Not unexpectedly, the organizing theme of the FDA’s Stem Cell workshop was that patients should only be able to receive their own stem cells for non-homologous use in FDA approved clinical trials until FDA marketing approval (i.e., until a New Drug Application is granted for some non-homologous use).
I’ve been involved in legal/policy issues relating to clinical trials for a long time. I understand that clinical trials is the standard of care for patients when FDA approved treatments (on or off-label) are not available for whatever reason. Still, I’m here to tell you that from the perspective of patients with life-threatening/incurable diseases, clinical trials aren’t always the best answer for them. Here is why I think so.
- The Purpose of Clinical Studies is to Test Drugs, not to cure patients
The fundamental and indeed the stated purpose of a clinical trial is to test the safety and efficacy of a therapeutic intervention, not to cure a specific patient of a specific medical condition.
One of the presenters mentioned some empirical data indicating that there is a disconnect between this purpose and the patients’ understanding of the meaning and purpose of clinical studies. My take-away from what he was saying was that many people mistakenly believe that the primary purpose of a clinical trial is to get the patient better. That misunderstanding is consistent with my experience over the course of several decades interacting with patients on clinical trials.
That the purpose of clinical trials is to test interventions, not to cure patients has specific practical consequences for patients which sometimes mean that patients do not get optimal care for the good of the study.
- Some Phase 1 study patients may not get enough of the drug/intervention
In phase 1 or toxicity studies, patients are specifically told that the purpose of their participation is to study a drug’s toxicity, not to test the efficacy of the drug, and while the investigators hope the patient will obtain some benefit, that is not the goal of the patient’s receiving the drug.
Early patients in some phase 1 studies receive relatively low doses of the drug, based on what the investigators believe to be the therapeutic dose. Doses often get escalated in later subjects in a phase 1 study. I believe this is common in toxicity studies. It’s kind of like you shouldn’t buy a car that was made right before a holiday weekend or on a Monday. Sometimes, it’s not ideal to be one of the first study participants in a phase 1 study, because you may not get what the investigators expect to be an therapeutic dose.
- How are you helped by a placebo?
Some studies are placebo controlled. Obviously there is no therapeutic intent for those patients. In cancer and other life threatening diseases, placebo controls are no longer employed, and in some placebo controlled studies, placebo recipients are sometimes offered the study drug later or much later. Still, if a patient is in a placebo controlled study. There’s a 50% chance the patient won’t receive the study drug (at least initially).
- In Phase 3 studies, you still might not get the study drug
You still might only have a 33-50% chance of obtaining the study drug in a phase 3 trials,
Most phase 3 studies compare the study intervention with FDA approved standard of care therapies. Patients are randomly selected into the different arms of the study, arms being the different groups that receive the study drug or the standard of care therapy. Some studies involve more than one standard of care control arm/option. If there are two different control arms, there is only a 33% chance of receiving the study drug and a 66% chance of receiving a therapeutic option which probably hasn’t worked too well.
- Most drugs in clinical trial drugs are not ultimately approved
It is true as reported at the Workshop that less than 5% of therapies entering clinical trials obtain NDA approval, but 1. There could be reasons other than efficacy why that happens, 2. Some agents just don’t work on a high enough percentage of patients to justify NDA approval but they do work on some, and if you’re one of those lucky people, you’re a happy camper. So I don’t see the fact that there is a low approval rate of study drugs as strongly supporting the banning of stem cells outside of clinical trials just because of that fact.
- What happens after the clinical trial is over for you?
Therapeutic interventions in clinical trials are usually given over a relatively short period of time and often there is some surrogate endpoint or target which is less than a complete cure. In cancer it’s called a response. Let’s say you get a response, or the target improvement in pulmonary function or whatever the parameter the drug is intending to influence. You’re a responder but not cured. Can you still get the Intervention if you need it?
In drug studies, there is a serious issue of continued access to study drugs after the termination of the study. Drug companies are not required to provide study drugs after the conclusion of the participant’s time in the study. There is a movement afoot to change that. I don’t know whether that is an issue in autologous stem cell clinical trials, but it could or would be if the guidance documents become final because it would then be illegal (supposedly) for the person to have access to his/her stem cells after the study.
- The Biggest Problem with Requiring Clinical Trials for All Autologous Stem Cell Transplants
Here is the big one. The underlying assumption of the FDA’s and the Workshop’s position –that autologous stem cell transplants should only be available in clinical trials – is that any patient who wants an autologous stem cell transplant can enter a clinical study. That seems unlikely, but that’s just my gut feeling. I’m not familiar enough with the stem cell clinical trials to know whether there is a large unmet demand, but in many diseases like cancer, a relatively small percentage of patients enroll or can enroll in clinical trials. In cancer, I think it’s something like 3 or 4%, and I’ve seen numbers like 40% of cancer patients would enter a clinical trial if they could. There are many reasons why some patients aren’t eligible for clinical trials, tied to a variety of factors. Some are too sick for the protocol entry criteria. Some may have had a prior disqualifying treatment (like a previous clinical trial). But my supposition is that there are many more patients out there why would participate in clinical trials involving stem cells, but can’t for one reason or another.
Assume that to be the case.
What are the policy implications and practical consequences?
On a policy level, there is going to be an arguably significant number of patients who have no therapeutic options. Of course the immediate response to that is what good is an unproven, possibly dangerous option? While it’s a fair question, it’s a better question for foreign interventions than a therapy derived from the person’s own body, because as stated, there are fewer safety concerns.
And, respectfully, I think it’s a too facile response by academics not facing no treatment options for a life-threatening condition. Let these guys who are so quick to cut-off treatment options come back after they have walked in the shoes of these terminal patients and their families.
What about the practical effect of the FDA’s plan to make illegal same day autologous stem cell procedures?
That’s easy and no crystal ball is needed. The cat’s already out of the bag, the cow has left the barn. Patients want the ability to use their own stem cells to treat a wide variety of medical conditions. Former Governor Rick Perry and Bart Starr believe in the therapy, and I dare say tens or hundreds of thousands of others do, and would try it in a heartbeat in there was no other reasonable alternative, whether or not there is an existing clinical trial for which they could qualify. If you’re the Governor of Texas, you can have someone shoot you up, consequences be dammed. Others will have to find other options.
It seems obvious that the effect of the FDA’s intended action will be to drive more people into stem cell tourism and to places which have less substantive and facility regulations than in the U.S. That’s not necessarily a good thing.
I hear one highly-regarded stem cell transplanter might suggest an expansion of the facility registration requirements (contained in 21 CFR 1271.10) to same day transplant facilities (exempt from that requirement under 1271.15). It would certainly enhance the safety profile of these clinics by providing some federal regulatory oversight. It’s a good and creative idea, but it would require a revision to the current regulations.
I have to believe there are far less draconian solutions to the legitimate safety, training and false or unsubstantiated claims concerns which worry the FDA and the institutional players. But maybe it’s time for some creative thinking, rather than a knee-jerk reaction to eliminate what seems to be much needed treatment options for many patients.
To my presenter friends and colleagues, looking forward to hearing what you have to say, (via the web anyway).
Rick Jaffe, Esq.