The FDA held a listening session recently to hear what patients (and their advocates) had to say about clinical trials for gene therapy. The presentations were absolutely amazing, especially some of the early ones where organizations had really done their homework, holding focus groups and disseminating surveys to learn more about their community’s preferences and concerns about clinical trials for gene therapy. I highly recommend watching the videos from the event. You can watch the recordings here. It’s long, so if you can’t watch the whole thing (although I highly recommend making the time, even if you have to take breaks and return to it later), at least take a look at the first hour or so of testimony (you can skip all the introductory stuff if time is short; and go straight to where the first advocate speaks, which is around minute 20).
The only things I thought were missing were: 1) comments from representatives of a non-life-threatening disorder, and 2) concrete ways to ensure early patient engagement in designing clinical trials. I tried to fill those gaps a tiny bit with my comments, which I’ve pasted below (and I’ll talk more about the video presentations in a post next month):
I am a patient with x-linked hypophosphatemia (XLH), or, more generally, a form of chronic hypophosphatemia. All of the chronic hypophosphatemias (genetic or tumor-induced) are progressive and, to various degrees, disabling, but generally not fatal. Given the role of phosphates in virtually all systems of the body, patients with low blood-phosphate levels have whole-body, whole-life, and whole-family symptoms.
While the speakers for the event did absolutely amazing work, I believe they (and the five commenters before me) all had or represented a condition that was either terminal in the short term or potentially terminal (e.g., blood clotting disorders). Accordingly, they could not present the point of view of patients whose conditions significantly reduce quality of life while not (directly) reducing quantity of life.
The chronic hypophosphatemias, like my XLH, are an example of: disorders that are not either potentially or imminently terminal (other than GACI, fatal for some, not all infant patients), but are nevertheless severely disabling over time. The risk-benefit analysis may be somewhat different than when the condition is terminal, but the basic principles remain the same: patients deserve the best possible treatment at the earliest possible time, and to ensure that outcome, we need to participate in the development of that treatment, and we need to be truly heard when it comes to our perceptions of the risks and benefits of the treatment and the clinical trials to develop it.
Accordingly, I’m here to say that quality of life matters in risk-benefit analyses. The basic position taken by the presenters during the live event remain the same for non-terminal disorders: patients (or caregivers of pediatric patients) understand better than anyone else the risks of doing nothing (or remaining on a marginally effective treatment). We may not be at risk of dying, but we know that our conditions are progressing; and we know that the day is coming when our quality of life will be so bad as to be not worth living. Please believe us (and take steps to encourage treatment sponsors to truly listen to us) when we say how bad our quality of life is (or is likely to become). Too often our descriptions of pain, fatigue, and mobility restrictions are discounted as inconsistent with what the health care professionals mistakenly think they already know about our lived experience.
During the risk-benefit analysis, it will also be important to look at the whole life of a patient with these quality-of-life disorders, not just whether they’re significantly disabling at the time of diagnosis or at the time when a treatment regimen (or potential treatment in a clinical trial) is developed. The chronic hypophosphatemias are clear examples of disorders that can be relatively mild in childhood (there is a wide range of symptom severity), and yet without early treatment those seemingly mild symptoms often progress to destroy a patient’s quality of life at a relatively early age. I had virtually no obvious symptoms other than short stature and some mildly warped leg bones during childhood, and did not start to recognize more serious symptoms until I was in my twenties, and yet I became totally disabled in my forties, all due to a combination of secondary effects from the early warping of my bones, plus the ongoing lack of phosphates over the years. By the time my symptoms (the calcification of the spine and all major joints) became disabling, it was too late to undo the damage. This kind of progression can be glacially slow, so even the patient doesn’t consciously notice it until it’s too late, which is why it’s important to provide treatment early on, when the symptoms seem mild but are highly likely to evolve into a seriously disabling collection of irreversible secondary effects of the underlying condition (like calcification). If patients with a quality-of-life disorder are not provided with the best possible treatment at the earliest possible time, the damage from the disorder may progress to a point of no return before treatment is offered. Therefore, the long-term risks from progression of the disorder need to be factored into the risk-benefit analysis, not just the immediate risks and benefits.
Beyond that slight difference in the risk-benefit analysis, I whole-heartedly endorse what the other patient advocates said during the event, namely that patient engagement should happen very early in the process (when protocols and endpoints are first considered). I would like to offer some concrete ways in which the FDA could support that, and would suggest looking to PCORI for ways to better ensure that treatment sponsors are truly engaging with patient-advocates at the very earliest point in the planning for a gene therapy (or any therapy really) clinical trial.
Everyone likes to say that engaging patients early in the research/development process is a good thing. And, logically, it makes sense. The last thing anyone wants is to waste time and money and limited resources (including the FDA’s time) on a treatment for an endpoint that none of the patients/caregivers care about. But then patients/advocates ask to be involved early in the process and are blocked, either by the treatment sponsor thinking they already know what patients want, or by the FDA’s own procedural rules.
There are two concrete steps the FDA could take to improve the early engagement of patients/caregivers in the process. First, require treatment sponsors to certify in their applications that they have, in fact, engaged in significant discussions with the patient community, and require that they list the steps they have taken to do so, including the names of the patient advocacy groups they interacted with and the topics of discussion. And give the patient advocacy group for the disorder, if there is one, the opportunity to acknowledge that they did engage with the sponsor and whether they believe there is anything the FDA should know that they felt was not adequately addressed by the sponsor. This will put some pressure on the sponsors to take the patients more seriously than the engagement that I see too often, which is all (mostly) talk, no (little) action.
Second, change the rule that patient advocates cannot attend sponsor meetings with the FDA unless the sponsor itself invites the patient advocates. Ideally, I’d like to see an invitation to the relevant patient group be issued by the sponsor as a routine part of the application. Alternatively, I’d like to at least see the sponsor be required to list the relevant patient groups in the application, and then either indicate a willingness for appropriate representatives to attend the meetings, or an explanation for why representatives should be excluded, or what topics will be too confidential for patients to participate in, while otherwise attending the remainder of the meeting.
I can already hear the objections, most of which relate to confidentiality and protection against the sponsor’s competitors. But that infantilizes the patient community. Many patient advocacy organizations have excellent, professional representatives (as demonstrated by the extraordinary presentations during this events), capable of signing and holding to a confidentiality agreement. To say otherwise is to, once again, revert to the medical community’s tendency to view patients as children who need to be protected from themselves, instead of as the competent adults that we are, and is detrimental to achieving the very best results from medical research and clinical trials. I believe we miss out on so many potential opportunities for breakthroughs because scientists don’t know what they don’t know, and aren’t always willing to listen — really listen — to patients who do know the lived experience.
I’ve also heard the objection that we wouldn’t understand the technical discussions or we’d be bored. Seriously? It’s our lives (quality or quantity) on the line. We can handle a little boredom. Everyone might even be surprised by how much technical information we understand. We may not be organic chemists or geneticists, but we also know not to overstep our expertise to comment on those issues. What we do know, and what research can benefit from, is when a protocol is going to be burdensome (and therefore reduce participation or diversity) or when there’s an assumption about our lives that’s simply wrong, even if it’s not yet documented in any journal yet. Please trust us to know when to talk during sponsor meetings and when to listen and remain silent. Then make invitations for us to participate mandatory, rather than at the discretion of the sponsor.
Thank you again for holding this listening session. I look forward to seeing future guidance on clinical trials for gene therapy, as well as the day when the chronic hypophosphatemia community is involved in our own gene therapy trials!
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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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