Something I learned from the FDA’s listening session on clinical trials for gene therapy (which you can watch here), is that there are some unique considerations for whether to participate in this kind of trial, especially in the rare-disorder setting.
There are risks and benefits to the patient in any clinical trial. The most serious risks, of course, involve side effects of the treatment being studied, while the benefits involve the possibility that the treatment will be as good as its developers hope it will be! Before enrolling in any kind of study, patients are given information that is supposed to lay out those risks and benefits, and it’s important for the patient (or caregiver of a minor) understand them thoroughly.
I’ve been involved in two interventional drug studies (meaning that a drug was provided as part of the study, as opposed to others that simply observe without providing a treatment; natural history studies are NON-interventional studies). In the first study, I was aware that it was highly UNlikely the treatment would offer any real benefits to me personally, but the information would be useful to understanding XLH in general, ruling out a particular treatment as not providing significant benefits (which, ultimately it did; you can read the conclusions here, and remember than a negative conclusion — that a treatment did not work — is just as important scientifically as a positive one). So the “benefit” for enrolling in that study was mostly a philanthropic one — contributing to scientific knowledge. The risks, on the other hand, were pretty minor, because it was a drug that had been used for other purposes, with few side effects, none of them particularly significant. Since I care about increasing scientific understanding of XLH, and the study’s timing and location were convenient, it was an easy decision for me, with the benefit outweighing the tiny risks and small travel burden.
The second study I participated in was interventional, for a new treatment (burosumab). The risks were a little higher, since it had only been tested on a very few patients and therefore could potentially have side-effects that were unknown up to that point. On the other hand, the possible benefits were huge; if it worked as expected, it might prevent my severe symptoms from getting any worse, so I would be independent longer. So, again, it was a simple decision for me, with the risks outweighed by the potential benefits.
The same kind of risk/benefit comparison needs to happen when considering a gene therapy clinical trial. In general terms, the analysis is the same as for other types of treatments, but there are a couple differences that I hadn’t been aware of before this listening session.
In simplest terms, from what I understand, gene therapy involves two elements: the virus that delivers the treatment, and the treatment itself (the modified cells). The delivery viruses have been studied widely, and the consensus is that they are safe, so we don’t need to worry too much about that element. By the time a treatment (specific modification of cells) gets to the point of human trials, we also know that the treatment is effective at the cellular level, and there’s no real reason to expect any side effects, since the treatment simply corrects a genetic defect, as opposed to introducing a foreign substance like a drug/antibody. So the main question for gene therapy clinical trials (in addition to confirming safety and effectiveness), is the appropriate dose.
And that’s where the analysis for a patient considering participation in a study gets tricky. As I understand it, and based on what is known today by scientists, patients have one chance at gene therapy for a given disorder. Gene therapy is intended to be “one and done” treatment, unlike drugs/antibodies, which require ongoing administration. So with a drug/antibody treatments, a volunteer might get a specific dose initially, and then adjustments can be made over the course of the study, with each subsequent dose, or might get a different dose after the study, once the treatment becomes commercially available. With gene therapy, however, there are no do-overs. There’s just one dose given per patient, and it either works (completely) or it doesn’t. And in the clinical trials, there has to be a range of doses randomly assigned to patients, from the lowest that’s believed to be effective to the maximum that’s believed to be safe. Plus, there will be a placebo group that does not receive a treatment at all (although they will eventually be able to get a dose once it is commercially available).
That introduces all sorts of complexity into the decision-making. A patient entering the study has no way of knowing if they will 1) get the real treatment at all rather than placebo, or 2) whether they will get a dose that’s sufficient to cure them. And unlike with a drug/antibody treatment, if the initial dose is real but insufficient, the patient cannot simply be given a different dose in the future. Plus, there are apparently rules that would prevent a patient who receives the placebo from enrolling in a different study later on (within a fairly long time-frame), which would give them a chance at getting the real treatment before it becomes commercially available. (These rules may get changed eventually; it was an issue that advocates encouraged the FDA to find solutions to.)
The uncertainties, of course, focus on the worst-case scenarios (which, as a lawyer, I’m trained to look for). There are also best-case scenarios, where participants will indeed get the real treatment AND at a dose that’s either completely or largely effective, and more participants are likely to fall into those categories than in the worst-case scenarios. The decision to participate (or not) will probably depend in large part on a given patient’s (or caregivers of minors) risk tolerance and the severity of their symptoms. A patient with severe progressive symptoms is more likely to be willing to take risks than someone with milder symptoms, especially with a progressive disorder, and a long wait until the treatment becomes commercially available (easily five to ten years after the trial begins). On the other hand, a patient with milder symptoms might decide to wait. (One speaker in the video linked above did indeed decide to wait for commercial availability of gene therapy for his disorder, because his symptoms were well-managed with then-current treatments.)
There’s no right or wrong decision here, no decision that’s better for everyone, but it’s important that patients (and caregivers of minor patients) understand the risks and benefits so they can make the decision that is right for them. The video linked above, especially the first hour or so of advocate presentations, starting around the twenty minute mark, is really worth spending some time with now, so you’re prepared later on when opportunities arise, and you’ve gotten information from a reliable source. Everything about gene therapy is complicated, and there’s a lot of scary misinformation out there, so it would be easy to feel overwhelmed or jump to a conclusion that’s wrong for you (either to participate or to wait).
I want you to be able to make the best decision possible for yourself and your loved ones, and that starts now, learning a bit about the basics of gene therapy and how it’s tested in clinical trials. Let me know if you still have questions about gene therapy clinical trials (short of what requires a PhD to understand!), and I’ll do my best to get answers.
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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