The FDA answers this question in a newly released guidance titled Postmarketing Studies and Clinical Trials: Determining Good Cause for Noncompliance with Section 505(o)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act (here).  “[H]olders of applications for human prescription drugs (hereafter applicants) who are required to conduct postmarketing studies or clinical trials under section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)” are subject to the contents of the guidance.  These are agreed upon by the applicant and the FDA at the time of application approval and are commonly known as postmarketing reports (PMRs); however, timetables for submission of protocols and submission of clinical studies are often missed. 

The Agency had issued another guidance in April 2001 titled Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (here) that discusses how the Agency would administer the provisions of the legislation in detail, including a description of enforcement tools that it would employ for failure to meet study dates and requirements unless it was for “good cause.”  The tricky thing is, how do you define “good cause” so it doesn’t trigger a noncompliance status? 

In the new guidance, the FDA notes that what constitutes “good cause” applies only to new drugs approved under section 505(b) and biologic license applications approved under section 351 of the Public Health Service Act, and only to PMRs required under section 505(o)(3), but does not apply to over-the-counter drugs marketed under an approved application or generic drugs approved under 505(j).  In addition, it does not apply to the following types of PMRs: 

  • Pediatric studies required under section 505B of the FD&C Act (see 21 CFR 314.55(b) and 601.27(b)) 
  • Trials required as a condition of accelerated approval under section 506(c) of the FD&C Act and accelerated approval regulations (21 CFR 314.510 and 601.41) (although the accelerated approval process is getting additional scrutiny by both Congress and the FDA recently) 
  • Trials required as a condition of approval based on evidence of effectiveness from studies in animals under subpart I of 21 CFR 314 (21 CFR 314.610(b)(1)) and subpart H of 21 CFR 601 (21 CFR 601.91(b)(1)) 

If applicants fail to meet established milestones for the various elements of study design and execution, or fail to complete annual reports on time, they are considered to be in noncompliance with their commitments, again unless they can demonstrate “good cause.”  The FDA expects firms to provide their explanations as to why they have not been able to abide by the milestones, completion of the studies, or meeting report timelines.  The FDA is responsible for judging whether an applicant’s explanation justifies a finding of “good cause.”  The FDA considers PMR noncompliance to be reasonable when it results from circumstances that meet the following three criteria: 

  • The circumstance is directly related to the missed milestone; AND 
  • The circumstance was out of the applicant’s control; AND 
  • The circumstance could not have been reasonably anticipated and factored in at the time that the original PMR timetable was finalized. 

The guidance document provides examples of what may meet these criteria.  Remember, the word “AND” is of utmost importance as all three criteria must be met.  The Agency notes that “it may also consider any other available information that it deems pertinent.” 

Types of enforcement actions that the Agency might consider in the face of noncompliance include: 

  • Issuance of a warning or untitled letter 
  • Misbranding charges (which would mean that the product could not be introduced into interstate commerce) 
  • Civil monetary penalties (see the guidance for the substantial fines that could occur) 

It is uncertain what prompted the timing for issuance of this guidance.  It could be that applicants requested further clarification of what “good cause” means to the FDA, or could it be a harbinger of increased enforcement activity in response to Congressional inquiries to the Agency?  In either case, it would behoove firms to review their PMR commitments and discuss any pertinent issues with the FDA prior to any enforcement action taking place.