FDA To Provide Expedited Approval Desktop Reference

Comprehensive guidance document is expected to describe FDASIA changes and clarify terms that have become confusing as more pathways emerge to speed drug approvals.

FDA expects to write one comprehensive guidance explaining its expedited approval programs to eliminate confusion and more easily meet some of the requirements of new user fee legislation.

In addition to explaining new pathways, like the breakthrough therapy designation, the guidance will serve as a desktop reference guide of sorts – more clearly defining the existing programs and ensuring their differences are clear.

The guidance should outline how expedited approval pathways function, such as priority review, rolling review and fast-track designation, as well as describe expectations for the new breakthrough designation and plans for expanding accelerated approval triggered by the FDA Safety and Innovation Act.

John Jenkins, director the Center for Drug Evaluation and Research’s Office of New Drugs, said many of the pathway descriptions use the same terms, which is creating problems.

How Confusing Does It Get?

The overlapping definitions of fast track, accelerated approval and priority review are highlighted in an explanatory page on FDA’s website, which notes that “because each of these approaches implies speed, there can be confusion about the specific meaning of each and the distinctions among them.” While the programs have clear differences, the terms used in their definitions aren’t as distinct.

• Fast Track: A process for facilitating drug development that can begin early in development, and is a prerequisite to submitting a rolling NDA or seeking accelerated approval. To qualify, drugs must treat serious diseases and fill an unmet medical need.
• Accelerated Approval: A pathway for earlier approval of drugs to treat serious diseases and that fill an unmet medical need based on a surrogate endpoint that is correlated with a clinically meaningful outcome, which must be verified in post-market trials.
• Priority Review: A shortened review period given to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. It can apply to drugs for treating serious diseases and for less serious diseases. Under FDASIA the review time is eight months versus 12 months for standard review; previously the clock was six months versus 10 months.

“We’re rolling them all together [into one guidance] because there is so much confusion on all the expedited programs,” Jenkins said following an Oct. 22 presentation during a conference on rare diseases sponsored by the Drug Information Association and the National Organization for Rare Disorders. “The idea is to clarify the pathways so [sponsors] can use them appropriately.”

The guidance may be as much for FDA’s benefit as it is for sponsors. With so many different, and potentially conflicting, systems that can speed an approval, reviewers and regulatory staff on both sides likely need a handy manual to help them determine the best route for an application.

Jenkins said he expected the comprehensive expedited approval guidance to meet the related guidance requirements in the statute.

Not only did FDASIA reauthorize the prescription drug and medical device user fees and create new programs for generics and biosimilars, it also included policy changes from Congress intended to make drug development faster and simpler – and charged FDA with drafting guidance to clarify the new programs (Also see "FDASIA Is Signed, Not That White House Wanted Anyone To Notice" - Pink Sheet, 16 Jul, 2012.).

Breakthrough Description Expected

Perhaps the most important part of the guidance will be FDA’s explanation of how it will administer the breakthrough program.

The breakthrough therapy designation was included in the statute for drugs showing a dramatic improvement over existing therapies.

It could be the most original change among the drug development items, but it is also most in need of clarification.

Breakthrough designation would allow sponsors to work with FDA to design smaller and/or abbreviated clinical trials, among other advantages (Also see "“Breakthrough” Designation Another Harmonization Opportunity, Woodcock Says" - Pink Sheet, 9 Apr, 2012.).

Given the expedited nature of the program, a more detailed description of it likely will be in the expedited approval guidance.

Jenkins said FDA is already reviewing several breakthrough requests, but also has decisions to make about program function, since it is expected to draw investor attention to the sponsor.

He said the breakthrough standard should be a high bar (Also see "Industry Wants A Breakthrough Therapy, Even Without All The Standards" - Pink Sheet, 29 Oct, 2012.).

FDA Will Detail How Accelerated Approval Will Be Expanded

The guidance may be a key step in the agency’s efforts to expand the use of accelerated approval, another requirement in FDASIA. Much of the language in the legislation was a restatement of what FDA already had codified in regulations, but there were sections intended to promote its use (Also see "TREAT Act Wants Accelerated Approval Change, But Uses Existing Language" - Pink Sheet, 20 Feb, 2012.).

A common view had been that the pathway was largely only available for cancer and HIV therapies, when in reality it can be used for other drug classes.

The legislation said the agency should work harder to promote its use outside those areas, including sending more information about the program to physicians, advocacy organizations and pharmaceutical companies. The agency also has to encourage development of biomarkers and surrogate endpoints that could help accelerated approval applications.

The statute requires the agency to issue draft guidance by July 2013 outlining how those changes will be made. The document must specifically consider rare disease issues related to the accelerated approval and fast track pathways and include novel approaches to surrogate endpoint review.

Rare disease advocates believe the accelerated approval expansion could help spur orphan drug development, in part by clarifying surrogate endpoints that would be accepted for approval (Also see "PDUFA V: Accelerated Approval Expansion May Outshine Rare Disease Improvements" - Pink Sheet, 17 Sep, 2012.).

Final guidance is due one year after the draft is issued and comments are received.

Jenkins would not say when the comprehensive draft guidance would be issued, but it seems that July 2013 may be the target date, since FDASIA requires the accelerated approval draft guidance to be issued about that time. The breakthrough draft guidance is due six months later.

While pulling the various guidance requirements together may be an efficient way to meet statutory requirements, there are potential pitfalls in creating an all-encompassing document. FDA infamously labored on a proposed rule covering many aspects of safety reporting, known as “The Tome” because of its size, for seven years, before ultimately splitting it up (Also see "FDA IND Safety Reporting Rule: New Types Of Data Must Be Submitted" - Pink Sheet, 4 Oct, 2010.).