Emergency Use Authorization to Full Approval—Charting a Course in Unexplored Territory
Part 2: Demystifying the 505(b)(2) Route for Drug Approval
David L. Rosen
Foley & Lardner LLP
J. Shawn Roach
Halloran Consulting Group

n Part 1 of this two-part series on “Emergency Use Authorization to Full Approval—Charting a Course in Unexplored Territory,” we outlined the pathway to bring a novel therapeutic from Emergency Use Authorization (EUA) to Full Approval. In Part 2, we demystify the 505(b)(2) route for drug approvals and provide key considerations if your organization is considering this pathway to develop a therapeutic to respond to the current public health crisis.

Despite challenging years due to COVID-19, 11 EUAs were granted for COVID-19 therapeutics. Out of the 11 EUAs, several are not novel molecular/biological entities but instead are previously approved drugs which are being repurposed with a new indication. These repurposed drugs, which have been granted EUAs, had been previously approved as either arthritis treatments or anesthetics. These drugs had shown promise either through action against similar biochemical pathways as those caused by COVID-19, or as safe longer-term anesthetics for those who had to be placed on ventilators while battling the disease.

The 505(b)(2) regulatory pathway provides applicants a process to obtain approval of new chemical entities (NCEs) or to make changes to existing drug products without having to repeat all the nonclinical and clinical underlying data that supports a product’s safety and effectiveness. This can be an attractive route for drug developers responding to the current public health crisis, as there are clear benefits in expediting the process of development.

The 505(b)(2) pathway has been utilized to support the approval of many products, including COVID-19 therapeutics. Companies should understand the 505(b)(2) submission and approval requirements to use this regulatory pathway efficiently and effectively. Approximately 60% of the New Drug Applications (NDAs) approved in 2020 were submitted via the 505(b)(2) pathway.

Types of New Drug Applications

Section 505 of the Federal Food, Drug, and Cosmetic Act (the “FD&C Act”) describes three types of new drug applications: Section 505(b)(1)—full, novel application; Section 505(b)(2)—application which relies upon previously reviewed and approved information in addition to novel information specific to the new indication; and Section 505(j)—application which shows the drug is identical in composition and action to a previously approved drug (Abbreviated New Drug Applications, or ANDAs).

It is also important to note that a supplement to an application is also considered to be a new drug application.

The Genesis of the 505(b)(2) NDA

The 505(b)(2) NDA roots were in the FDA’s Paper NDA policy. When the Paper NDA policy came about, ANDAs were limited to drug products that were approved prior to 1962 and that were safe and effective. Under FDA’s Paper NDA policy, the requirement that an NDA contain full reports of investigations to demonstrate safety and effectiveness could be satisfied through the summary of publicly available literature reports. These reports did not have to be conducted by or sponsored by the applicant and could be the sole basis of safety and efficacy that would support FDA approval. An applicant under FDA’s Paper NDA policy was required to compile and summarize the nonclinical and clinical literature to support a decision by FDA that the proposed drug product was safe and effective.

With the passage of the Drug Price Competition and Patent Term Restoration Act (the “Waxman-Hatch Act”), the ANDA process was opened up for products originally approved for safety and effectiveness after 1962. The Waxman-Hatch Act included the provision for 505(b)(2) NDAs. The 505(b)(2) pathway is now an appropriate regulatory pathway for the approval of several drug products.

The 505(b)(2) Pathway in 2020 and 2021

Use of the 505(b)(2) pathway for new indications, such as the treatment of COVID-19, is attractive when the safety profile of the proposed drug is well established. Additional work is typically required to ensure the safety profile is maintained as well as the demonstration of efficacy. However, the established history gives development a significant head start.

Types of Products That May Be Submitted Under Section 505(b)(2) Under the FD&C Act

Through the 505(b)(2) regulatory pathway, an applicant may develop and seek FDA approval without performing all the nonclinical and clinical studies required for approval of an NDA submitted under Section 505(b)(1) of the FD&C Act. These drugs are not strictly generics but are often not entirely novel new molecular entities either. 505(b)(2) can be an option for drugs with a new aspect related to indication, dosage form or regimen, strength, combination with other products, or other unique traits. Unlike an ANDA, the 505(b)(2) pathway does not convey that the products are the same as a reference product.

FDA guidance provides information on the types of products that can be submitted under Section 505(b)(2) under the FD&C Act. These products include new chemical entities, new molecular entities, and changes to a previously approved drug. Such changes include, among others, changes in dosage form, routes of administration, strength, changes in an active ingredient in a combination product, formulation, indication, and Rx-to-OTC switch.

Information Upon Which an Applicant Can Rely in a 505(b)(2) NDA

An applicant may rely on published literature. If the applicant did not conduct the study(s) or has not obtained a right of reference to the raw data underlying the published study or studies, the application may be submitted as a 505(b)(2) NDA.

An applicant for a 505(b)(2) NDA may rely on the agency’s previous finding of safety and/or effectiveness for a change in an approved drug, according to 21 CFR 314.54. The reliance is primarily limited to information contained in the FDA-approved labeling of the listed drug.

Insight on Using the 505(b)(2) Pathway for Developing COVID-19 Therapeutics

In Halloran Consulting Group and Foley & Lardner’s experience, the 505(b)(2) pathway can be used to develop therapeutics for treating COVID-19. Over the last 18 months, some firms have prepared and submitted pre-IND meeting requests that outline the proposed development program for: (1) new molecular entities; (2) repurposed approved drugs changing the indication, dosage form, dosage regimen, or route of administration; and (3) botanical products all seeking to ultimately submit an NDA through the 505(b)(2) process.

Similar to developing novel treatments for COVID-19 during the current public health crisis, getting feedback on your 505(b)(2) development program from FDA through the pre-IND process is quite advantageous. Since most 505(b)(2) applications are hybrids relying on published literature, FDA’s approved labeling for the reference listed drug, and studies conducted to bridge the information and data necessary to support the changes proposed in the application, it is strongly recommended that these issues be discussed in a pre-IND meeting.

Our experience submitting pre-IND meeting requests for the types of COVID-19 therapeutics described above is that FDA is receptive to applicants ultimately submitting 505(b)(2) NDAs for the products. While the 505(b)(2) pathway is a viable option for these products, FDA has requested a significant amount of nonclinical data to bring the pharmacological and toxicological data up to today’s standards and requests a significant amount of bridging clinical studies to support labeling for COVID-19 therapeutics. We strongly recommend engaging with FDA early in the process, so that companies can gain an understanding of FDA’s expectations on the data requirements and plan their COVID-19 drug development program.