1K.B. Institute of Pharmaceutical Education and Research, Kadi Sarva Vishwa Vidyalaya, Gandhinagar, Gujarat.
2HOD of Pharmacognosy & Regulatory Affairs, K.B. Institute of Pharmaceutical Education and Research, Kadi Sarva Vishwa Vidyalaya, Gandhinagar, Gujarat.
3Assistance Professor, Department of Regulatory Affairs, K.B. Institute of Pharmaceutical Education and Research, Kadi Sarva Vishwa Vidyalaya, Gandhinagar, Gujarat.
The pharmaceutical industry faces stringent regulatory requirements, particularly concerning the submission of Electronic Common Technical Documents (eCTD) to the United States Food and Drug Administration (USFDA). A critical aspect of this process is the Refuse to Receive (RTR) filing, wherein submissions may be rejected due to non-compliance with regulatory standards. This article presents an in-depth exploration of optimizing RTR filing procedures to ensure enhanced regulatory compliance and expedited approval timelines. Through a thorough analysis of USFDA eCTD publishing guidelines and best practices, this study identifies key challenges and proposes actionable strategies for pharmaceutical companies to mitigate RTR risks. By integrating advanced technologies and regulatory intelligence tools, organizations can streamline their submission processes, minimize errors, and ultimately accelerate market access for innovative therapies. This article serves as a comprehensive guide for pharmaceutical professionals navigating the complex landscape of regulatory compliance in drug development and submission.
An FDA RTR (Refuse to Receive) decision includes a finding that an ANDA is not materially complete. A substantially complete ANDA is “an ANDA that, on its face, is sufficiently complete to permit a substantive review.” It lists certain deficiencies and some recurring deficiencies that, in the FDA's experience, have caused the FDA to RTR an ANDA. The amended ANDA will be considered a new submission as of the date of submission, and a new ANDA fee will be needed if the applicant chooses to submit additional materials. Seventy-five percent of the filing fee will be returned to the applicant without the need for a formal refund request if the FDA determines that an ANDA was not received for reasons unrelated to nonpayment of fees. If the applicant takes no action within 1 year of a non-receipt, the FDA may consider the ANDA withdrawn.[1,2,3]
Table 1 ANDA Fees as per GDUFA (2024)
Note: 1 US Dollar equals to 83.06 Indian Rupee
BACKGROUND
The Office of Generic Drugs (OGD) has been tasked with a number of duties following the passage of the Generic Drug User Fee Amendments of 2012 (GDUFA). One of these responsibilities is to develop enhanced guidelines for RTR ANDAs and submit associated applications by the conclusion of the first year of the program. The FDA rejected 379 ANDAs during Fiscal Years (FY) 2013 and 2015 for reasons other than nonpayment of the GDUFA fee. According to frequency, the top five causes for an RTR determination in FY 2015 were as follows:
LIST OF REQUIREMENTS THAT ARE NOT FULFILLED (CATEGORY WISE) WHICH LEADS TO RTR
Upon filing evaluation of an ANDA, the FDA will identify any major or minor deficiencies. A serious deficiencies is one that the FDA considers to be of a noticeable significance. According to the FDA, a minor deficiencies is one that is easily fixed and of a modest nature. FDA shall advise the applicant of any defects by phone, fax, or email if it determines that an ANDA contains nine or fewer minor deficiencies, or fewer than ten minor difficulties. Applicants may amend or repair any minor errors in the ANDA within seven calendar days, at FDA's discretion. If the requested data is not obtained within seven calendar days, FDA will RTR the ANDA.
Table 2 List of Requirements that are Not Fulfilled (Category Wise) Which Leads to RTR [1,2,3,4,5
BRIEFING THE ANALYSIS OF THE USFDA ECTD PUBLISHING [6]
CONCLUSION
Compliance with RTR requirements outlined in Table 2 is vital to avoid screening queries and RTR from the agency, ensuring timely acceptance of ANDA, and meeting company goals. Failure to comply results in a 25% loss of the ANDA submission fee and forfeits first-filer status and exclusivity for FTF ANDA submissions. Adhering to RTR requirements is crucial to preventing unnecessary losses. Submission types like NDAs, ANDAs, and BLAs have been in eCTD format since May 5, 2017. IND submissions and Master Files transitioned to eCTD format on May 5, 2018, excluding Type III DAMTs. eCTD offers advantages like streamlined agency management, enhanced readability, and simplified lifecycle management. Following the FDA's PDF Technical Specification Guidance is vital to avoiding screening deficiencies. Compliance with the FDA's Technical Rejection Criteria for Dataset in Module 4 and Module 5 is necessary to prevent submission rejection. ECTD submission packages must be sent via the Electronic Submission Gateway (ESG) to the US agency.
REFERENCES
Manisha B. Divraniya, Maitreyi Zaveri, Zuki Patel, Optimizing RTR (Refuse To Receive) Filing For Enhanced Regulatory Compliance In Pharmaceutical Submission And Briefing The Analysis Of The USFDA ECTD Publishing, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 5, 1866-1872. https://doi.org/10.5281/zenodo.11403389
10.5281/zenodo.11403389
