Firms that are active in the biologics space face many possible challenges but the possibility of getting an FDA warning letter is one of the most intense.
The goal of today’s post is to explain what an FDA warning letter is all about. This analysis includes what such a letter means and what steps come next. How does this play out in the cell therapy space specifically too?
What’s in this article
For some of the companies in the stem cell space who get such an FDA warning, they may not really know what a warning letter even means.
What does the agency expect of them? Are they in serious trouble?
What is an FDA warning letter?
Once a week, the FDA posts new warning letters on a hub of enforcement actions. These now-public letters tend to be newish. However, sometimes the agency will delay posting a warning letter publicly for some time. I feel like we are seeing that kind of delay less often these days, which is good.
An FDA warning letter is essentially a formal notification of one or more major violations. Here’s how the FDA defines it:
“A letter notifying a regulated industry about violations that FDA has documented during its inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act (the Act), its implementing regulations and other federal statutes.”
The agency doesn’t waste time sending a warning letter for minor things.
What is the structure of a typical letter of this kind?
It usually starts with recounting a recent inspection of the firm. The early part of the letter typically also references why the FDA has authority in this case. In the cell therapy space, we often see an initial statement in the letter that the firm is marketing an unapproved drug product. Also, it’s common to see statements that the clinic or other entity is not eligible for exemptions to specific regulations.
Then the letter may list specific violations. I’ve seen letters with nearly two dozen bullet points and sub-bullet points. Others are much shorter but highlight major problems.
For stem cell clinics, this list frequently mentions failure to comply with cGMP standards. Such a letter usually is sent by CBER.
Examples of warning letters
Here are some typical kinds of warning letters in the stem cell space.
- FDA warning to stem cell clinic supplier Utah Cord Bank
- Sizing Up Sizzling FDA Warning Letter to Fat Stem Cell Clinic Stemgenex
- ‘Captain Kirk’ regenerative clinic supplier Invitrx gets long FDA warning letter
- FDA Warning Letter to Irvine Stem Cell Treatment Center Clinics Across US
Of course, the FDA can send warning letters outside the cell therapy space as well. Here are two examples of such letters.
- Pfizer FDA warning letter. In 2020, the FDA sent a warning letter to Pfizer regarding its plant in India.
- Prevagen FDA warning letter. The firm received this letter a decade ago. I haven’t seen any more recent agency action here. I recently wrote a fact-check of Prevagen and found serious reasons for concern.
What is an FDA untitled letter?
Most firms in our field contacted by the FDA don’t get a warning letter. Instead, an untitled letter arrives.
In a general sense, an untitled letter from the FDA is a step below a warning letter in terms of seriousness. However, I’ve seen FDA untitled letters to stem cell clinics that seem similar in content and tone to warning letters. It’s not always clear how the agency decides whether a letter is untitled or a warning.
One difference is clear. Most often, a warning letter follows an in-person FDA inspection and generation of a 483 inspection report, while an untitled letter does not.
I sometimes refer to untitled letters as “mini-warning letters.”
These letters could mean more action is to come in the future. The FDA has sent hundreds of untitled letters to regenerative firms just in the last few years. However, it’s unclear if they will follow up on those firms that continue to be non-compliant in a serious way.
I’ve suggested that the agency sometimes forgo requiring itself to do an inspection and issue a 483 form prior to issuing a warning letter. This change is meant for the stem cell clinic industry where hundreds of non-compliant firms are likely ignoring untitled letters. It’s not practical for the FDA to inspect all of them, but serious action is warranted.
How should firms respond to warning letters?
Typically, the FDA ends a warning letter by indicating what the firm should do next. The agency also will give the recipient a specific period of time during which a response is required. Most often this is around fifteen days. Maybe a few weeks.
There’s a sense of urgency.
If the recipient of the letter has one or more FDA compliance experts on staff, they should develop a plan to respond to the letter.
Firms in the unproven stem cell space that receive warning letters often have little-to-no FDA compliance expertise. It’s difficult for them in the short time given for a reply to bring new expertise on board, but it’s essential. There are consultants out there including law firms that can help devise a practical response to an FDA warning. You want someone with many years of expertise.
The response should be constructive. Either the firm should indicate it is going to do what the FDA wants or explain convincingly why not. Some letters do both, depending on the list of issues. It’s unusual for firms to respond aggressively but I’ve seen it a few times. I’m not sure that is an effective way to go.
While the FDA can be slow in taking the possible next steps for persistent non-compliance issues after a warning letter, the ultimate response could be serious. In rare cases, it could lead to an injunction effort.
Most often we never learn what happens after a warning letter or untitled letter. Two years ago the FDA sent out an unusually large number of letters in a short time but did that 2020 burst change anything more broadly? Hard to say.
If all goes well in your response to the agency’s warning letter, you will receive an FDA close-out letter indicating as much.
References & notes
- FDA definition of actions including a warning letter.
- The FDA page listing recent warning letters in a searchable format.
- I’m not an attorney and this post is not intended in any way as legal advice.