Director, Frank J. Sasinowski) on the flexibility in FDA’s review of potential treatments for patients with rare diseases.FDA’s proposed rule addresses 13 specific issues (some of which we touched on earlier this week when we reported on an OOPD Standard Operating Procedures and Policies):(1) Demonstration of an appropriate “orphan subset” of persons with a particular disease or condition that otherwise affects 200,000 or more persons in the United States, for the purpose of designating a drug for use in that subset (21 C.F.R. § 316.20(b)(6));(2) Eligibility for orphan-drug designation of a drug that is otherwise the same drug for the same orphan indication as a previously approved drug (21 C.F.R. §§ 316.3(b)(3), 316.20(a), and 316.20(b)(5));(3) 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 (21 C.F.R. § 316.31);(4) Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval (21 C.F.R. § 316.3(b)(3)(iii));(5) Requirement for submitting the name of the drug in an orphan-drug designation request (21 C.F.R. § 316.20(b)(2));(6) Required drug description and scientific rationale in a designation request (21 C.F.R. § 316.20(b)(4));(7) Required information in a designation request relating to the sponsor's interest in the drug (21 C.F.R. § 316.20(b)(9));(8) Timing of a request for orphan-drug designation (21 C.F.R. § 316.23(a));(9) Responding to a deficiency letter

SOPP”)prepared and used by FDA’s Office of Orphan Products Development (“OOPD”) for the review of orphan drug designation requests was recently made public and provides some interesting (and helpful) insight into OOPD’s policies. Of particular interest are several of the appendicies to the SOPP, including Appendix B (“Scientific Rationale Supporting a Request for Orphan Drug Designation”), Appendix C (“Medically Plausible or Orphan Subsets Supporting a Request for Orphan Drug Designation”), Appendix D (“Lymphoma as the Subject of a Request for Orphan Drug Designation”), and Appendix E (“Recombinant Products and Orphan Drug Designation”). While we have seen the policies described in the SOPP implemented in product-specific sponsor correspondence (or know them through OOPD designation precedent), never before have we seen them discussed in a more general policy document like the SOPP.Scientific Rationale Supporting a Request for Orphan Drug Designation – FDA’s orphan drug regulations at 21 C.F.R. § 316.20(b)(4) require that a designation request contain “[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.” FDA may refuse to grant designation on the basis that “[t]here is insufficient information about the drug, or the disease or condition for which it is intended, to establish a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of that disease or condition” (21 C.F.R. § 316.25(a)(2)).

But first, some background on the case and the issues involved. . . .FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “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” (emphasis added). The term “orphan drug” is defined in FDA’s regulations to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act” (i.e., FDA considers a drug to be an orphan drug regardless of whether or not it has been designated as such).

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 a

Why? Because of issues surrounding what constitutes an “orphan drug” and under what circumstances “clinical superiority” must be shown.FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “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” (emphasis added). Over the years, there has been some confusion as to how FDA interprets the term “orphan drug” in this regulation.

Because WILATE is the “same drug” as HUMATE-P, the issue of “clinical superiority” comes into play – for obtaining orphan drug designation and for obtaining orphan drug exclusivity.FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “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.” FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways: (1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials; (2) greater safety in a substantial portion of the target population; or (3) demonstration that the drug makes a major contribution to patient care.As FDA explains in the petition response (as well in the Agency’s 2011 proposed rule – see our previous post here):Though the sponsor of a subsequent orphan drug must set