ANDA Refuse-to-Receive Challenges Become More Common – And More Successful

Teva official calls for improved staff consistency as a new GDUFA headache emerges for FDA.

FDA’s inconsistency in judging whether ANDAs are suitable for review may be creating more work and slowing the operation, in addition to angering sponsors.

Refuse-to-receive actions, which allow FDA to return an application because it is substandard or missing critical elements essential for a review, are being rescinded at a relatively high rate.

Scott Tomsky, Teva Pharmaceutical Industries Ltd. VP of generic regulatory affairs North America, said half of all refuse-to-receive (RTR) challenges are successful.

A number of factors appear to be contributing to the situation. Tomsky said it does not appear that agency subject matter experts are consulted for the filing review and comments from staff are inconsistent.

In some cases, the requested data were included in the original application filing, but the reviewer overlooked it and gave the refuse-to-receive action.

“I think it really throws into question the training and the need for more and more training with regard to filing reviewers,” Tomsky said during the Generic Pharmaceutical Association CMC Workshop in June.

“Making sure that all reviewers, filing reviewers, are on the same page and working from the same standards will just help industry derive consistency from application to application because it’s difficult for industry to know what are the must-haves versus the preferences from one filing reviewer to another.”

While the RTR inconsistency is troubling, it also likely is not surprising, given FDA’s hiring spree to expand its generic drug and related staff to handle its new responsibilities under the generic drug user fee program.

More than 1,000 new people have been hired by FDA since fiscal year 2013 for GDUFA purposes, well above stated hiring goals (Also see "FDA’s Generic Drug Staff To Be Reduced When Workload Under Control" - Pink Sheet, 20 Jan, 2015.).

Consistency Not A New Concern

Reviewer consistency has been a concern of the generic industry for some time. GPhA asked during a June public hearing that GDUFA research dollars be used to analyze it across disciplines.

And the lack of consistency, at least within the filing review function appears to be creating more work for the agency.

“The rescission process involves concurrence and documentation clearance from [the Division of Filing Review], OGD Policy and other experts to ensure consistency,” FDA told "The Pink Sheet." “The volume of rescission requests received during FY 2015 has proven to be onerous for the Center.”

Sponsors should send requests for reconsideration or clarification of an RTR to [email protected].

As word of the success rate for RTR challenges spreads, sponsors may be more likely to try it, requiring more staff time within the Office of Generic Drugs to be devoted to it rather than other tasks.

FDA would of course rather focus on approvals, which have undergone a surge after several lean months (Also see "ANDA Approvals Strong Again; Has FDA Turned The Corner?" - Pink Sheet, 8 Jul, 2015.).

RTR Actions Increase During GDUFA

OGD tightened its filing review standards as part of GDUFA.

Agency officials wanted to end the practice of sponsors submitting an incomplete ANDA and then adding the necessary items to it while it was under review.

Refuse-to-receive actions have increased steadily each year since GDUFA launched. The agency had issued 134 refuse-to-receive actions in FY 2015 by the end of May, which is ahead of the pace seen the previous two fiscal years (see chart).

The current agency output could result in more than 200 RTRs issued by the end of the fiscal year.

Refuse-To-Receive Actions
Fiscal Year	October-May Total	Annual Total
2013	80	150
2014	121	173
2015	134	N/A
Source: FDA Office of Generic Drugs activity data

FDA said it is still verifying data on the number of RTR challenges it has received in FY 2014 and FY 2015.

Final guidance on OGD’s refuse-to-receive standards states sponsors can respond to up to 10 minor deficiencies within a specific time without losing their original receipt date (Also see "ANDAs Get More Time – Or Maybe Less – To Correct Minor Deficiencies" - Pink Sheet, 17 Sep, 2014.).

The practice is intended to help cut the number of review cycles required for an ANDA approval as well as the average time to approval.

Most ANDAs need two to five review cycles before they are cleared, according to FDA data (Also see "FDA ‘Real-Time’ Communications Deemphasize Phone Calls" - Pink Sheet, 9 Dec, 2014.).

More Communication Would Help

Tomsky argued the problem with RTRs and challenges has to do with communications between the agency and sponsors.

There is less communication now than before GDUFA, but more RTRs. The perception is that FDA is forbidden from sharing information, Tomsky said, and a number of issues could be resolved if the reviewer checked with the sponsor before sending an RTR letter.

“I think some RTRs may be avoided with better communications, maybe a phone call,” he said.

Many in industry feel that FDA is using a “check-the-box filing determination,” Tomsky said. And deviations from the checklist can lead to filing review comments or an RTR.

Sponsors have not been able to gain much information when checking on the status of an ANDA undergoing filing review. Tomsky said often it is a scripted email.

He said industry wants FDA to institute a policy detailing how filing reviewers consult other divisions and offices and training for them to talk with sponsors before finalizing a filing review decision.

OGD already has made a number of communication changes in part to give industry a better sense of where applications are in the review process.

Agency officials have started assigning target action dates to applications that do not have formal review goals, among other things (Also see "FDA/Generic Communications Plan Restoring Best Of Past Practices" - Pink Sheet, 18 Dec, 2014.).

The issues also likely will be discussed during GDUFA II negotiations, which are set to begin in a few months (Also see "GDUFA II Negotiations: Contract Manufacturers Gain Seat At Table" - Pink Sheet, 6 Jul, 2015.).