Attending the International Symposium on ALS/MND in person, it was humbling to see 1,300 plus attendees committed to improving the lives of people living with ALS and searching for a cure. In talking with clinicians, researchers, doctors, and advocates, I did not meet a single person who was not absolutely committed to this community. It was clear that these folks were not there because of their job, but were there because of their mission. Whether they were involved in clinical research to find out whether compounds might impact the disease, basic science to improve our understanding of the disease, epidemiological studies to generate future hypotheses, therapeutic methods to help us lead fuller lives while living with the disease, or developing technology to change what it means to be disabled, these people were devoting their careers to helping me and my family. If I could only list one take away from the weekend it would be that. 1,300 people doing everything in their power for me, my friends, my wife, and our kids. That is never taken lightly.
However, no one is stopping me at one take away, so read on if you wish….
After three days of nonstop presentations and reading about hundreds of additional posters, it is hard to distill down what I learned. I think what is most exciting about the research landscape right now is the diversity of approaches. Researchers continue to race up the learning curve and are attacking the disease from a number of different directions. Neuroimaging, genetic discovery, telemedicine, antisense therapies, brain interface, induced pluripotent stem (iPS) cells, machine learning… While the opening session stressed how much we still do not know, it is incredible how fast we are filling in gaps. If you are interested in reading about these ideas, I encourage you to scan through the program here.
One of the purposes of the ALS/MND Patient Fellows program was to make sure the patient perspective was not lost in the scientific proceedings. Overall, I was deeply impressed by how connected most of the discussions were to the patient experience. In hindsight, I think there were two areas where the patient voice could have been stronger: invasive ventilation and ineffective placebo arms in trials.
Even with all of the exciting work that is going on and all of the people working around the clock to find a cure, the reality is we are still taking baby steps. We hope that some of treatments in the clinic may modestly slow progression. We hope that new approaches will enable us to have an impact on some subgroup of patients. These are not insignificant goals. It would be amazing if we could slow progress down by half. Four-to-ten years sounds a lot better than two-to-five. Patients surviving twice as long, means there would be twice as many of us around. However, we must deal with the reality that is today. Solely in terms of survival, no treatment or approach that was discussed at the conference is close to as effective at extending lives as invasive ventilation. Even with all of the complexity of the disease, patients die simply because their weakened diaphragms cannot pump enough oxygen in and out of their lungs. If a machine does it for you, you can live a long time.
The downside of invasive ventilation is that all of your muscles still die off, and you need someone to monitor your ventilator 24 hours a day to make sure it is clear and working properly. Many patients understandably choose to not go this route because they cannot imagine continuing their life attached to a machine for the rest of their life. However, many others have the motivation to go on and believe they could maintain a healthy quality of life on a ventilator, but cannot bear to impose the financial, physical and emotional burden on their families that goes with around the clock care. You either force a family member to give up the rest of their life to care for you 24 hours a day or you pay out-of-pocket for 24/7 care. Because of these factors, less than 10% of patients in the United States elect to go on a ventilator. In contrast, Japan’s national health service provides generous home health coverage and over 30% of ALS patients make the choice to go on invasive ventilation (Japan prevents patients from choosing to go off their ventilator once they go on it, which I believe prevents even more patients from going that route).
This is common knowledge in the community. Patients learn this early on and every neurologist understands it. However, I still think the topic of invasive ventilation should have remained a larger part of the conversation at the conference. Many clinical trials use time until “death or tracheostomy” to measure survival. They use Kaplan Meier survival curves and Cox hazard models to generate their analysis and it makes sense to use this definition when looking at the efficacy of a treatment. However, I think it may also lead us to lose perspective over the magnitude of the impact of a ventilator versus anything else we are considering. Nothing else can extend life by years for advanced patients. We measure the impact on survival of investigational products in terms of months. Sometimes weeks. Yet studies of patients in Europe show that among those who elect to have a tracheostomy, roughly 40% to 50% of patients choose to remain on their ventilator and survive longer than two years. When we grow accustomed to glossing over the statistics, we lose the political will to advocate for more generous health insurance coverage for care that could significantly extend lives.
When we compare the cost of providing the home health care needed to relieve the financial burden on families, it is no more expensive than a new drug. If patients received 100 hours a week of care, how many more would choose to go on a ventilator because it would no longer bankrupt their families or force a spouse to sit at their bedside? These patients would live years longer. Yet the cost would be about the same as the sticker price on a new drug in the rare disease space. I understand the need for drug companies to make money. I understand that high prices on new drugs attract more research. Pharmaceutical companies are making billion-dollar investments. We need more of them to do that in the ALS space, and that is happening. I have no problem with high drug prices. However, how do we rationalize covering $150,000 per patient per year for a drug that has a small effect, while not covering financially commiserate home care that would allow patients to live substantially longer? If there was a drug or a device that ensured an ALS patient could breathe 24 hours a day, researchers would declare it a game changer, patients would be ecstatic, insurance companies or Medicare would consider $150,000 a year a bargain… However, insurance coverage for paying a Certified Nursing Assistant (CNA) the same amount to do the same job is rarely discussed. Every researcher who includes a survival curve in their analysis should include a line for patients who go on a vent just to make sure we do not lose sight of what is possible for patients right now. I believe continuously reinforcing these ideas is necessary to generate needed momentum in the community to achieve real change that could immediately impact patients’ lives.
Ineffective Placebo Arms
The second area where I thought the patient voice could have been stronger was with regard to placebos. Patients are rarely excited about the possibility of receiving a placebo in a trial. When you enter a trial and endure all of the burdens that come along with the process (though it is exciting to see many researchers thinking creatively to minimize this burden), you selfishly hope that the treatment will help you out. Most trials require patients’ initial symptom onset to have occurred within the last three years. So once they are diagnosed, many patients are only able to enroll in a single trial before they “age out”. When your prognosis is two-to-five years and nothing currently on the market has a big effect, this may be your only shot. However, especially in ALS, many clinical trial participants are also eager to enroll to help further the search for a cure. You feel helpless, so here is something you can actively do. We do not have very effective means to measure the effectiveness of treatments, so an important part of the trial process is establishing an accurate baseline. To figure out if something works or not, you have to be able to estimate how trial participants would have progressed without treatment. Placebo arms are one way to try and get at this.
My concern is that in multiple presentations researchers made offhanded remarks about how maybe the placebo group just happened to progress slower than expected when explaining negative results from trials. As a patient, this was a huge red flag. In order to further the science, we reluctantly agreed to enroll in trials where there was a possibility we would receive a placebo, yet the trials were designed in such a way where we didn’t learn from our participation?!?! I don’t think the researchers truly realized what they were implying to patients who volunteered for their studies.
Perhaps including placebos is a necessary evil, but if that’s the case, let’s make certain that our placebo arms are accomplishing their mission. If we learn something does not work, fine, we move on. But we cannot repeatedly say we don’t trust our baselines that were established by a bunch of patients using their one shot to serve as the controls.
The biggest issue with establishing a baseline in ALS isn’t that there are oversized or unknown placebo effects, it is that people progress at different rates and even their own progression rate varies over time. There was session after session about heterogeneity and all the problems it presents and how much we don’t understand. Phenotypes, clinical presentation, genetic variation, etc.… So why are we basing this crucial part of our trial on how a small group of patients, who unfortunately got allocated to the placebo arm, happen to progress?
Researchers talk about finding a balance between having enough patients on placebo in order to conduct good science, while not having so many as to impose an undue burden on their volunteers. However, it does not have to be this way. We have thousands of data points from failed trials. We have tracked thousands of patients who participated in trials, but were on placebo. They thought they were being treated. Instead of reestablishing this baseline for each trial from scratch, let’s leverage what we have learned. If we believe there is a need for concurrent placebo controls in a trial, let’s at least supplement the data with a bunch of observations from people with similar characteristics so that our results aren’t dependent on whether one patient who ended up in the placebo arm happened to do better or worse than average. If we really want to move into the 21st century, let’s leverage data analytics to see how patients in each arm of the trial do compared to predictions of their likely progression based on patients on placebo from other trials. If you are super conservative, include this supplementary data to generate secondary endpoints. If you insist that stratification is the way to go, then stratify on a prediction of likely progression informed by thousands of data points, not a necessarily small number of characteristics that may crudely be associated with progression.
No matter what we do though, let’s ensure that patients are not using their one shot in vain. The only thing worse than finding out you were in the placebo arm, is finding out that you were in a placebo arm that was constructed in such a way that we didn’t learn anything from it. We showed up at repeated follow-up visits. We endured all sorts of tests. After all of that, researchers must ensure that we are playing a valuable role in the process.
NOTE: The above blog post was written by Stephen Finger, Ph.D., a person with ALS and ALS/MND Patient Fellow. Only minor edits were applied to it by a Selection Committee member prior to publication, mainly to remove shorthand or jargon originally used. The opinions expressed are Stephen’s and are not necessarily a reflection of those held by other Patient Fellows or Selection Committee members. To learn more about Stephen or to contact him, click here.