The FDA grace period for stem cell clinics and others using regenerative medicine products like stem cells is over. It appears the agency is serious about enforcement moving forward.
They have released several statements about the end of what they call the “enforcement discretion” period, which just means in English a grace period for marketers of cellular therapies is over. The latest FDA piece on this topic is a question and answer document.
This FDA Q&A is quite interesting on a number of levels. I actually found it funny in some ways (OK, maybe I’m a bit of a stem cell nerd sometimes) because it is saying so much more than just what appears on face value in the text, but it’s not always very easy to understand.
Below I have pasted the list of Q’s and the A’s, along with my translation in a sense of what I think the FDA’s points are for each question and I simplify how they answer it. Sometimes reading between the lines a little. With the caveats that I could, of course, be wrong in some cases and I don’t speak at all for the agency, hopefully you’ll find this useful. Some of this ends up being like an FDA Rosetta Stone.
Note that you can read my post on FDA approved stem cell therapies.
The FDA Q&A translated by The Niche
Q: Why did FDA announce a compliance and enforcement policy for certain HCT/Ps?
A: As stated in the guidance, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use, issued in November 2017 and updated in July 2020, FDA announced this policy to give manufacturers time to determine if they need to submit an IND or marketing application in light of this guidance and, if such an application is needed, to prepare the IND or marketing application.
PK: The FDA has taken a bit of criticism for giving a three-and-half-year grace period to clinics and others. I think the agency here is just trying to explain/defend that decision again. I wasn’t a fan of such a grace period. Why not? This discretionary period was abused by hundreds of clinic firms. That was predictable.
Q: After May 31, 2021, what is FDA’s compliance and enforcement policy for HCT/Ps?
A: After May 31, 2021, FDA no longer intends to exercise enforcement discretion with respect to the IND and the premarket approval requirements as described in its Compliance and Enforcement Policy Regarding Certain Regulatory Requirements.
PK: In other words, we’re no longer going to pull our punches. If you do illegal or at best “violative” things, the agency in theory will respond with concrete action. I’m guessing the FDA will focus on the 400+ firms that they sent letters too over the past couple years.
Q: When the compliance and enforcement policy expires, what will be FDA’s approach to compliance and enforcement for HCT/Ps that were subject to this policy?
A: As a general policy, FDA does not comment on its compliance or enforcement approach and therefore cannot comment further.
PK: We’re not going to tell you in advance what we’re going to do if you are noncompliant still.
Q: For an HCT/P that is not regulated solely under section 361 of the Public Health Service Act (PHS Act) and the regulations in Part 1271, and instead is regulated as a drug or biological product under section 351 of the PHS Act and the Federal, Food, Drug, and Cosmetic Act, what must a manufacturer do?
A: FDA expects all establishments that manufacture HCT/Ps regulated as drugs or biological products to have an approved biologics license application (BLA) or an investigational new drug application (IND) in effect. An approved BLA is required to lawfully market these products. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect.
PK: You have to work with us and get our OK before you market (promote or use) a cellular product that is a drug.
Q: I currently market/offer for sale an HCT/P that requires FDA premarket approval but does not have it. May I continue to offer this product for sale after May 31, 2021?
A: A product that requires but lacks premarket approval may not be lawfully marketed, including when a sponsor has an IND or is pursuing an IND or BLA. After May 31, 2021, FDA no longer intends to exercise enforcement discretion with respect to the IND and the premarket approval requirements, as described in its Compliance and Enforcement Policy Regarding Certain Regulatory Requirements.
PK: No, you can’t. That’s illegal. If you continue there’s an increasing chance you’ll get in trouble.
Q: What could happen if after May 31, 2021 I continue to market/offer for sale an HCT/P that requires but lacks premarket approval as a drug or biological product?
A: FDA no longer intends to exercise enforcement discretion with respect to the IND and the premarket approval requirements for certain HCT/Ps, as described in its Compliance and Enforcement Policy Regarding Certain Regulatory Requirements. If you market/offer for sale an HCT/P that requires premarket review as a drug and biological product, you do so at your own risk.
PK: Really, if you break the law, we intend to take action against you.
Q: If I submit an IND for my HCT/P, may I continue to market the product/offer it for sale?
A: A product that requires but lacks premarket approval may not be lawfully marketed/offered for sale, including when a sponsor has an IND or is pursuing an IND or BLA.
PK: No. Even a cleared IND just means you can study a product, not market it. A pending IND application doesn’t mean you can do anything with the drug product yet.
Q: I administered an HCT/P that requires but lacks premarket approval to a patient with a good response prior to May 31, 2021. Can I continue to administer this product to this same patient(s)?
A: No, a product that requires but lacks premarket approval may not be lawfully marketed. You may not administer an unapproved product without an approval or IND that is in effect.
PK: Just because you broke the rules before doesn’t mean you are somehow grandfathered in to continue your noncompliant or even illegal behavior.
Q: If I have an IND in effect, can I administer the same product to patients as treatment outside of the IND?
A: No, even if you have an IND in effect, the unapproved product may not be administered as a treatment outside of the IND.
PK: An IND is just to study a product for a particular possible use and is not an OK to sell a product.
Q: I have been administering a HCT/P that requires but lacks premarket approval to patients, and the manufacturer has informed me that there is an IND in effect for the product. Can I contact FDA to confirm that this is true – that the product has an IND in effect?
A: Under FDA’s regulations, the agency cannot disclose the existence of an IND. You can confirm whether a product has an IND in effect by obtaining from the sponsor the FDA-issued IND number as well as a copy of the official FDA communication acknowledging the IND.
Please keep in mind, however, that an IND is not marketing authorization for a product. Rather, when an IND goes into effect, a product sponsor can ship an investigational new drug and unlicensed biological product to clinical investigators without an approved marketing application (e.g., BLA). If you are receiving a product that has an IND in effect, then you would be considered a clinical investigator associated with the IND.
PK: This one is complicated so we’ll take the question first. The point is that many clinics sell allogeneic (someone else’s or a baby’s) “stem cells” or other products that are first purchased from a manufacturer. Oftentimes the clinics have little information about the product itself or its status with the FDA. Yet they are injecting it into patients. So the gist of the FDA listing this question here gets at the uncertainty in the relationship between the suppliers and the clinic folks injecting what is supplied. Can the clinics trust the suppliers? Probably not in many cases. Okay, now moving on, we get to the problem (as I see it) that the FDA keeps all IND matters strictly confidential. On one level this is completely understandable since there are IP issues at stake here and confidential data involved, but I believe the FDA could in a sense declassify some minimal basic IND factors like their numbers and status (e.g. cleared or pending). This would be useful and not harmful to sponsors. Finally, I wonder: are suppliers going to give clinics their IND info? I don’t know, but I’m skeptical it’ll be widely done.
Q: What must I do if I purchased an HCT/P prior to the end of enforcement discretion and want to administer it to a patient after the end of enforcement discretion?
A: An HCT/P that requires but lacks premarket approval should be administered only if there is an IND in effect for that product, for that sponsor, and applicable for that use.
PK: Put your current stock of unapproved cellular drug products in biohazard waste, folks.
Q: Can I recoup the cost of producing my HCT/P while it is being studied under IND?
A: FDA has issued regulations on charging for investigational drugs under an IND for the purpose of either research clinical trials or expanded access for treatment use. These regulations can be found in 21 CFR 312.8, and additional information is provided in FDA guidance. In summary, IND sponsors may recoup certain costs for a specified product; however, FDA must authorize such requests to charge.
PK: In other words, the hypothetical sponsor or clinic here is asking to charge patients for their experimental cellular injections. In theory it might be permissible to recoup costs, but not profit from it. Plus, you have to talk to the FDA first even to charge anything. This charging issue is problematic because even some universities are charging patients for stem cell offerings that aren’t proven to work or be safe.
Q: If I submit an IND for my HCT/P, may I charge patients for the product?
A: FDA has regulations on charging for investigational drugs under an IND for the purpose of either research clinical trials or expanded access for treatment use. These regulations can be found in 21 CFR 312.8, and additional information is provided in FDA guidance. In summary, IND sponsors may recoup certain costs for a specified product; however, FDA must authorize such requests to charge.
PK: If you want to charge to cover costs, talk to us first.
Q: I see that the FDA’s Tissue Reference Group Rapid Inquiry Program (TRIP) concluded March 31, 2021. Where can I direct questions as to how my HCT/P is appropriately regulated after this time?
A: Although the temporary TRIP program has concluded, there are many mechanisms available to determine how an HCT/P may be appropriately regulated:
First, you may wish to consult the FDA guidance, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-based Products, Minimal Manipulation and Homologous Use.
If after reviewing this guidance you still have questions, you may file a request for a recommendation with the Tissue Reference Group (TRG) or submit a Request for Designation (RFD) with the Office of Combination Products (OCP). Additionally, you are welcome to submit a pre-Request for Designation (pre-RFD) for a preliminary assessment of your product from OCP.
PK: Sponsors liked TRIP and now there’s some confusion about it being over. I feel like TRIP might be worth reinstating in the long run.
Q: Did the compliance and enforcement policy apply to platelet rich plasma (PRP)?
A: As stated in our guidance for industry, “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use”, updated July 2020, PRP is blood taken from an individual and given back to the same individual as platelet rich plasma. PRP is not an HCT/P because it is a blood product. Therefore, the compliance and enforcement policy did not apply to PRP or other blood products.
PK: PRP is not a drug. I guess this is true even if used in a non-homologous manner. However, my take is that if you combine PRP with another substance like stem cells, then the combo would be a drug.