FDA Provides Clarification for Organizations Submitting ANDAs
The Generic Drug User Fee Amendments (GDUFA) introduced user fees to the organizations participating in the bioequivalent drug industry and incentivized filing Abbreviated New Drug Applications (ANDAs) electronically. The law functions as an informal mandate by promising expedited review times to applicants who submit to the US FDA in eCTD format.
Another GDUFA stipulation addressed the Refuse-to-Receive (RTR) designation for ANDA applicants. The objective of this clause was to improve the overall quality of submissions sent to the Agency which would in turn help speed the approval of generic drugs and accelerate their path to market.
“FDA will develop enhanced refusal to receive standards for ANDAs and other related submissions by the end of year 1 of the program (GDUFA) and will publish such standards in advance of implementation.”
A new draft guidance outlining RTR standards was released by the FDA in early October, and while this document was not characterized as “final” there has been some confusion among industry participants as to what standards are currently being enforced as it pertains to ANDA submissions.
The FDA conducted a webinar this week to clarify implementation dates and discuss specifics covered in the draft guidance. Here are the major takeaways from the presentation – Guidance for Industry: ANDA Submissions – Refuse-to-Receive Standards.
The vast majority of deficiencies that led to an RTR response from the FDA in 2012 stemmed from scientific content (bioequivalence, chemistry, etc.) The FDA stressed that enforcement as it pertains to this content has not changed and is in line with historical precedent. The Agency spent a large majority of the presentation walking attendees through each module, identifying best practices and pointing out common errors.
Planned Implementation of New Items
A previously stated date for the implementation of the “new” RTR items was amended to “Upon issuance of the final guidance.” ANDA applicants will need to check the FDA’s GDUFA website for updates.
One of the new items included in the enhanced RTR guidance is the number of business days an applicant has to correct errors:
“An ANDA containing less than 10 easily remedied deficiencies will be contacted regarding the same. A response must be provided within 5 U.S. business days. Day 1 of the 5 U.S. business days will commence the day after notification is provided to the applicant.”
The ANDA will be Refused-for-Receipt if:
- The number of easily remedied deficiencies is equal to or more than 10
- A response to the fewer than 10 deficiencies is not received within 5 U.S. business days
Type II API DMFs
Lead time between the submission of an ANDA application and the submission of a Type II API DMF was a particular point of emphasis during the presentation. The FDA characterized this trend as one it badly wants to reverse.
The Agency revealed that only 30% of API DMFs were submitted beyond 60 days prior to the ANDA submission itself. Thirty-eight percent of API DMFs were submitted within 30 days of the ANDA submission, and of that 38%, 43% were submitted within 10 days of the ANDA submission.
“The trend needs to be reversed so that ample time is allowed for the Initial Completeness Assessment determination to be made and any identified deficiencies addressed, all prior to the ANDA submission, to ensure that the Type II API DMF is determined to be available for reference at the time of receipt.”
If the Type II API DMF is not on the FDA’s Available for Reference list at the time a receipt decision is due, that ANDA will incur an RTR response.
The FDA stated that as best practice applicants should submit the Type II API DMF at least 6 months in advance of the ANDA submission. Again, this is just a recommendation to help applicants avoid the RTR designation and not a binding rule.
New stability guidelines as per the Stability Guidance and Q&A are scheduled for implementation on June 20, 2014.