The Carolyn and Matthew Bucksbaum Professor of Clinical Ethics at the University of Chicago spoke about the ethical considerations of spinal muscular atrophy and its treatment.
Lainie Friedman Ross, MD, PhD
At the 47th Child Neurology Society annual meeting in Chicago, Illinois, NeurologyLive sat down with Lainie Friedman Ross, MD, PhD, Carolyn and Matthew Bucksbaum Professor of Clinical Ethics, University of Chicago, to discuss ethical, psychosocial, financial and quality of life issues raised by development and implementation of new novel therapies, particularly of spinal muscular atrophy (SMA). From an ethicist’s perspective, Ross questions when a novel therapy is ready for implementation into newborn screening and whether SMA is an appropriate condition to include in the Recommended Uniform Screening Panel.
With the approval of Spinraza having the potential to change the course of the disorder, a number of ethical challenges revolve around its use from its cost to the logistics of delivery.
Ross hopes that in the future, treatment for rare genetic disorders continue to advance and not merely slow down symptoms but are instead curative.
Lainie Friedman Ross, MD, PhD: I was part of the Presidential Symposium talking about New Conversations and Ethical Considerations in the Development and Implementation of 21st Century Novel Therapies. As the title suggests, my talk focused on examining the ethical issues raised by these novel therapies.
I used spinal muscular atrophy (SMA) as my case study to look at the question: when is a novel therapy ready for implementation. I was looking specifically at the question, when is a new therapy ready for implementation into newborn screening (NBS), into what’s called the RUSP, which is the Recommended Uniform Screening Panel. Ten years ago, SMA was rejected for inclusion in the RUSP by the Secretary’s Advisory Committee on Heritable Disorders of Children and Newborns both because an effective treatment did not exist and because of the lack of pilot data showing the utility of screening. Then several pilot studies showed that it was feasible to screen and in December 2016, Spinraza got approved which began to make implementation more feasible. Another obstacle for inclusion into newborn screening programs was that SMA screening requires genetic testing as first tier testing. First-tier genetic testing as part of newborn screening was only first added to the RUSP in 2010 with the inclusion of screening for severe combined immunodeficiency syndrome (SCID). This paved the way for NBS for SMA because it would be the second one to use the same methodology so the newborn screening laboratories already had the experience and the set-up. In fact, even before SMA was chosen for inclusion into the RUSP, screening had been implemented in several states.
From an ethicist’s perspective, one question is whether SMA is an appropriate condition to include in the RUSP? One of the things about including a condition in the RUSP is that you want to test for conditions in which early treatment will prevent morbidity and mortality, and, with SMA, we have very little data because the treatment was rushed through with FDA rapid approval. Thus, one concern is that we don’t have much long-term data. A second concern is that individuals with SMA fall along a broad spectrum including at least 4 or 5 different categories and some of them are associated with later onset. For example, Type 4 SMA does not develop until adulthood and some type 3 cases also do not present for decades. This means that you’re identifying people for whom not only don’t they need immediate treatment but for whom you are taking away their right to privacy from everybody—including privacy from their parents. Whether they would want that privacy is a separate issue. It also is a question of how do you get that information to the adult internist who may see the patient with symptoms 25 years from now, by which time the patient may have forgotten the risks his parents told him about or his parents may have not said anything because he didn’t need treatment and was asymptomatic and they may no longer remember or be alive to share the information when it becomes relevant.
The other aspect I talked about is that Spinraza is great, it’s really helping infants diagnosed with SMA-1, but it is not curative. It will change SMA from a fatal condition to a more slowly progressive disease. As such, new therapies still need to be developed and this raises the question of how do you do research ethically when a treatment already exists. Since there were no therapies, efficacy of Spinraza was studied by giving some participants placebo while others received Spinraza. A placebo-controlled trial was ethical because there was no standard of care, but now that Spinraza exists, it would seem problematic to withhold Spinraza from children with SMA, and this complicates how to test the new treatment. Research ethics documents like the Declaration of Helsinki state that all participants must be offered the standard of care.
How do you ethically test a new therapy when we have to make sure that all children have access to the best available treatment? One solution is to test a new therapy against Spinraza, but comparative studies need to be much larger than studies comparing an experimental therapy against placebo. Comparative studies also only show whether a new therapy is as good as an old therapy, but the gold standard for FDA approval is to show superiority. A second solution is to test the new therapy in a different class of patients with SMA for example, to test individuals with SMA 3 but here you don’t know when their symptoms would start so it is hard to know when to treat and how to know if the drug is working.
A third solution is to offer all participants Spinraza and then compare Spinraza plus new therapy against Spinraza plus placebo. This has problems because you have not shown that the new therapy works by itself, it also means that we’re going to be afraid to take away the Spinraza. Consider, for example, a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. If this therapy were successful, clinicians may still be afraid to stop Spinraza. Consider an analogous scenario: in the late 1980s, polyethylene glycol (PEG)- adenosine-deaminase deficiency (ADA) was FDA approved for SCID caused by ADA deficiency. The very first gene transfer trial for ADA-SCID began in 1990. The first patient, Ashanti de Silva received PEG-ADA, enzyme replacement therapy, prior to the trial, and so although 25% of Ashanti’s T-cells are still modified by the vector, she still receives intramuscular PEG-ADA. Spinraza is an intrathecal medication which has its own costs and risks.
LFR: Well, my hope for the future is that we continue to advance treatment for rare genetic disorders and develop therapies that do not merely slow down symptoms, but would be curative. I would also like to see fair access to novel therapies. Spinraza costs $125,000 per dose, it’s not clear that the access is going to be equally available to all communities in the United States. It also requires intrathecal administration which means that dosing must be done at a facility that has the expertise to perform pediatric intrathecal treatments. There are a lot of costs in terms of time and resources beyond the drug price tag. For example, intrathecal infusions of Spinraza will require trained personnel. Given the shortage of pediatric neurology providers, providing this therapy will exacerbate the shortage of neurologists who will be occupied with providing multiple doses of intrathecal medication, sometimes under sedation, while other patients wait to be seen. We have to think strategically about how we going to ensure that all kids have fair access to this good, even if it is not the perfect therapy.
Transcript edited for clarity.