Pharmaceutical companies concerned by US Food and Drug Administration (FDA) actions or decisions have a number of informal and formal ways to get in touch with and file appeals with the agency, two FDA officials told attendees at RAPS’ Regulatory Convergence last month.
The conversation on disputes came as FDA in September further clarified and updated its guidance on how it resolves complicated medical and scientific disagreements between industry and FDA.
On the informal side, Virginia Behr, ombudsman at FDA’s Center for Drug Evaluation and Research (CDER), made it clear that she can offer a confidential and neutral environment for industry to explain its issues with FDA decisions.
In 2014, Behr conducted 322 communications, mostly with industry, on various FDA decisions or response delays, import detentions, implementation of the Generic Drug User Fee Amendments (GDUFA), interpretation of tentative final monographs, inspection report delays and whistleblowers at clinical and manufacturing sites.
Working as the ombudsman since 2007, Behr said a lot of the conflicts that come across her desk are “just misunderstandings,” though she will highlight systemic issues with high-level officials if there are particular concerns. For example, she said she understood there would be negative consequences for some small active pharmaceutical ingredient manufacturers under the first GDUFA, so she “made sure that was on the table for negotiations going forward.”
But before contacting Behr (via email at Virginia.firstname.lastname@example.org) she says to consider the history of the dispute and company culture, as well as working relationships with the agency.
“I work quickly and efficiently – you’ll know quickly if I can help you,” she said.
But what Behr can’t and won’t do for industry includes looking into internal FDA databases and providing information or overturning a decision or action or forcing anyone to do the same. Other processes outside her purview include current good manufacturing practice requirements appeals, import and customs issues, requests for product designations or reconsiderations of such designations, and certain petitions.
If industry does contact Behr (no formal submission is necessary), she said she’ll discuss the history of the complaint, the desired outcome and, if she works on a complaint, she may request documentation or summaries and speak to FDA staff.
Formal Dispute Resolutions
On the other side of the dispute-resolution continuum is Khushboo Sharma, the formal dispute resolution project manager at CDER.
Sharma said upfront that there has to be a regulatory action for a formal dispute appeal to be made. For instance, if a company receives a complete response letter (CRL), has held a meeting with FDA and still isn’t satisfied, “then you can file a formal appeal.” But if it’s a case where a company received a CRL, and there’s a deficiency – additional data cannot be submitted in an appeal and needs to be submitted to the division.
She also laid out a number of considerations industry should consider before submitting a Formal Dispute Resolution Request (FDRR), including:
- Is working informally with the ombudsman more appropriate?
- Have I requested reconsideration of the decision by the division?
- Do I have new information/new analysis of previously viewed information?
- Do I want to request a Type A meeting (to help with an otherwise stalled product) with the deciding official of the FDRR?
- Do I want to request that the scientific matter be reviewed by an advisory committee?
In FY 2014, 29 FDRRs/appeals were submitted to CDER and Sharma noted that that number has continued to rise since 2012.
However, although the vast majority of appeals are accepted for review (81%), the overwhelming majority are later denied. Between FY 2011 and 2014, just five appeals were granted while 55 were denied.
Process for FDRRs
If an FDRR is submitted for an investigational new drug application, a biologics license application or a new drug application (which includes nearly 90% of all FDRRs filed) FDA has to respond to 90% of requests within 30 calendar days of the receipt of the FDRR under the Prescription Drug User Fee Act (PDUFA) and Biosimilar User Fee Act (BSUFA).
But for generic drug companies, FDA says it “aspires” to provide a response within 30 days of receipt of the dispute when possible. And if it’s a non-user fee product, Sharma said FDA will try to respond as quickly as possible.
Once a sponsor submits an FDRR, the sponsor is notified in writing of whether it’s accepted or not by the deciding official, and if accepted, FDA will say whether it can respond within 30 days.
If a sponsor submits a dispute resolution request and a Type A meeting request and the meeting is granted, it will be held in 30 days. A final response on the FDRR will then be sent 30 days from the meeting date.
In some cases, Sharma noted, FDA may issue interim responses for additional clarifying information, or FDA would like to request a meeting, or FDA requires limited discussion with one or more advisory committee members or internal/external experts.
If an FDRR is denied, often in the denial letter, an alternative path forward is provided, she added.
“Or you can appeal to the next management level – Office to Super Office to Center and then FDA Commissioner,” Sharma said. “Usually there is an alternative path forward that’s provided or a compromise is made where the appeal does not need to be made at the next level of FDA.”