I didn’t hear the first couple of presentations in the FDA’s Stem Cell workshop. However, I did listen from mid-morning to Dr. Irv Weisman’s closing. Yesterday’s post was my take on the highlights. http://rickjaffeesq.com/2016/09/08/really-tough-day-stem-cell-advocates/
Upon reflection, what is disturbing to me is what I didn’t hear, namely a discussion or even a mention of what I think should have been the most important question in the autologous stem cell public policy debate: whether autologous stem cell transplants should be treated differently by the FDA from other types of therapeutic interventions because the material comes from the person’s own body.
This question is both very simple and quite complex. It is complex because it involves not only scientific issues, but also public policy, legal jurisdictional issues, and even federal constitutional issues. And yet, I heard nothing about these issues from the FDA’s blue ribbon panel of thought leaders despite the extremely impressive academic credentials, accomplishments and experience of the workshop participants.
The question is also complicated because it’s only by virtue of the FDA’s as yet untested, convoluted and counterintuitive interpretation of its rules that it has arguable jurisdiction over most of the stem cell clinics it intends to put out of business with its draft guidance documents. (We’ll get into the legal weeds of statutory interpretation of the applicable rules later.)
The entire workshop’s discussion including the ethics presentations was predicated on the tacit premise that autologous stem cell transplants are just like any other therapeutic intervention. As I think about it, that tacit assumption led to a bizarre disconnect in the presentations.
Almost all of the presenters excoriated the use of stem cells therapeutics outside of clinical trials. Yet the most upbeat and heartwarming presentation, to me, was from the plastic surgeon, Peter Rubin who brought forth examples of fat transplants given to wounded warriors and breast cancer survivors. I don’t recall him saying that every one of his transplant patients were treated in clinical trials. I believe that many people receive autologous stem cells or fat HCT/P transplants for homologous use without FDA approval, including for reconstructive work such as he is doing.
Using a person’s body as the transplant material avoids many of the safety issues which occur from a foreign source, whether the source be another person’s stem cells, a chemical or an extract from a plant (like digitalis or vincristine,). Most non-self-interventions likely have L/D (lethal dose) toxicity limits and attendant serious safety concerns in terms of dosage and side effects. Not so with autologous HCT/P transplants.
Sure, in any transplant there are contamination issues, but that applies to any autologous (or allogenic) HCT/P or blood product transplant and thus is not unique to “unproven” stem cell transplanters. So if many of the safety concerns of drug therapies aren’t applicable to autologous stem cell transplants, then it all comes down to efficacy, and whether and how much proof is necessary for a person to be able to use material that comes from that person’s body.
Although none of the luminaries raised the issue yesterday, I think it’s worth asking why aren’t people allowed to use a technology or service which isolates and removes a body part (HCT/P’s) and reintroduces all or a part of it back into their own body without federal government oversight. Same day autologous transplants are basically medical procedures. Normally the FDA is not in the business of regulating medical procedures because it’s the “practice of medicine” which normally is within the jurisdiction of the state medical boards.
I don’t think it’s crazy to ask why should the federal govenrment be involved in medical procedures regulated by state law, and I’m not alone in thinking that autologous HCT/P transplants should have different rules, that the new drug rules do not or should not apply, and that these procedures should be policed by the state medical boards.
In fact, it was the FDA’s position as well, until the proliferation of these “unproven” stem cell clinics. (I discussed this in my first post on the guidance documents http://rickjaffeesq.com/2016/04/21/stemcells/)
I think the presenters yesterday forgot the actual reason the FDA is doing this whole public exercise: to sell its reinterpretation of its own rules. It’s not clear to me that the courts are going to go along with it. Here’s why.
It’s always a good idea to start with the law
The primary specific source of stem cell regulation is 21 CFR 1271.
In short, stem cells or more generally HCT/P’s (Human Cell and Tissue and Cellular and Tissue Based Products) are categorized or regulated in three ways:
- Solely under 1271 (basically tissue facility registration)
- As new drugs requiring full IND/NDA approval and registration, or
- Not regulated by the FDA
21 CFR 1271.10 sets out the requirement for registration but not new drug approval, and applies if, among other things, the product is not more than minimally manipulated and is for a homologous use.
What the FDA can’t regulate (at least until now)
21 CFR 1271.15 provides that the FDA doesn’t regulate the use of HCT/P’s if the extraction and reinsertion of the material is done in the “same surgical procedure.” Here is the exact language:
“(b) You are not required to comply with the requirements of this part if you are an establishment that removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.”
Under the plain meaning of this rule, all, most, many or some of what the “unproven” stem cell transplanters are doing is or was perfectly legal.
I have personal knowledge about this because around ten years ago, I contacted the FDA several times and asked them about this precise rule, on behalf of a client who wanted to do same-day autologous transplants and sought a legal opinion from me. I called the FDA several times, because sometimes you get different answers from an agency. Each time, I was told that the FDA doesn’t have jurisdiction over same-day autologous cell transplants. And so I gave my opinion clearing the procedure.
But that was before the 600 plus “unproven” stem cell clinics popped-up with all their purported claims of miracle cures. I’ve talked about this in a previous post. http://rickjaffeesq.com/2016/04/21/stemcells/ .
The point is that implicit in the words of 1271.15 – the reinterpretation of which is the reason we are going through this FDA public show – is that autologous stem cell transplants are different from medical therapeutics involving a substance not originating in a person’s own body, and are regulated differently.
In fact, same-day, autologous stem cell transplants were not regulated by the FDA, until its regulatory interpretive epiphany precipitated by the wild west stem cell business. That yesterday’s workshop didn’t even address the FDA’s prior position or the public policy and possibly constitution underpinnings of the actual language of the rule which divests the FDA from the business of regulating same-day autologous transplants, is disappointing, but not necessarily surprising, considering that the purpose of the workshop appears to be providing expert cover and justification for the FDA to make the draft guidelines final.
So how does the FDA get away with asserting jurisdiction over procedures which seem beyond its purview? The answer is in its Adipose Draft Guidance document.
Here is the draft guidance document:
It’s a nifty trick: It interprets the phase “implants such HCT/P’s” as meaning that anything the unproven stem cell transplanters do beyond rinsing the material turns the HCT/P’s into something other than the “such HCT/’s.” i.e. the HCT/P removed. Really!?
Here is the exact language where the magic happens:
“Limited handling such as rinsing and cleansing to remove debris would allow the HCT/P from adipose tissue to retain the structural function, while other processing steps such as cell isolation, cell expansion, or enzymatic digestion generally would not. Thus, if such other processing steps are performed that prevent the HCT/P from adipose tissue from remaining “such HCT/P,” the establishment manufacturing the HCT/P from adipose tissue would generally not be considered to meet the exception under 21 CFR 1271.15(b).”
It seems to me that the FDA’s interpretation is trying to backdoor the “more than minimal manipulation” idea contained in 1271.10 into the 1271.15 exemption from regulation and jurisdiction. But the “more than minimal manipulation” language isn’t in 1270.15. It’s an agency add-in, years after the regulation was passed, and as stated, it was not the FDA’s original position. The FDA’s textual jurisdictional reinterpretation seems far-fetched, inorganic and a somewhat desperate attempt to create jurisdiction over an activity which no one, including the FDA thought it had. Will it work?
In a fair fight; No, of course it wouldn’t work, but the FDA has the home court advantage on several fronts and these advantages might tip the scales.
First, in a court case, an administrative agency’s interpretation of its own regulations is given deference by the courts. I think the FDA’s position is attackable but you never know how far a court will bend over backwards to defer to an agency.
Second, you can’t sue the FDA on a draft or even a final guidance document because of non-intuitive and arcane non-finality rules of administrative law.
Ditto on warning letters. What that means practically is that if an “unproven” stem cell clinic keeps treating patients after receiving a warning letter, (which is basically an FDA cease and desist from engaging in illegal activity), the company can’t sue. It has to wait to see if the agency takes some kind of enforcement action. And here’s where it gets draconian.
Once there’s a warning letter, the doc or company is on notice that their actions are illegal, and specifically that they are violating what I call the FDA trifecta (introducing into interstate commerce an unapproved new drug, misbranding and adulteration). Before the notice, or actual knowledge of the violation, we’re talking civil liability and/or at most a criminal misdemeanor, which means probation.
After the warning letter, if there are continuing “violations,” that’s an intentional criminal act which means felony and hard time. So after a warning letter, the only safe play is to stop transplanting. (That’s what the Regenerative Science guys did after they got the warning letter. They sued, got thrown out of court, got sued by the FDA, fought the suit, but stopped doing stem cell transplants during the course of the litigation in case they lost, which they did.)
Bottom line is that docs and companies are disincentivized by the FDA and the system from challenging FDA action even if the action is or maybe outside of the FDA’s regulatory jurisdiction. But I’m hoping that if these guidelines go through and the FDA starts tossing out warning letters, some company is going to take a stand. I hope they do, and I’d like to be the one that smacks them down. Been there, done that, feels good (See chapters 2, 4 and 10 (on the first stem cell criminal investigation) in my book Galileo’s Lawyer).
So let’s get out of the legal weeds of administrative minutiea. It seems to me that the FDA is trying to exercise powers over same-day transplanters that it does not currently have. Maybe it should have that power, or maybe not. But whatever the ultimate policy answer should be, it needs to be discussed and studied. The luminaries yesterday didn’t do it, and I fear their myopic, one-sided view of the world and their ignoring of why autologous transplants are different and heretofore beyond the purview of the FDA regulators needs to be discussed. Since it hasn’t been done in this workshop, the FDA needs to arrange a do-over with other more open minded, informed thought leaders.
There’s more to be said beyond these legal and policy points, but the hour is late and tomorrow is another day.
Rick Jaffe, Esq.