FDA Issues Draft Guidance Clarifying When to Submit an ANDA Versus a 505(b)(2) Application

The US Food and Drug Administration (搜索)搜索该词条 (FDA) has updated its seven-year-old guidance to clarify the differences among abbreviated approval pathways and the data it will accept for these applications. These pathways include the traditional Abbreviated New Drug Application (ANDA) process under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the 505(b)(2) pathway.

"Many potential drug product developers are not familiar with the different abbreviated approval pathways for drug products under the FD&C Act described in sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(b)(2), respectively) or the types of data and information that are permitted to support approval under those pathways," states a notice announcing the guidance.

The draft guidance replaces a former version issued in May 2019. The agency notes that "changes from the 2019 version include providing additional information on duplicates and eligibility for approval under section 505(j) of the FD&C Act, as well as other updates that are intended to clarify FDA's recommendations to industry."

Four Categories of Applications

In the guidance, FDA outlines four different categories of applications. The 505(b)(1) is the stand-alone pathway for new drug applications under section 505(c) of the FD&C Act that requires full reports of investigations of safety and effectiveness for new drugs conducted by or for the applicant or for which the applicant has a right of reference or use.

A 505(b)(2) application is an NDA submitted that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. Drugs that can be submitted through the 505(b)(2) pathway include new versions of approved drugs that differ in the reference listed drug (RLD) in terms of active ingredient, dosage form, strength, route of administration, formulation, or when there is a new indication.

The 505(j) pathway is for a product that is a duplicate of a previously approved drug product. An ANDA relies on FDA's finding that the previously approved reference listed drug (RLD) is safe and effective. An ANDA generally must contain information to show that the proposed generic drug product is the same as the RLD with respect to the active ingredients, conditions of use, route of administration, dosage form, strength, and labeling, and its bioequivalence to the RLD.

A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient, and for which FDA has determined, in response to a suitability petition, that studies are not necessary to establish the safety and effectiveness of the proposed drug product.

Duplicate Drugs and the 505(b)(2) Pathway

One of the most significant updates in the new draft guidance concerns when it is appropriate to submit a 505(b)(2) for a duplicate drug, defined as "a drug product that has the same active ingredient(s), dosage form, strength, route of administration, and conditions of use as a listed drug."

As a general matter, FDA will refuse to file a 505(b)(2) application that is a duplicate of a listed drug and that is eligible for approval as an ANDA. In some instances, the studies typically expected to support an ANDA cannot be conducted because the RLD and reference standard have been withdrawn and there are no other drug products listed in the Active Section of the Orange Book that can be used as a reference standard for that RLD. The updated draft guidance explains that this is not automatic justification for submitting a 505(b)(2) application. Rather, it is recommended that sponsors, with the help of the Office of Generic Drugs (OGD), first consider alternative methods of establishing bioequivalence that are adequate to support an ANDA.

If FDA determines there are no acceptable alternatives to establish bioequivalence between a duplicate and the RLD, circumstances do exist in which submitting a 505(b)(2) application is appropriate. To determine when that is the case, the draft guidance now directs applicants to discuss their proposals with the appropriate review division of the Office of New Drugs (OND). That discussion should explain how the sponsor intends to bridge the proposed drug product to the listed drug, for example, by relying on published literature.

ANDA Waivers for Formulation Differences

The revised guidance also discusses circumstances in which FDA may waive the ANDA formulation requirements for parenteral, ophthalmic, and otic products. This clarifies FDA's pre-existing waiver authority and incorporates the policy set forth in the guidance, Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use.

Under section 505(j), a generic drug generally is allowed to have different inactive ingredients than the RLD. However, FDA regulations state that for some types of generic drugs, such as parenteral, ophthalmic, and otic drugs, sponsors are limited in their ability to make changes to the inactive ingredients of a formulation, and generally must have the same inactive ingredients as the RLD, though may still differ in certain excepted categories of excipients called "exception excipients."

For example, a sponsor of a parenteral product that differs from the RLD in composition of the inactive ingredients would generally be required to submit a 505(b)(2) NDA rather than an ANDA. But in this new guidance, and the previous guidance on waiver requests for pH adjusters, FDA has indicated that it may use its longstanding waiver authority under the regulations (21 CFR 314.90, 314.99(b)) to allow formulation differences outside the traditional exception excipients provided there is suitable justification from the sponsor.

Therapeutic Equivalence Evaluations

The final guidance provides an overview of therapeutic equivalence evaluations, including explaining when FDA evaluates therapeutic equivalence for 505(b)(2) NDA products and assigning therapeutic equivalence (TE) codes in the Orange Book. The guidance also includes a FAQ section.

For ANDA products, FDA assigns TE ratings automatically upon approval. FDA will not routinely conduct TE evaluations for "standalone" 505(b)(1) NDAs or 505(b)(2) NDAs. However, under the statute as amended in 2022, FDA is required at the sponsor's request to undertake TE evaluations for certain 505(b)(2) products — namely, products for parenteral, otic, or ophthalmic administration when the sole difference from the listed drug is a difference in inactive ingredients not permitted under 505(j). Sponsors of 505(b)(2) NDAs may also use the citizen petition process to seek a TE evaluation where the drug product may otherwise meet the requirements for a TE rating while still being ineligible for approval under 505(j).

The guidance also describes differences between the 505(b)(2) and the listed drug that may preclude FDA from making a finding of TE. For example, the final guidance indicates that labeling differences beyond those permitted in an ANDA would generally preclude an A-rating. Similarly, differences in formulation, presentation, or other differences that give rise to a different clinical effect or safety profile when administered to patients under the conditions specified in the labeling may also preclude an A-rating. For example, a difference in the device constituent part of a drug-device combination product may give rise to human factors, useability, and labeling issues that make an A-rating inappropriate.

A principal benefit of an ANDA is to receive an A-rating as therapeutically equivalent in the Orange Book upon approval. With an A-rating, the generic drug product generally would be eligible to be substituted for the RLD at the pharmacy level. Although FDA is not precluded from assigning an A-rating to a 505(b)(2) product if it is pharmaceutically equivalent and bioequivalent to a listed drug, the A-rating is not automatic.

The deadline for submitting comments on the draft guidance is 19 October. Comments should be sent to www.regulations.gov and reference Docket No. FDA-2017-D-5974.