FDA Draft Guidance Looks to Help Speed New Generics to Market
The blitz of new US Food and Drug Administration (FDA) guidance (11 draft and final documents in the last three days) continued on Friday with the release of a draft helping to clarify for generic drug companies how to define and use several terms, and new ways to expedite generic approvals.
In a shift in direction for the agency, and in order to speed the availability of generics, FDA “now will approve a generic drug for which it has made a final determination that the [reference listed drug] RLD was not withdrawn from sale for safety or effectiveness reasons even if that determination has not yet published in the Federal Register, and will proceed with Federal Register publication as expeditiously as is practicable.”
The agency goes on to define a “reference standard” as the drug product selected by FDA that an applicant seeking approval of an abbreviated new drug application (ANDA) must use in conducting a required in vivo bioequivalence study.
“Now FDA also will consider selecting a new reference standard when the Agency determines that the quantity of the current reference standard in distribution is so limited that a potential ANDA applicant is not able to obtain a sufficient quantity for in vivo bioequivalence testing (even if the current reference standard is not in the Discontinued Section of the Orange Book),” the draft says.
In light of confusion over what RLD, reference standard and basis of submission mean, the agency also offers explanations for all three and the discontinued marketing of many approved drug products and FDA’s identification of reference standards with the RLD symbol (“+”) in the print version of the Orange Book, and under the “RLD” column in the electronic version.
FDA also notes that when an applicant has mistakenly identified the reference standard as the RLD on FDA Form 356h or elsewhere, the applicant “may submit an amendment to a pending ANDA or a supplement to an approved ANDA to correct the information. FDA considers this error to be a deficiency related to identification of the appropriate listed drug as the RLD, rather than a change in the RLD itself. The cover letter for such a submission should clearly identify that the purpose of the submission is ‘Correction of RLD information.’”
The agency looks to dispel other misconceptions, noting that the “common practice for some stakeholders to refer to some generic drugs that are reference standards as second RLDs" is not accurate. "For example, FDA often receives citizen petitions requesting designation of a second RLD, when in fact the petition is requesting that FDA select a new reference standard.
"In addition, ANDA applicants mistakenly have compared their proposed generic drugs to a reference standard to meet requirements for approval other than in vivo bioequivalence," FDA explains. "While the reference standard is selected by FDA for the purpose of conducting any in vivo bioequivalence studies required for approval, an ANDA applicant must demonstrate that its proposed generic drug meets the sameness requirements in section 505(j) of the FD&C Act [Food, Drugs & Cosmetics Act] and Agency regulations in relation to the RLD. Accordingly, an ANDA’s proposed labeling and formulation must be compared to the RLD, and not the reference standard, and the applicant must address any unexpired patents and exclusivity for the RLD as required."
The guidance also explains the “Basis of Submission for an ANDA for a Generic Drug that is the Same as its RLD,” “Basis of Submission for First Petitioned ANDA,” and “Basis of Submission for a Generic Drug that is the Same as a Drug Product Approved in a Petitioned ANDA.”
Referencing Approved Drug Products in ANDA Submissions: Draft Guidance for Industry