I had something else planned for this week, but then a journal article came out that struck me as a really bad harbinger of limited access to expensive treatments in the future, not just for the XLH community, but for all patients and all conditions, both rare and common. Sometimes patient advocates are warned not to get angry, because then our arguments can be dismissed as the hysterical ravings of a lunatic. But I think a bit of focused and righteous anger is justified in some circumstances, and this is one.
Why am I so angry? Because the XLH community, along with other rare-disorder communities that are lucky enough to have an effective treatment, is becoming a test case for how to limit access to expensive treatments — biologics now, and gene therapy soon.
As treatments become more expensive, more and more patients will be told that they’re not suffering enough to justify the cost. We’re not alone in getting this response (I’ve heard of examples in other rare disorders), but we’re in the forefront, as one of the very few rare disorders to have a treatment. We’ve seen this kind of analysis in rulings by governmental agencies in Canada and France, which have decided that only children are suffering enough to get effective treatment. Everyone else, well, who cares about us adults? Apparently fractures, spinal stenosis, enthesopathy, chronic pain/fatigue, and increasing disability aren’t enough to justify access to the only treatment that actually works.
I obviously disagree with that conclusion, but I can understand that the payor of the bulk of the cost (governmental agency or insurer) is going to do a cost/benefit analysis and try their hardest to avoid paying. It’s quite another thing to suggest that clinicians should decide on a treatment plan based on the cost, and contrary to the best interest of the patient.
But now we’re seeing this kind of analysis from the point of view of the clinicians. There’s a new journal article that essentially says XLH children with “mild” symptoms aren’t suffering enough to justify access to a demonstrably better but expensive treatment. It’s in the Endocrines journal’s special issue on XLH: “Treatment of XLH in children.” Here’s the conclusion: “While clinical trials have so far shown burosumab to be more effective than conventional therapy in severe XLH, the effect of burosumab on mild XLH is still unknown. Further, the annual cost of burosumab therapy is enormous (about US $200,000). Therefore, conventional therapy should be attempted first in mild cases.”
There’s just so much wrong there. And the authors would know that, if they’d ever listened to patients. Really listened. And understood the whole-body, whole-life, whole-family nature of XLH.
First, the authors are making a big leap of logic, going from “the effect of burosumab on mild XLH is unknown,” to acting as if there were proof that “the effect of burosumab on mild XLH is not beneficial.” Admittedly, there are no studies of the benefits of burosumab on mild symptoms IN CHILDREN (but there are in adults). The pediatric clinical trials recruited patients with more severe symptoms for obvious reasons; having serious visible symptoms made the benefit of treatment (or the lack of benefit) easier to quantify. But it’s disingenuous to say the lack of data specific to a vague, undefined subgroup of patients is a reason to hold off on providing some patients with state of the art treatment. We do have evidence in adult trials of benefits across a range of symptom severities, and there’s no conceivable logic for why kids with mild symptoms wouldn’t benefit the same as (or even better than) adults with mild symptoms. In the absence of evidence that burosumab is actually harmful (the authors didn’t posit any, and I can’t see any conceivable reason why it would be in mild cases if it’s not in severe cases), why wouldn’t clinicians offer the state of the art treatment to all patients? Especially when choosing wrong (is it really a mild case?) has devastating life-long consequences for the patient. What if, as adult studies suggest, burosumab is actually significantly more effective than phos/calcitriol across a wider range of symptoms, but we don’t have the data to prove it for another ten or twenty years, since the most disabling symptoms like enthesopathy don’t appear until several years into adulthood? The damage done by not having access to effective treatment in those intervening years, especially relating to growth in kids and progressive enthesopathy in adults, is irreversible. We’ll end up with another whole generation of disabled XLH adults, except that this generation could have been helped if only their clinician hadn’t wrongly concluded they didn’t deserve state of the art treatment.
Second, what is a “mild” case of XLH? There’s no recognized definition for it, and if clinicians are going to deny a patient access to state-of-the-art treatment, it ought to be based on a scientific and objective standard. There’s no guidance in the journal article, and I can’t think of any test that would work. It’s well-known that there is a wide range of severity among XLH patients, including those with the same genetic variant, so you can’t assume that the child of a mildly affected adult will also have mild symptoms. The Rickets Severity Score (x-ray readings) have a subjective element, in that they depend on the skill and experience of the person reading the x-rays, and very few radiologists will have seen enough images of rickets to score them. Further, given the whole-body nature of XLH, there really is no such thing as an objectively “mild” case. There may be mild visible symptoms, as some bodies can apparently cope better with the low blood phosphorus than others. But doctors should know that the external, visible symptoms aren’t the whole story. We can have symptoms that show up on x-rays, and symptoms that can only truly be diagnosed with a bone biopsy (i.e., poor mineralization in places other than the ends of bones, where it’s visible as rickets). We also have invisible symptoms that, because they’ve been present our entire lives, are widely under-reported, especially to doctors who aren’t truly listening to patients but are judging us on visible symptoms. I had persistent chronic pain and fatigue as a kid, but because I’d never known what it was like to live without them, I never mentioned them to anyone, least of all my doctors. So if your definition of “mild” is based on visible signs, you’re under-treating your patients.
Third, a so-called mild case in childhood, if not treated as comprehensively as possible, frequently become a severe case in adulthood, and there are no crystal balls for pediatric endocrinologists to see the patient’s future to know which mild cases will become severe. I had mild visible symptoms as a kid — short stature, but taller than most girls with XLH, and only slightly bowed legs. But that mild case has become severe in adulthood, with widespread enthesopathy and spinal stenosis, all presumably related to the poor mineralization in childhood. The patient community is rife with examples of mild pediatric cases, including those who were well treated (to the limits of scientific knowledge at the time, with phos/calcitriol) during childhood, who are now adults with disabling symptoms.
Fourth, the article assumes that the old phosphorus/calcitriol treatment is effective and that’s why it’s good enough for mild cases. Except, as patients know, the old treatment really isn’t comprehensively effective. If the authors really thought about it, they’d even admit it. They say, “conventional therapy is effective, but leg deformities and diminished adult height persist in some patients with XLH despite long-term therapy.” The only way to conclude that the old treatment is effective is to define effectiveness very narrowly, as improving leg bone formation and overall height. Even then, as the authors admit, the old treatment leaves at least some patients with leg deformities and short stature. And they’re ignoring all of the other “whole body” symptoms, especially the clearly established fact that the old treatment doesn’t adequately mineralize bones (unlike burosumab), which is why adults who were treated with phos/calcitriol as kids have gone on to develop progressive, disabling enthesopathy at an early age. (There’s a good new journal article on the cause of the enthesopathy being related to poor mineralization, which I’ll discuss in the future.) If you look at the whole range of symptoms, not just leg bones and height, you can see that the old treatment was never truly effective, not for mild symptoms and not for severe ones. In the past, it was all we had, so its marginal benefits were better than nothing (except for, yanno, the permanent kidney calcification and hyperparathyroidism we’re left with, due to the treatment). But we have a better option now, so why on earth is anyone suggesting we continue to use a proven-inadequate treatment with serious side effects?
Fifth, the article gives the impression, which has been disproven and we patients are working so hard to counter, that XLH is purely a pediatric bone disorder, and once our bones are formed, we go on to have normal health. Both authors are pediatric endocrinologists, so it’s unlikely that they’ve treated enough adults with XLH to see just how bad the health of their pediatric patients becomes over the years. I can’t tell from the article if they’ve ever read the articles on the burosumab studies in adults or reviewed the data, but the authors don’t cite them in their overview of the clinical trials. If they had read them, I don’t know how they could have reached the conclusion that “the effect of burosumab on mild XLH is still unknown.” There may not be evidence specific to kids, but there is ample evidence in the adult studies, which did not have a requirement of severe symptoms. The adult studies involved a wider range of severity than in the pediatric studies, and yet, virtually all of the patients in the adult studies benefited from burosumab. I would add that I doubt we could ever get data comparing burosumab to phos/calcitriol for kids with mild symptoms, given ethics considerations. How could researchers justify withholding a known-to-be superior treatment from kids who have a limited window of opportunity to grow and form straight bones, just to confirm that, yes, even mild symptoms in kids do respond better to burosumab, just like they do in adults? How could a clinician look a patient’s parents in the eye and say that withholding state-of-the-art treatment for a year (or longer!) didn’t carry the risk of leaving the kid permanently worse off (remember the nephrocalcinosis and hyperparathyroidism with phos/calcitriol) than if they’d had access to the newer treatment in that timeframe? And what truly informed parent would consent to it?
Sixth, even if you agree with the basic assumptions, the conclusion makes no sense. Let’s say it’s true that there are objectively identifiable mild cases who will never develop severe symptoms, and that these patients may not get AS MUCH benefit from burosumab as the severe cases do. So what? Viewed purely from the point of view of the patient’s best interest, how does that matter when, if nothing else, burosumab has no irreversible adverse side effects and the old treatment does? The authors point to absolutely no evidence that mild cases would do WORSE on burosumab, and I can’t even imagine any scientific explanation for why that would ever happen, especially given that it’s been shown in the adult trials that adults with relatively mild symptoms do better on burosumab than they did on the old treatment. It’s also incontrovertible that phos/calcitriol has serious, irreversible side effects (kidney calcification and hyperparathyroidism), while the authors admit that burosumab has no significant side effects whatsoever. So, if the clinician just looks at what’s best for the patient, why on earth would they prescribe something that is consistently less effective (in both practice and theory), and that ALSO has serious side effects, when there is a demonstrably better treatment with no irreversible side effects? As long as there’s no reason to think the new treatment is WORSE for patients (which there isn’t), why not give the patient the benefit of the potentially better outcome?
The only explanation — and it’s pretty horrific from the patient point of view — is that the authors are advocating that clinicians use a cost/benefit analysis, rather than doing what’s in the best interest of the patient. Price is the only reason given for NOT using what’s either an equal or, as I believe the data shows, a demonstrably better treatment for some of the pediatric patients simply because, in their judgment, the patients are suffering enough to just a cost that’s “enormous.” Seriously? Do we really want the treating doctors deciding which of their pediatric patients are worth spending money on and which aren’t? (The price of pharmaceuticals is a problem, but that’s something to solve in the political arena, not in the doctor’s office.) Health care providers have a duty to their patients, not to the entity paying for the treatment (insurer or government agency).
I don’t know about you, but I expect my doctor to be advocating for the best possible treatment for me, not one that’s “good enough” in light of the doctor’s perception of my degree of suffering. It’s the role of the insurance company (or in national health care systems, the governmental agency) to argue that my condition isn’t bad enough for an expensive treatment, and that a less expensive one will work. And for XLHers, the treating doctor should then respond with the existing, absolutely clear evidence that the less expensive option does not work anywhere near as well, and the adverse effects won’t be seen for decades, when they’re too late to fix. Doctors advocate for their patients all the time, so why make an exception for XLH patients? It would be different if we were talking about the choice between a brand-name treatment and a generic one, but we’re talking about the difference between the ONLY truly effective and government-approved treatment for XLH and an off-label treatment that has only minimal benefits while also causing significant adverse side effects.
I really wonder if the authors of the article (and all the peer reviewers who approved it) realized the implications of what they are saying — that some patients aren’t suffering enough to be worth effective treatment, and that doctors should be the ones to decide who is suffering enough, based on some vague impression of what the current symptoms say about their future health, and who isn’t suffering enough. If this becomes a precedent, the future of access to new treatment options is really bleak. Imagine in a few years when there’s gene therapy for XLH, a once-and-done option that will likely cost far more than burosumab up front (but save money in the long term, while also improving our quality of life). Do clinicians really want to be doing a cost/benefit analysis for their patients, deciding that some are only suffering enough to justify the cost of phos/calcitriol treatment, some are suffering enough to get burosumab, and a lucky few others are suffering enough to get gene therapy? And how are the clinicians going to feel twenty years later when that first group starts developing enthesopathy and spinal stenosis due to inadequate treatment during childhood when there was an effective treatment available, but their clinician didn’t think they were suffering enough to get it? Will they be suffering enough then?
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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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