Few things can be more damaging to a pharmaceutical company than the refusal by the Food and Drug Administration (FDA) to review their New Drug Application (NDA) or Abbreviated New Drug Application (ANDA). When a company submits their application for authorization to market a new or generic drug and receives a Refusal to File (RTF) or Refusal to Receive (RTR) letter from the FDA, the damage to the company’s credibility and finances can be irredeemable. The irony is that such a situation is most often completely avoidable.

The Details of a Refusal to File and Refusal to Receive

When the FDA receives an application for a new drug or a new generic drug, the reviewing division must first make a decision if the application is complete enough for a substantive review. If the agency determines that the application is too deficient, it can simply refuse to review it. For new drugs, either new chemical entities under the 505(b)(1) procedure or new versions of old drugs under the 505(b)(2) procedure, the FDA will issue a Refusal to File (RTF) letter to the company. For generic drugs, under the 505(j) procedure, the FDA will issue a Refusal to Receive (RTR) letter. In practice, there is little distinction between the two. RTF/RTR, in general, are regulatory tools for the FDA to avoid unnecessary review of incomplete applications, because such applications lead to multiple-cycle reviews and inefficient use of resources.

The Increasing Trend

Recent data indicates the number of such letters may be on the rise over the past few years. The reason for the possible uptick in RTFs may be the result of several factors.

In 2008, the FDA began implementation of an initiative to improve the efficiency and effectiveness of their overall drug review process, the 21^st Century Review Model.

Prior to the enactment of the Prescription Drug User Fee Act (PDUFA) with its prescribed deadlines for review actions, Refusal to File decisions were very rare and limited to those applications that were extremely deficient. In order to be compliant with the PDUFA timelines, FDA reviewers must assess the application at the time of submission for completeness and compliance with applicable standards and guidelines. Standards for acceptability being applied across CDER and CBER are uniform.

In the past few years, FDA has issued new policies, procedures and guidelines to codify these standards.

As described in these guidelines, there are many reasons the FDA uses to justify a Refusal to File/Receive action. These include:

• Inadequate clinical data in the application, i.e. the clinical studies may not have met the FDA or ICH standards, or may not have shown adequate evidence of effectiveness using the studies’ own statistical analysis plan.
• Inadequate CMC data resulting from formulation issues, incomplete stability data, and inactive ingredients above the limits found in the Inactive Ingredients Database without appropriate pharm/tox supportive data, etc.
• Procedural, i.e. missing or incorrect use of the official FDA forms, electronic submission rules not followed, patent certification is inadequate, etc.
• Applicant’s failure to submit environmental assessment; provide accurate and complete English translations for parts of application not in English; include a statement for each nonclinical study for its compliance with the regulatory requirements; or include a statement for each clinical study for its conduct in compliance with the IRB and informed consent regulations.
• The drug product that is the subject of the submission is already covered by an approved application on file and the applicant of the submission: (1) has an approved application for the same drug product; or (2) is merely a distributor and/or re-packager of the already approved drug product.
• The application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval under section 505(j).

Examples of Refusal to File / Receive

In 2016, several instances show how serious a Refusal to File action can be for a small- to medium-size pharmaceutical company. 

Example 1: Catalyst

In December of 2015, Catalyst submitted an NDA for FIRDAPSE® (amifampridine) for Lambert-Eaton Myasthenic Syndrome (LEMS) in adults. LEMS is an Orphan Indication in the US and Catalyst had previously obtained Breakthrough Therapy designation for this product. In February 2016, the FDA issued a Refusal to File letter to Catalyst, requesting an additional clinical study in pediatric and adult patients with LEMS.  In December 2016, Catalyst reported they have initiated this additional study and expect top-line results in the second half of 2017.

Example 2: PTC Therapeutics

In December of 2014, PTC Therapeutics initiated a rolling NDA submission for TRANSLARNA® (ataluren), an oral, first-in-class, protein restoration therapy for treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). In Europe, PTC received a conditional approval for ambulatory patients who are five years or older pending outcome of planned Phase 3 trials. In February of 2016 the FDA issued a Refusal to File stating that the application was not sufficiently complete to permit a substantive review, since both Phase 3 studies failed to meet primary endpoints. In response, PTC submitted a Request for Dispute Resolution to the FDA which was refused in October 2016. Meanwhile, the European Medicines Authority renewed the conditional approval in November 2016, pending the outcome of a new 18-month randomized placebo-controlled trial on ambulatory patients five years and older with genetic testing confirmatory of a nonsense mutation in the dystrophin gene. PTC has stated that they intend to escalate the Dispute Resolution in the US.

Example 3: Innocoll Holdings

Most recently, Innocoll Holdings submitted an NDA, XARACOLL® (bupivacaine collagen matrix), for post-surgical pain. On December 29, 2106, the FDA issued a Refusal to File letter, stating that XARACOLL should be classified as a drug-device combination product and would require additional device related information in order to be acceptable for review.

Results of a Refusal to File / Receive

For Catalyst, their stock price plummeted by 37% in a single day and the company was required to commit to an expensive and time consuming additional Phase 3 clinical study. In the case of PTC Therapeutics, the company’s stock fell by 80% and the company was forced to lay off 18% of its US workforce. It is too soon to see the full impact of the action on Innocoll, but in the short term, the company stock fell by 65% on the first day of trading after the regulatory action.

How to Avoid an FDA Refusal to File / Receive

Despite the significant negative impacts such actions can have on a company, most of Refusal to File or Refusal to Receive actions are preventable. There are many ways in which a company can enlist the cooperation of the regulators during the drug development process. Premier Consulting has an outstanding history of first-cycle NDA approvals following the 505(b)(2) regulatory pathway. We can help your company define your development program from pre-IND all the way through to NDA submission and approval and we can work with you to insure your submission meets all of the relevant standards for acceptability to review. We can support you throughout all of your interactions with the FDA including:

• Pre-IND and IND preparation and submission
• Pre- and post-IND and NDA meetings with the FDA
• Preparation and submission of NDAs, ANDAs and 505(b)(2) NDAs

Don’t let such unforced errors cause your company to lose credibility and suffer financial losses. Premier Consulting has helped numerous sponsors avoid review delays and refuse-to-file actions by performing due diligence on the development program and/or reviewing the NDA before submission to the FDA. Contact us today.