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Pink Sheet – Refuse-to-File Turns 25: New Guidance Changes In Style, But Not Substance

Pink Sheet – Refuse-to-File Turns 25: New Guidance Changes In Style, But Not Substance

Executive Summary

US FDA’s revised draft guidance spelling out its policy on ‘refuse-to-file’ decisions differs little in substance compared to predecessor issued in 1993. But difference in style is telling sign of the times.


The US FDA is replacing its 25 year-old guidance on “Refuse to File” (RTF) decisions for NDA/BLA submissions with a new draft guidance published Dec. 12.


There is very little difference in substance between the new draft and the predecessor guidance issued in 1993. But the guidances are very different in style, changes that reflect the evolution in the drug review process since the user fee era began.


The RTF policy is very much a creation of the user fee era: the groundbreaking feature of the program – FDA’s commitment to complete reviews within a fixed timeframe – necessarily involved stipulating a process for the agency to decline to review an incomplete application.


The simple action of withdrawing the previous guidance and issuing a modernized version with few changes likely serves the purpose of alerting inexperienced sponsors about FDA’s rigid guidelines for what constitutes an incomplete application that will be rejected out of hand. The original guidance issued on July 12, 1993 was withdrawn on May 19 of this year.

The old guidance can be viewed as advice to FDA’s own drug reviewers as much as to regulated industry. The revised 2017 version is more directly tailored to drug sponsors.

On one level, it is remarkable how little has changed. The guidance continues to make the point that RTF actions are intended to address “complex significant deficiencies that cannot be corrected before filing,” and are not appropriate for “easily correctable deficiencies.” And the guidance continues to finesse the most difficult issue: when it is acceptable to refuse an application because it lacks on its face adequate evidence of efficacy (i.e., two adequate and well controlled trials, or a sufficient explanation of why a single trial suffices).


But from a stylistic perspective, the two guidances are quite different. The updated RTF guidance falls under the new streamlined, just-the-facts approach for guidances outlined by CDER Director Janet Woodcock at the Nov. 14 Prevision Policy/Friends of Cancer Research Biopharma Congress. (See sidebar.)


Language from the original that could be categorized as narrative or literary flourish has been replaced with more technical, bulleted advice to sponsors.


For example: “The practice of submitting an incomplete or inadequate application and then ‘repairing’ it in the course of an extended review period is inherently inefficient and wasteful of agency resources,” the 1993 guidance states. “It is probably wasteful of limited industry resources as well.”


RTFs are “based on omissions or inadequacies so severe as to render the application incomplete on its face,” the old guidance states. “To be a basis for an RTF, the omissions or inadequacies should be obvious or at least once identified and not a matter of interpretation or judgement about the meaning of the data submitted.”


In that sense, the old guidance can be viewed as advice to FDA’s own drug reviewers as much as to regulated industry. The revised 2017 version is more directly tailored to drug sponsors.


The 1993 guidance also harks back to a time when guidance writing was a more centralized activity. In particularly, CDER Deputy Director for Clinical Science Bob Temple had a large hand in the original guidance. “I don’t recall who wrote the guidance but I am quite sure I had input,” Temple said of the previous guidance. He was not directly involved in the new draft – except insofar as the 1993 guidance was clearly the starting point. (Senior Regulatory Health Project Manager Amalia Himaya is identified as the primary point of contact on the new draft.)


FDA lists six deficiencies that will likely draw an RTF, none of which should be surprising to sponsors:

  1. Materially lacking or inadequately organized applications.
  2. The application contains inadequate information for one or more indications when multiple indications are submitted in the same application. In those case, “FDA may accept for filing those parts of an application that represent complete submissions for particular indications but refuse to file those parts that are determined to be incomplete for other indications,” the guidance states. That is unchanged from the 1993 version.
  3. Reliance on a single trial to support approval of an application without adequate justification, and particularly in cases where FDA already formally requested more than one trial, at the end of Phase 2 meeting, for example.
  4. Failure to submit an assessment of studies related to the potential abuse of a drug that are necessary to inform drug scheduling under the Controlled Substances Act and the development of drug product labeling.
  5. Required content is not submitted electronically where the FDA has specified it must be.
  6. For NDAs or original BLAs reviewed under the Program, if minor components agreed upon for late submission are not received within 30 calendar days after receipt of the application.…