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In the News: July 2021 Regulatory and Development Updates

Each month, Camargo’s “In the News” series highlights important changes and advancements in the regulatory and development space and explores how those changes could impact your program.

Approval of the Month: Repurposed Transplant Drug Approved Based Only on Real-World Evidence

In July, Astellas Pharma US received FDA approval for the use of Prograf (tacrolimus) capsules, injection, and oral suspension for the prevention of lung transplant rejection. Notably, the approval was based solely on the use of real-world evidence (RWE) – a retrospective analysis of existing data.

Prograf was originally approved in 1994 to prevent organ rejection in patients receiving liver transplants, based on the traditional two randomized, open-label, active control trials. The product was later approved to prevent organ rejection for heart (2006) and kidney (2009) transplants, the latter based on a single prospective clinical trial. In short, the entire regulatory history of tacrolimus until now, spanning 25+ years, has been based on prospective clinical trials. This prospectively developed comparative evidence was used to great advantage by Astellas as RWE in its submission for this new approval.

Astellas also used outcomes data collected on all lung transplants in the US from the Scientific Registry of Transplant Recipients (SRTR) as well as information from the Social Security Administration’s Death Master File as a trusted repository of mortality data. These data were used to create a statistical comparison of lung transplant patients taking tacrolimus versus transplant patients with the well-documented natural history of taking no or minimal immunosuppressive regimens.

As Camargo has discussed before, a key to successfully using RWD and RWE is the availability of a credible, reliable natural history. In this case, the SRTR, while administered by a third party, has oversight by the U.S. Department of Health and Human Services.

The FDA took advantage of this new approval to show how RWE can be used in lieu of prospective studies: “This approval reflects how a well-designed, non-interventional study relying on fit-for-purpose real-world data (RWD), when compared with a suitable control, can be considered adequate and well-controlled under FDA regulations.”

FDA Inspections Ramping Up?

The House Committee on Energy and Commerce recently sent a letter to the FDA (specifically Acting Commissioner Janet Woodcock) asking for information regarding the re-initiation of inspections at FDA-regulated sites. Though domestic inspections resumed in July, hundreds of drug plant inspections must be cleared that have piled up in the FDA backlog during the COVID-19 pandemic.

Over about three pages, 13 questions were posed. Dated July 22, the letter requested a response from the FDA by August 5, and many of the questions were rather pointed, for instance:

How many New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologics License Applications (BLAs) have received complete response letters since March 10, 2020, citing a deficiency in the application related to FDA’s inability to conduct a preapproval inspection, a surveillance inspection, or a requested reinspection of a facility following a notice of Official Action Indicated (OAI)? Please also provide information regarding whether inspections related to such applications were for foreign or domestic drug manufacturing facilities.

A number of Camargo clients are stuck in situations similar to this, with such inspections being the only remaining hurdle before their products are approved. Will this congressional scrutiny move in-person inspections forward or prompt the FDA to rely more on alternative or remote inspection options? Stay tuned.

FDA Provides Answers to FAQs on Field Alert Reports

No sponsor is eager to submit a Field Alert Report (FAR). But, when they become necessary, it is important that FARs be done correctly. A new guidance titled “Field Alert Report Submission Questions and Answers provides useful specifics for dealing with and submitting FARs. Regulations require that a FAR be submitted for a distributed product within three working days of receiving one of the following:

  • Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article.
  • Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specification established for it in the application.

The guidance describes initial, follow-up, and final FARs, which should be submitted on FDA Form 3331a. It also lists a series of frequently asked questions—for example, “Does every consumer or other customer complaint warrant submission of an FAR?” (The answer: No.) The document also outlines the correct mechanics for submitting a FAR and emphasizes several times the importance of complying with the three-working-day requirement, offering a detailed explanation of how to calculate the period (Question 3a).

A potential FAR situation cannot be taken lightly, and the guidance provides some useful direction. Camargo is always available to help navigate difficult situations like these with sponsors.

Filing Submissions in an “Alternate” Format

Although the deadline requiring that NDAs, BLAs, ANDAs, DMFs, and commercial INDs be submitted in eCTD format has come and gone, there are situations in which a sponsor may be exempt from the requirement or receive a waiver from the FDA. In a brief guidance titled “Providing Regulatory Submissions in Alternate Electronic Format,” the FDA lays out the formatting specifics for sponsors with an exemption or waiver for their submission.

In short, the submission should still be electronic and in basically the same format as typical submissions are in, but without the Extended Markup Language (XML) “backbone” that gets installed via eCTD software. The folder structure, granularity, file formats, datasets, etc. should be constructed as they are for a typical eCTD, and submissions 10GB or smaller should go through the Electronic Submissions Gateway (ESG). Camargo has a high level of expertise in developing and transmitting both conventional and alternate submissions.


Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President, Regulatory Operations