Refuse to Receive Standards
02 Mar 2019
ANDA Submissions- “refuse to receive standards” Draft Guidance
Prepared by: Mr. Bhavesh J. Rathod, Mr. Nishant R. Christian & Mr. Manoj K. Patel
Over the years, there have been many questions raised by the applicants of Abbreviated new drug applications regarding “refuse to receive standards” (RTR) and “filing review processes”. A new draft guidance has been released by the US FDA which includes Q&A based on agency experience regarding refuse-to-receive issues.
An RTR decision indicates that the US FDA has evaluated that the abbreviated new drug applications (ANDAs) application is not a “substantially complete application and thus a substantive review is not possible”.
The RTR standards are very important after the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA). The practice of submitting an ANDA that is not sufficiently complete (i.e. contains all the information required under section 505(j)(2)(A) of FD&C Act and does not contain a deficiency described in 21 CFR 314.101(d) and (e)) and then repairing is considered inefficient and wasteful of resources due to extra reviews and letters.
This guidance covers original ANDAs and certain prior approval supplements (PASs).
Agency may allow applicant to correct deficiencies considered minor in nature as identified in an Information Request (IR) within seven calendar days. Then the submission will be received retaining the original submission date or else RTR determination may occur. For major deficiencies, though deficiency may be corrected quickly, considering the magnitude of error at first instance, it would result in an RTR determination. Thus the ANDA, if resubmitted, would not retain the original submission date.
To avoid RTR determination, comprehensive responses are expected for all type of deficiencies received. Further, the resubmission is expected to be in line with current recommendations relevant to filing that are in effect at the time of resubmission. All deficiencies identified should be corrected before resubmission of an ANDA. If not possible do so, applicant may choose to withdraw the application under 21 CFR 314.99. In any case, agency may consider the ANDA withdrawn after one year if no actions are taken.
A provision to pursue “request for reconsideration” is allowed within seven calendar days by the agency for minor deficiency. Though specifically not defined for major deficiency, to systematize the review process, the agency needs to define an acceptable time frame to revert with the request for re-consideration. Applicant can either submit only a “request for reconsideration” (No additional GDUFA fee) or a “request for reconsideration with the resubmitted ANDA” (Applicable user fee to be remitted). In the latter case, the applicant’s resubmission should be identified as related to a pending request for reconsideration on the resubmission cover page, with supporting information. In any case ANDA will remain in RTR status, meaning that no technical review will commence.
Agency is firm that it will not review any unsolicited amendment submitted, other than an administrative amendment identifying a change in contact information or ownership, while the ANDA is pending filing review.
Inarguably, FDA will not revoke RTR decision for a typographical error (numerical value, alphabetical letter, symbol, or other text) that resulted in a major deficiency and subsequently led to RTR determination.
The applicant may receive an IR if ANDA doesn’t contain English translation for any content including headers and titles. If applicant fails to provide comprehensive translated document in IR response to the agency, it will be refused for receipt. The translation page should be printed in font size 12 and be placed next to the original page in the different language.
To respond in a timely manner to the decisions taken by the agency, an accurate email address has to be provided on the FDA Form and the email has to be checked regularly, even if the designated point of contact is out of the office as no additional time is allowed by the agency.
Absence of additional information as requested in certain product-specific recommendations (e.g., providing adequate measurements at time points identified in the guidance) would be considered major and could lead to RTR determination. On the other hand, failure to provide data sets or definition files (e.g., type of data recommended, format, and file structure) as recommended is considered a minor deficiency.
FDA clearly states that it will RTR an ANDA that deviates from any study or standard described or recommended in a product-specific recommendation without providing justification on the alternate approach. Hence, a sound justification is deemed necessary in module 2.7 of the ANDA if ANDA has information that doesn’t comply to the BE recommendations for specific products along with reference of any controlled correspondence in this regards with OGD, if applicable, to avoid a major deficiency determination.
Long-term storage stability (LTSS) data and its location are required to be provided in the Bioequivalence Summary Table 10 and data in Module 18.104.22.168 stating Module, Section, Subsection, and pages along with hyperlink. Failure to provide LTSS data in only one of two locations would be classified as minor but if it’s not included at any location, the FDA will RTR the ANDA.
Though categorized as minor, at least the BE summary tables shall be appended in the dossier when an applicant references BE data submitted in another ANDA, which has already been received by the agency for review. Summary tables shall be included for each applicable study. Omission of tables in module 2 and relevant data in module 5 will lead to RTR determination.
At the end, a list of individual documents that should be included in the study report in accordance with ICH E3 is included with clarity that omission of any of these reports would be considered a minor deficiency.
All applicants are urged to thoroughly review this draft guidance to understand the requirements to submit a complete ANDA application that conforms to all of the conditions specified in the document, prior to filing.