FDA’s Office of Generic Drugs will begin in January 2012 to routinely issue complete response letters for generic drug applications that complete the review process but cannot be approved or tentatively approved.

The CRLs will provide sponsors with a clear report on an application’s deficiencies, OGD Acting Director Keith Webber told the Generic Pharmaceutical Association’s fall technical meeting Oct. 5.

Sponsors can then “send in a single submission to address all those, and if addressed appropriately, [there] should be a two-cycle review … and approval process,” he said.

OGD operates under two sets of regulations for communicating with sponsors. One governs CRLs, an end-of-review communication tool, while the other allows reviewers to ask questions that can be answered easily while the review is being conducted.

OGD will balance the two approaches, Webber assured attendees. “Minor bits of information that need to be changed” are examples of early information requests that will be pursued, Webber said.

But as the review progresses and reviewers in the various disciplines complete their assessments and find stumbling blocks to approval, the CRL provides the opportunity to give sponsors clarity and transparency on what the issues are and the status of their applications, he pointed out.

CRLs A Metric In Meeting User Fee Goals

OGD has written complete response letters “relatively infrequently” in the past, Webber noted. “We haven’t used them as much as we could.”

Now, an incentive for their use is the agency/industry agreement on generic drug user fees (Also see "ANDA User Fee Negotiations Finished; Backlog To Be Mostly Cleared By Year Five" - Pink Sheet, 12 September, 2011.).

That agreement requires FDA to show that it is meeting specific timelines for reviewing ANDAs.

To do that, it needs to be “very clear that we reach an endpoint, one way or another, on an application within a given amount of time,” Webber explained. FDA must have an organized system to measure its performance and CRLs are a crucial component of such a system, he added.

If OGD currently sent more complete response letters, the backlog of ANDAs awaiting FDA action – now about 2,000 awaiting approval – would not be as imposing, Webber implied.

“There are a lot of applications that are in the hands of the sponsors, not in our hands,” he pointed out. “We count them towards the queue because we really don’t have the tools in our database management system in order to segregate those out easily.”

That will change with the coming of complete response letters, as FDA will have a mechanism to move ANDAs to a new category: those for which the agency is awaiting sponsor action in order to continue a review.

The plan to begin issuing a complete response, approval or tentative approval letter for all ANDAs in January gives FDA a head start on this portion of the generic drug user fee program, which Congress is expected to approve for launch in fiscal year 2013, which begins Oct. 1, 2012.

The push for CRLs nine months early “will give us an opportunity to start at a point as applications pick up, … really focusing on moving them to a point of clear response to industry of what the deficiencies are,” Webber said.

An aid to help reviewers develop CRLs and meet the GDUFA goals is a Review Flow System being implemented by OGD. This system tracks the application throughout the review cycle by the various disciplinary teams.

“It will certainly help us as we move forward in establishing complete response letters so we know, really, is the review complete across the office, or where we need to focus getting the review to completion,” Webber said.

The goal of the system is “essentially moving things along within the office, make the flow smoother as the applications move from review to either approval, tentative approval, or complete response,” he said.

Biannual Inspections On Horizon

Webber also reported that OGD is transitioning to a biannual surveillance inspection process for generic drug manufacturing sites.

The benefit for ANDA sponsors will be to eliminate the need for a pre-approval inspection for listed manufacturing sites that are existing facilities and already have been inspected, Webber explained.

This will “make everyone’s life quite a bit easier, at least in terms of uncertainty about when any inspection is scheduled and whether or not it’s going to meet the timelines for approval progress that you have,” he said.

The GDUFA agreement does not call for inspection fees per se, although they were discussed early on during negotiations.

However, Gordon Johnston, GPhA senior advisor for regulatory sciences, recently told a Senate committee that the performance goals will result in 40% to 50% of the generic drug user fees going toward inspections (Also see "Inspection Fees For Drug, Ingredient Manufacturers Could End Up In PDUFA, Sen. Harkin Says" - Pink Sheet, 14 September, 2011.).

With regard to the fees themselves, Webber told the conference that FDA is still assessing how to handle ANDAs for which sponsors fail to submit a one-time backlog fee (see related story, Also see "ANDA Backlog Fee Non-Payment: FDA Will Weigh Fairness Vs. Public Health" - Pink Sheet, 10 October, 2011. ).

By Cathy Dombrowski

ANDA Complete Response Letters To Become Routine In 2012

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