|Footnotes for this article are available at the end of this page.
Last month, the Food and Drug Administration’s Office of Orphan Products Development (“OOPD”) found that one prescription drug company was able to, essentially, breach another’s orphan drug exclusivity (and have its new drug application approved) and obtain its own orphan drug exclusivity.1 FDA’s interpretation and exclusivity of the orphan drug rules continues to evolve.
This Bulletin will summarize many of the highlights of FDA’s decision and offer our own observations. Previous AGG Bulletins have described orphan drug laws in detail.2
- The 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 condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.”
- Section 527(c)(2) of the FDC Act defines “clinically superior” to mean that “the drug provides a significant therapeutic advantage over and above an already approved or licensed drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care [‘MCTPC’].”
- FDA’s regulation defines “clinically superior” as follows:
Clinically superior means that a drug is shown to provide a significant therapeutic advantage over and above that provided by an approved drug (that is otherwise the same drug) in one or more of the following ways:
(i) Greater effectiveness than an approved drug (as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs; in most cases, direct comparative clinical trials would be necessary; or
(ii) Greater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects. In some cases, direct comparative clinical trials will be necessary; or
(iii) In unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care.
- In both the statutory and regulatory definition, the subsequent drug must provide a significant therapeutic advantage “over and above” an already approved drug in only one way — greater efficacy, greater safety, or by providing a MCTPC — to be considered clinically superior.
- There is no additional requirement that, to provide a significant therapeutic advantage in one of the three measures, the drug must also be at least comparable in the other two areas.
- In this case, the agency noted that section 527(c) only relates to potential eligibility of a subsequent drug for its own period of ODE. It does not address whether a subsequent drug’s approval is blocked by another drug’s ODE, even if there is a clinical superiority determination.
- It reiterated that section 527(a) relates to the blocking effect of ODE of a previously approved drug.
- FDA’s regulation defines “same drug” to mean, in relevant part, “a drug that contains the same active moiety as a previously approved drug and is intended for the same use . . . except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.
- The “same drug” definition has a chemical and clinical component.
- In the 1992 Final Rule for the orphan drug regulations, FDA said that “two drugs would be considered the same drug if the principal, but not necessarily all, structural features of the two drugs were the same, unless the subsequent drug were shown to be clinically superior” and that “either differences in active moiety or clinical superiority will be sufficient to make two micromolecular drugs different.”
- If the sponsor of the subsequent drug for the same indication or use can demonstrate that its drug has a different active moiety or is clinically superior to the first drug with ODE, the subsequent drug is not the “same drug” as the drug with ODE and, therefore, that first drug’s ODE will not block approval of the application for the same indication or use.
- To recap, whether a first drug’s unexpired ODE blocks approval of subsequent drug, FDA reviews the following:
- If the subsequent drug contains the same active moiety for the same indication or use as the drug with an unexpired ODE, FDA will evaluate whether the subsequent drug is clinically superior to the drug with ODE.
- If it is clinically superior, the subsequent drug is not the “same drug” and, therefore, FDA can approve the second drug for the same indication or use.
- On the other hand, whether a subsequent drug with the same active moiety for the same indication or use as a previously approved drug is eligible for its own term of ODE (section 527(c)), FDA compares the subsequent drug to all such previously approved drugs, even if ODE for those drugs has expired if the subsequent drug is clinically superior to each, it is eligible for its own ODE term.
Applicability to Specific Case
- FDA said the second drug was clinically superior to the other approved products, so it was eligible for its own ODE term.
- The agency said the drug could demonstrate a MCTPC over a previously approved drug, even if the drug is not as effective or safe in every respect as the previously approved drug.
- There was a MCTPC because the drug provided a once-nightly dosing regimen that avoids a nocturnal arousal to take a second dose, which is a notable benefit for patients with known sleep disorders.
- FDA said the formulation made the product more convenient for patients, an advancement in the ease of drug administration, and a reduction in treatment burden.
- FDA acknowledged the second drug’s safety concern, but said neither the statute nor its regulations require a MCTPC to benefit the entire patient population for which a drug is intended.
- Comparative trials are not required for a demonstration of MCTPC.
- The regulatory definition of “clinically superior” notes that demonstrating greater effectiveness requires direct comparative clinical trials “in most cases,” and that demonstrating greater safety requires direct comparative clinical trials “in some cases.” However, there is no similar language requiring comparative trials for a MCTPC.
- Types of factors that FDA considers when determining MCTPC (e.g., 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) are not typically studied in a clinical trial for marketing approval.
- FDA said that finding clinical superiority based on one significant advantage to patients, even if the drug is less safe, does not undermine the value of the ODE incentive.
- The agency believes that the ODE incentivizes “the development of better versions of drugs for the treatment or prevention of rare diseases or conditions.”
- The new drug’s safety standard is not to be as safe as the previously approved drug, but to meet FDA’s approval standards for safety.
- In the recent decision, FDA explained its interpretation of ODE requirements, particularly as it relates to “clinically superior” and ODE eligibility.
- The decision reiterates FDA’s aim to incentivize new product development, even if innovators with existing exclusivities view this as a loss of their protection.
- We believe FDA will continue to look for opportunities (or be forced) to further clarify its implementation of the orphan drug rules, as court and citizen petition challenges continue.
- There are many nuances in understanding ODE rules, so companies looking to develop orphan drugs should constantly stay updated on the latest. To continue the sunrise theme, as Sir Elton John sang, “Don’t let the sun go down on me” (or you).
 Access the decision here: https://www.fda.gov/media/168376/download.
 Access previous AGG Bulletins about these developments here: https://www.agg.com/news-insights/publications/orphan-drug-company-refuses-to-take-it-easy-and-prevails-in-court-case-against-fda-relating-to-orphan-drug-exclusivity/; https://www.agg.com/news-insights/publications/the-sun-will-come-up-tomorrow-or-will-it-fda-issues-notification-about-orphan-drug-exclusivity-in-light-of-recent-court-decision/.