What is the answer to the question?  Apparently, at the FDA’s Center for Drug Evaluation and Research (CDER) Small Business Industry Assistance (SBIA) Generic Drug Forum for 2024 (held April 10-11), it was Controlled Correspondence (CC).  The FDA conducted two presentations exclusively on CCs and responded with that answer on more questions than not throughout the forum, or so it seemed. 

Seemingly, CCs are a great path for industry to get information.  However, as we know, CCs are not the end-all, be-all route to answers (as discussed in previous blogs here, here, here, and here).  This is for multiple reasons: 

  • Getting a CC accepted can take two or three tries, even for those who submit them regularly.  The FDA clearly stated that it rejects CCs for spelling errors (even if minor) as well as other minor errors as the Agency considers that these could cause reviewers to have erroneous information during their review.  However, the majority of the rejections that this author has observed are not to key content, but rather minor (often non-substantive) details. 
  • CCs are now “expected” for questions where it seems that the FDA could give some guidance to follow or allow industry to follow the guidance without worry of it coming back to bite industry (for example, the number of batches needed to support a change; bracketing or matrixing, even when following the guidance; or using the Referenced Listed Drug (RLD) as the Reference Standard (RS)). 
  • Additionally, CCs do not offer detailed responses—the majority of responses by the FDA to CCs are 1 to 1.5 pages long, and much of that is standard, boilerplate language that is found in every CC. 
  • Though a Level 1 CC has a 60-day review period, industry does not always have 60 days (or potentially 120 days for a Level 2 CC) to wait for an answer on such things as an Inactive Ingredient Database (IID) clarification or what to use as the RLD.  Often industry does not realize that there is a question until something comes up during preparation for a study or in preparation for the ANDA submission. 

Marcia Fields, Lieutenant Commander, U.S. Public Health Service, Office of Regulatory Operations (ORO), OGD (Office of Generic Drugs), CDER, U.S. FDA, gave a presentation on Best Practices for CCs that will be available for viewing in a couple weeks (SBIA presentations are available for review and download within two weeks of meetings usually, and the audio/visuals of presentations can be viewed on YouTube).  Some helpful information Lt. Cdr. Fields shared: 

  • Your CC should be submitted on corporate letterhead, dated within seven days of the submission (not post-dated), and should include complete contact information, including your name, company name, title, email, and phone number.  She noted that if the email domain does not match the company’s domain, this should be explained (for example, if a Gmail account is being used for email). 
  • For Q1/Q2 evaluation:  One strength per CC; three formulations per CC; avoid ranges; composition needs to be presented as if in an ANDA (including hydration state, salt, etc.) 

Lt. Cdr. Fields also provided statistics showing that approximately 35% of the CCs since Fiscal Year 2019 have been deemed “Not Appropriate” at first submission. 

Dr. Zhen Zhang, Master Pharmacologist, OB (Office of Bioequivalence), OGD, CDER, U.S. FDA, shared some surprising numbers in an overview of CCs received by the OB; from April 2021 to March 2023, 903 CCs were assigned to the OB and included the following topics: 

  • Maximum Daily Exposure of Inactive Ingredients – 759 CCs! 
  • Retention Samples Related to in vivo Pharmacokinetic (PK) Bioequivalence (BE) and in vitro BE Studies – 43 CCs 
  • Other BE Study-Related Questions – 101 CCs (additional details on these are outlined in the presentation) 

I would suggest that 759 CCs in two years on a single topic should be a signal to the FDA that some Guidance is needed from the Agency (or that further enhancements to the IID are warranted, judging by the volume of CCs seeking an answer on this issue).  Looking at these numbers, it begs the question:  Is the answer to submit a CC, or is the answer for the FDA to review the most frequently asked questions and try to address them through guidance or another approach? 

Industry acknowledges that CCs have been very helpful in some areas, but they cannot be the answer for everything.  We continue to need additional, clear guidance on regularly asked questions so that CCs are for unusual situations, not every situation! 

If you have any need for assistance with CCs or regulatory strategy, Lachman can help!  Please contact the author at r.welton@lachmanconsultants.com.