what may constitute a plausible hypothesis of clinical superiority for certain categories of products, for example plasma-derived products, which may help address some of the concerns articulated previously.”  Id. 

Eligibility for Multiple Orphan Drug Exclusive Approvals.  Because of some confusion articulated in comments to the proposed rule on the issue of multiple exclusive approvals and subsetting, FDA has decided to clarify 21 C.F.R. § 316.31 regarding the scope of exclusive approval by replacing “subset [of uses]” with “select indication(s) or use(s).”  FDA also provided clarification on the concept of multiple exclusive approvals with the following example: 

A drug may be designated for use in ovarian cancer but approved for use in only stage 4 ovarian cancer, based on the data and information in the marketing application.  As new data emerge, FDA may approve the drug for additional indications or uses within the rare disease or condition for which the drug is designated (e.g., stages 1, 2, and/or 3 of ovarian cancer).  The advantage to the sponsor in this hypothetical scenario is that, if the drug is later approved for additional indication(s) or use(s) within the rare disease or condition for which it is designated, the sponsor would not have to submit additional designation requests for the drug to cover these additional indication(s) or use(s) – because they would fall within the original designation.  Additional orphan-drug exclusivity may attach upon approval of these new (not previously approved) indications or uses that are within the scope of the original designation.

78 Fed. Reg. at 35123-24.  FDA then followed the example to its logical conclusion as follows:

Assume, for example, that a drug is designated for use in ovarian cancer (all stages) but is approved for use in only stages 1 and 2 of ovarian cancer (‘first drug’).  A subsequent sponsor may seek designation of the same drug (‘second drug’) for the remaining unapproved uses within ovarian cancer (i.e., stages 3 and/or 4) without having to provide a plausible hypothesis of clinical superiority over the first drug, although the prevalence determination would be based on ovarian cancer regardless of stage (unless an orphan subset were shown).  Designation of the second drug for the uses already approved for the first drug (i.e., stages 1 and 2 of ovarian cancer) would require a plausible hypothesis of clinical superiority over the first already approved drug.

Id. at 35124.

Demonstration of Clinical Superiority – Major Contribution to Patient Care.  FDA decided to delete language it had proposed regarding the “major contribution to patient care” (or “MC to PC”) basis for clinical superiority (i.e., requiring “a demonstration that the drug provides safety and effectiveness comparable to the approved drug”) because the comments indicated that there was confusion over the proposed language.  FDA stated that it had not intended to change the standard for MC to PC or suggest that direct proof of comparability to the approved product was necessary (e.g., through non-inferiority trials).  FDA stated that, rather, it had “intended to convey that [MC to PC] determinations can be complex and encompass consideration of a number of factors that potentially implicate safety and effectiveness, which are evaluated on a case-by-case basis for each drug product.”  Id. at 35124.

FDA also identified the factors it believes may be taken into consideration when determining whether a drug makes a MC to PC (most of which were previously described in the preamble to the 1992 final rule):  “The following factors, when applicable to severe or life-threatening diseases, may in appropriate cases be taken into consideration when determining whether a drug makes a major contribution to patient care:  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.”  Id. at 35125.  FDA declined to add “increased quality of life” or “improved patient compliance” to the list of factors as it believes they are already reflected in the other factors.  Id.  FDA also stated that, in its experience, “showings of [MC to PC] remain unusual” and “FDA still expects these showings to be less frequent than greater safety and greater effectiveness showings.”  Id.