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Clarified that FDA will notify the sponsor in writing whenever FDA considers a designation request voluntarily withdrawn (21 C.F.R. § 316.24(a));(6) Clarified that the reasons for denying a

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 from FDA on an orphan-drug designation request (21 C.F.R. § 316.24(a));(10) FDA publication of information regarding designated orphan drugs (21 C.F.R. § 316.28);(11) FDA rec

FDA intends to determine whether variants of a vector from the same viral group are the same or different on a case-by-case basis.In a case where two gene therapy products express the same transgene and have/use the same vector, FDA may also consider additional features of the final product when determining “sameness,” such as regulatory elements (e.g., promoters or enhancers). In these instances, FDA generally intends to determine “sameness” of gene therapy products on a case-by-case basis.[1] 21 CFR 316.3(b)(14).[2] 21 CFR 316.3(b)(14)(ii).

Bulletins have described orphan drug laws in detail.2BackgroundThe main issue in the recent decision was whether the orphan drug exclusivity (“ODE”) for a calcium, magnesium, potassium, and sodium oxybates drug product blocked the approval of another new drug application (“NDA”) for a sodium oxybate for extended-release oral suspension product for the treatment of cataplexy or excessive daytime sleepiness (“EDS”) in adults with narcolepsy.The first product received ODE for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. The sponsor demonstrated, at the time of approval, it was clinically superior to (yet) another product, which was previously approved for the same indication. According to section 527(a) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”), (21 U.S.C. § 360cc), an ODE prevents FDA from approving a new drug product that is the “same drug” as another for the same use or indication until the first exclusivity ends.By regulation (21 C.F.R. § 316.3), a drug is the “same drug” if it contains the same active moiety for the same use or indication, unless the new drug product is clinically superior to the first with ODE.In this case, FDA found that the second drug was clinically superior to the first. Therefore, it was not the “same drug” within the meaning of the law.In addition, the agency concluded that the second product was eligible for its own ODE term because ODE can only block approval of “same drugs” for the same uses or indications. According to section 527(c)(1) of the FDC Act, if FDA has previously approved a drug that is otherwise the same drug for the same use or indication, the subsequent drug may be eligible for its own term of ODE if the sponsor demonstrates that its product is clinically superior to every previously approved drug.A sponsor of a drug that is “otherwise the same as an already approved drug may seek and obtain [orphan drug designation (‘ODD’)] for the subsequent drug for the same rare disease or con

16See Letter from U.S. Food & Drug Admin. to Lassman Law+Policy, Counsel to Braeburn, Inc. (Nov. 7, 2019); see also U.S. Food & Drug Admin., Orphan Drug Designations and Approvals: Subutex, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=75293.17 21 C.F.R § 316.3(b)(14).18Seeid. §§ 316.20(b)(5), 316.25(a)(3), 316.34(c).

The FDA is relying on these sections of the Act to determine that cannabidiol (CBD) is a violative ingredient when added to food or contained in a product labeled as a dietary supplement.2 Most recently, FDA relied on Section 201(ff)(3) to inform a distributor of dietary supplements that one of their Ingredients, NAC, an ingredient that, by some accounts, has been marketed in dietary supplements for decades, is excluded from being an ingredient in dietary supplements.3 For the purpose of Sections 301(ll) and 201(ff)(3), as indicated in the current version of FDA’s draft guidance on New Dietary Ingredient Notifications, the agency has interpreted:• the word “article” to mean either the entire product or a component of the product;• the term “active moiety” to follow the definition under 21 C.F.R. § 316.3(b)(2); and• the term “authorized for investigation” to mean that the article is the subject of an IND that has gone into effect as described in 21 C.F.R. § 312.4.4AGG Observations• The agency’s current interpretation of sections 301(ll) and 201(ff) is likely based on precedents that are no longer determinative:• Determining an article’s “active moiety” and evaluating its regulatory status relative to sections 301(ll) and 210(ff)(3) is ingredient specific and, oftentimes, is relatively complicated:• FDA’s interpretation of the term “authorized for investigation” may be flawed in that INDs are not authorized by FDA;• The determination of whether an IND exists for a particular article or its active moiety can be difficult, if not impossible, as the general public doesn’t have access to required information; and• Companies should carefully consider the exclusion issue when designing and conducting studies on ingredients or products that may be considered drugs and dietary supplements.[1] See21

To address whether these modifications bar a finding of “same”-ness, the FDA could potentially import the kinds of considerations that govern “same”-ness of other kinds of large-molecule products, such as “polynucleotide drugs” or “closely related, complex partly definable drugs with similar therapeutic intent” (e.g., viral vaccines). See 21 C.F.R. §§ 316.3(b)(14)(ii)(C), (D). However, this is not clear from the Draft Guidance.The Draft Guidance also does not explain what will factor into the “case-by-case” basis assessment of whether viral vectors from the same viral class are the “same.”

FDA’s Orphan Drug RegulationsFDA’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.21 C.F.R. § 316.3(b)(3). FDA has explained in its response granting in part and denying in part a citizen petition (Docket No. FDA-2011-P-0213) that the standard for obtaining designation as a clinically superior drug is different from the standard for obtaining exclusivity:Though the sponsor of a subsequent orphan drug must set forth a plausible hypothesis of clinical superiority over the previously approved drug at the designation stage, such a sponsor faces a higher standard at the time of approval.

Notably, the term “active moieties” is associated with small-molecule drugs, not typically with larger molecules such as biologics. See 21 C.F.R. § 316.3 (14)(i), (ii).In contrast, the Senate bill requires this information for all drugs that “are covered by the same designation” as the § (a)(2)(B) drug. Thus, the House bill’s analogous provision may be more burdensome because it encompasses sales information for each drug with shared structural features, regardless of how closely the drugs are otherwise related.

Therefore, the sponsor has demonstrated that the newly approved dosing regimen is safer than the previously approved dosing regimen, and thus clinically superior for the purposes of orphan-drug exclusivity. 21 CFR 316.3(b)(3), 316.34(c).New clinical superiority determinations will be added as they are made by FDA.