The era of personalized medicines has begun. These are medicines that are tailored specifically for a single patient, using that patient’s specific DNA or other blood characteristic as a guide or actual source component. The new chimeric antigen receptor T-cells (CAR-T) is an exciting example. It results in the conversion of a patient’s own T-cells into cells that are able to recognize the specific type of cancer cells that the patient has, and thus able to attack them in the same way that normal T-cells attack normal infectious cells. In short, it’s a way of manipulating a person’s own immune system to attack cancer cells that it would normally be blind to. When it works, the results can be breathtaking. The question is, how are these drugs treated under today’s serialization and tracing regulations? Let’s take a look.
I’m certainly not an expert on CAR-T manufacturing, but I do know that it involves the collection of a blood sample from the patient, processing that sample in a lab, and then infusing the results back into the same patient. The blood sample provides the raw material (T-cells) and the target cancer cells. Once processed, the T-cells that result will target the cancer cells that match the genetic makeup of the original sample. Right now, CAR-T therapies are approved only for a limited set of blood cancers, but everyone hopes this is just the beginning.
CAR-T therapy falls under the class of drugs that are based on “autologous” blood extraction, meaning blood that is removed and intended to be re-infused into the same patient at a later time. This is in contrast to “allogenic” blood extraction, which is intended to be re-infused into other patients. Scientists are hopeful that CAR-T therapy can someday be successful using allogenic blood. If/when that happens, the resulting drugs could be off-the-shelf, just like most other cancer therapies. But until that day, no CAR-T therapy is just sitting in stock somewhere.
HOW DOES THE DSCSA TREAT AUTOLOGOUS THERAPIES?
There isn’t a single statement in the Drug Supply Chain Security Act (DSCSA) that exempts autologous therapies like CAR-T, but through the application of some logic, you can determine that the law likely does not apply to them. In fact, there are two approaches that lead to the same conclusion.
The DSCSA only applies to drug and biologic products that are intended to be introduced into commerce. This implies that the product would be sold to members of the supply chain, eventually arriving at a dispenser, who would administer the product—unmodified—to the patient. But in the case of CAR-T therapies, the product is “manufactured” specifically for a named patient (specific patient), from that patient’s own blood. Most importantly, the product is never the subject of a DSCSA “transaction” since the “manufacturer” ships the “product” to an authorized treatment center for infusion into only the named patient (see “The HDMA Supply Chain Product Transaction Scenarios For DSCSA”). Unlike most drugs, this is an entirely closed circuit transfer. By not being subject to a DSCSA Transaction, the product and the various shipments of it are not covered by the DSCSA.
This approach to the analysis relies on the autologous nature of the drug. The purpose of any future allogenic CAR-T therapies would be to lower the costs and make them more “off-the-shelf”. In that case, this argument may no longer apply since an allogenic-based CAR-T therapy (if one ever exists) would likely be subject to DSCSA transactions in the supply chain. That is, they would probably be sold through specialty distributors.
A CAR-T therapy is composed of “blood components” that are infused into a patient. Section 581(24)(vi) of the DSCSA contains an exemption for “…the distribution of blood or blood components intended for transfusion”. “Transfusion” has characteristics similar to “Infusion”. I’m not an expert on the differences, but if the FDA agrees that these differences are not significant for the purposes of the DSCSA, then this specific exemption would apply to CAR-T therapies as well.
This approach to the analysis does not rely on the autologous nation of the drug, so it might result in an exemption even if CAR-T therapies can be manufactured with allogenic blood someday. (See also “Is Your Drug Exempt From The Federal Drug Supply Chain Security Act?”.)
HOW DOES THE EU FMD TREAT AUTOLOGOUS THERAPIES?
Applying autologous therapies to the Falsified Medicines Directive (FMD) in the EU is a little easier. Annex I of the Delegated Regulation (EUDR) contains a “List of medicinal products or product categories subject to prescription that shall not bear the safety features, referred to in Article 45(1)”. That is, anything in that list would be exempt from bearing both the anti-tamper device and the unique identifier.
One of the entries is: “Advanced therapy medicinal products which contain or consist of tissues or cells”.
CAR-T therapy medicinal products contain cells extracted from the patient, so it appears that they fall into this exemption category. Notice that this would not only apply to autologous therapies, but to allogenic therapies as well.
WHAT DOES THIS MEAN?
It appears that “drugs” that are “manufactured” the way today’s CAR-T therapies are made should be exempt from both the DSCSA and the FMD. However, I urge any manufacturer of these drugs apply to the FDA for a waiver to confirm that they agree with my analysis or your own. Of course, I cannot grant you a waiver just for applying my logic. I am not a lawyer and my logic may have an obvious or hidden flaw. Only the FDA can grant such a waiver or acknowledge an exemption. The same is likely true in the EU.
CAR-T therapies are in their infancy. Odds are, we are going to see them applied to a growing list of cancers in the future. Maybe the same approach can be used for other conditions down the road. As long as they are based on autologous blood extraction, they will likely all be exempt from the DSCSA, but even those that might rely on allogenic blood extraction in the future will likely be exempt from the FMD and perhaps even the DSCSA.