Before you mail us your Christmas cards this year, shoot me a text or an email and I will send you our new address. We moved to Atlanta this spring. It was somewhat out of the blue, but in hindsight it was probably for the best.
In 2015 we realized that we needed to move out of our current house because it was two levels and I was having a harder and harder time with the stairs. We sat down realizing that moving would only become more difficult for us as I progressed, so we tried to figure out where we wanted to be long-term. We decided we were very happy with our lives in South Carolina, so we found a house in Columbia, totally renovated it, made sure it was completely accessible, and made it our home. As things typically play out, then about a week after moving in, the company Cara worked for was bought. Over the next year her job got crazier and crazier and it was apparent that she needed to get out. Unfortunately, she was working at the only place in town that really did what she wanted to do. So we reevaluated our choices, she began looking for jobs in cities that we would consider moving to, and now we are in Atlanta.
Timing wise, the move wasn’t so bad. Mary Adair got to finish up first grade at a new school, and wasn’t yet too tied to her old one. James will start kindergarten in the fall, so he was already going to be at a different school from a bunch of his buddies. It meant that after a disappointing 4K year, he got a couple of months of Papa camp to get ready for the fall. I was already scheduled to go out on disability from the University of South Carolina. So other than leaving a bunch of really good friends, a routine we were super comfortable with, a city and a state that felt like home, and a house we had put a lot of effort into, it wasn’t such a big deal. But moving is never fun.
Mentally the transition was sort of complicated for me. It was hard to separate what the move would do to me versus what my progression would have done to me no matter where we lived. It was convenient to put on the calendar that once we moved to Atlanta, I would no longer drive. I had been saying I would drive for two more months for about three years, but the time had come. Mentally though it was easy to blame moving to Atlanta for not being able to drive. I was already scheduled to leave my job and stop going into my office, but the dropdead date was determined by the move. I am typically able to be a somewhat rational person, so whenever I focused on this, I tried to stop myself and realize these changes were coming no matter what. But it wasn’t always easy.
There was this weird abrupt transition. When Cara started her job in Atlanta, me and the kids were still in Columbia while some work was done on our new house. One day, the three of us woke alone together in the old house. I drove us to Dunkin’ Donuts. We had breakfast. I drove them to school. I went to my office. I drove and picked them up. The three of us drove to the run down hibachi restaurant around the corner from our house. And then we called it the night. The next day, we moved and in Atlanta I didn’t drive.
There were a million things to do around the house, but I couldn’t really do them. Things that I did 18 months before in our last move, were now out of the question. Now they all fall on Cara. My job was to meet with the handyman and a handful of contractors coming in and out of the house, but even that got taxing. I got tired and didn’t notice a rug was lifted up a little bit, and I tripped, my head bouncing off the hardwood floor like a billiard ball that jumped off the table. I tried to take a shower in the bathroom we had just torn up to make accessible, and I slipped getting out. Hell, I read too many books in a row on my phone and all the swiping caused my left thumb to twitch for four days straight, leaving me dependent on my right middle finger for placing the amazon orders and operating the remote. Going to new places is complicated and when you move everything is new. What is the entrance like? How crowded will it be? Do I need the scooter even if we are only going to be there for five minutes? Will there be any steps at all, making it a no go?
After living with this disease for four years, I am used to making adjustments. It just was a lot all at once. But after a couple of months, it is starting to feel like home again. I am used to the new house and intuitively know where the rugs are and where the furniture is. If the kids pick up their toys (if), I can comfortably walk around. I found a spot on the new couch where I can wedge myself down far enough so I can rest my neck. We figured out a solution to help me get out of the pool, so I still have that activity with the kids. We tested out Marta, and if someone drops us off at the station, the kids and I can get ourselves to the aquarium and have adventures. I “walked” them to camp up the street this morning. After going to two Atlanta United matches (Thanks Jonathan and Arod!) All four of us are totally hooked. Mary Adair takes it almost as seriously as her papa. Almost. Once they move into their new stadium, we have ADA season tickets lined up. Mary Adair got Sorry and Trouble for her birthday and we have been having fun battling it out. Card games don’t really work for me, but if one of them pops the bubble in Trouble, or flips the cards in Sorry, we are good to go. We hired an assistant who helps me shower, get dressed, and run errands a couple of days a week. I had my first appointment at the Emory ALS clinic and am excited to be close to the therapists. Charlotte was great, but it is harder to have follow-up appointments when it is 90 minutes away. The occupational therapist was eager to have me come into the office to show me all the gadgets they have for interacting with my phone or computer as my left thumb gives out for good. I went back and had a two hour visit with the physical therapist testing out all of the different wheelchairs and putting in my order.
And most importantly the big things have gone smoothly. After her very first day at her new school, Mary Adair got off the bus beaming and every morning jumped out of bed at 6:20 ready to head off. James and I had a great couple of months of Papa camp, powering through workbooks, reading stories, and exploring the neighborhood. He has met a bunch of kids who will be rising kindergartners with him in the fall. Cara likes her new job. Her mom moved down here and is a huge help keeping the trains running on time.
Moving is always awful and with ALS is even more so. Adjustments are hard, and a bunch all at once are harder. But other than missing some really good folks in South Carolina (and that banged up hibachi place), I think we have gotten it right.
This summer in Columbia has been absurdly hot. Columbia comes by its tagline of “Famously Hot” honestly. When it’s 100° every day, you really can’t go outside unless you are getting in a pool. Just about every day during the week, I pick the kids up early in the afternoon and we go home and swim. They took lessons at the beginning of the summer and after spending hours in the pool they have both become fish! They dive for toys, they swim back and forth, they jump in over and over again. But more than just being an activity for them though, it’s an activity for us. In the pool I don’t have to worry about falling over or be concerned with one of them running under my feet. We can all act silly together.
I can still walk around okay day to day, but it takes all of my concentration. I am constantly staring at the ground in front of me making sure there is nothing that is going to grab hold of one of my toes. In the back of my mind I am always aware of the consequences of one misstep. Walking around the yard, they know to give me space. They can run around, as long as they keep their distance. Even when I pick up James at school, I know to brace myself so that when he runs over to give me a hug he doesn’t knock me over. But in the pool we don’t have to worry about that. I can’t really use my arms to swim, but can keep up with them enough just kicking my legs. They can climb on me. I can give Mary Adair bucking bronco rides. James can give me a big bear hug and then we can jump up and down in the deep end, springing off the bottom of the pool. In the water, I can pick them up and wrap my arms around them.
There are also nice little discrete accomplishments that they can achieve in the pool. Last summer, Mary Adair was growing more confident swimming but still needed to grab the wall every few feet. I encouraged her to try and go a little bit further and a little bit further without holding on. Finally I convinced her that she might be able to swim the whole way across. After doing it, she was so proud. I didn’t really feel pride in her accomplishment, swimming across the pool isn’t the most impressive thing she has done, but I felt joy. Joy in seeing her pride in herself. The same way I felt joy this school year at how proud she was of her reading or of being able to solve little math problems. James realized he could swim without his floaty a month or so ago and I got him to try swimming across the pool. When he did it, mostly I had to fight to not laugh, seeing him climb up the steps and stand on the edge of the pool Ronaldo-esque, shirt off, hands on his hips, with his chest puffed out. Like his dad, he doesn’t really hide his pride. I could hardly hide my joy.
Mostly, the pool has been a place this summer where we can interact somewhat “normally”. There are plenty of other things that we do together and will continue to do together even as I become more limited physically. The simple conversations we have alone in the car on the way to school are a treat that we will eventually have to give up, but I know there will be something else we find to share. For now though, even without being able to throw them across the pool, or being able to do the craziest dives, playing in the pool is still something we can do together. And at least for the summer of 2016, that’s pretty special.
For the past 10 month I have served on the Benefit/Risk Working Group and ALS Patient & Caregiver Advisory Committee for the ALS guidance document (http://www.alsa.org/advocacy/fda). The first public draft was released this week and comments are being accepted until May 30. (http://www.alsa.org/advocacy/fda/assets/als-drug-development-guidance-for-public-comment-5-2-16.pdf). I have great respect for the patients and researchers who have participated in crafting this draft. I would never doubt their commitment to this community. I myself have tried to play an active role in this process and fully take my share of the blame for its shortcomings. This draft does a good job discussing the natural history of the disease. It describes many of the complexities of the disease, the current understanding of the disease, and its horrific impact on patients and their families. Each section touches on the urgent need to find new treatments. There are also instances with regard to evidentiary standards and alternative endpoints in the Benefit/risk section, where this need is reflected in our guidance.
However, I do not believe the majority of the recommendations that it provides to sponsors are based on or address the specific nature of this disease. Nor do they truly reflect the needed urgency. More so, I do not even believe that the guidance reflects the degree of flexibility that the FDA is currently willing to provide given the prognosis that patients face and the current lack of treatment options. We, as a community, have the opportunity to describe how current FDA regulations should be applied given what we as scientists and patients know about ALS. However, instead of trying to be thought leaders on how to conduct clinical trials in a way that directly addresses the nature of the disease and truly aim to speed effective treatments to patients, we are putting forth a document that is even more cautious than the Agency’s current positions.
Somehow other disease spaces like HIV or many different cancers or DMD can utilize the flexibility that the FDA grants in terms of endpoints, expedited approval pathways, or trial design, but we must fall back on using the same techniques that have been discussed in intro biostats classes for generations. I cannot fully express my degree of frustration at the disconnect between the lip service given to the urgent need to get effective treatments to this generation of patients and the recommendations that all tend to fall back on the ultra-cautious status quo. The President and Congress have repeatedly told the FDA that they should be flexible when it comes to serious conditions with unmet needs. The FDA has gone on record stating that they are willing to be flexible in working with sponsors. Yet here we are advocating for essentially nothing new or novel. We are telling sponsors to ignore the FDA’s public stance. Either we don’t believe the FDA will honor their word and we are not willing to hold their feet to the fire, or we are not willing to go out on a limb and advocate for something new, that while not perfect, is clearly better than the status quo.
When I agreed to participate in crafting this document, I believed its purpose was greater than simply spelling out the cruelty of the disease. I believed we were going to discuss this specific nature of ALS and then use that to inform improved ways of conducting trials within the FDA’s current regulations. Somehow, instead we were satisfied to briefly discuss potential new techniques, but then close each section describing their limitations and recommending we stick with what has (not) worked in the past without any discussion of the HUGE limitations of our current methods or how they have contributed to recent failures. Saying that something new does not work perfectly is not justification for sticking with something old that is highly flawed. How can we open the Clinical Trial section talking about how failures are due to heterogeneity and inefficient trial designs, but then insist on methods that in no way address these inefficiencies and are solely based on minimizing bias? How can we talk about how many people will die over the next two years and the willingness of patients to take greater risks but then only give passing mention to Accelerated Approval or any of the FDA’s other expedited pathways? How can we discuss the importance of finding biomarkers and then give sponsors one sentence describing how they can be used as surrogate endpoints? Are we really going to lay out “guidance to sponsors” without discussing any lessons learned from the two biggest (failed) ALS trials of the past 20 years?
I am simply asking that we live up to what we say in the introduction, “This guidance reflects the FDA’s current thinking regarding the weight that should be given to the preferences of ALS patients and caregivers with regard to benefit/risk tradeoffs in light of the severity and rapid progression of the disease coupled with the lack of effective treatments.”
I am not advocating an abandonment of science or throwing out everything we have learned from the past. I am not advocating anything that violates current FDA guidelines. If anything, our document should more closely reflect the ideas in FDASIA 2012 than the FDCPA of 1938, or its amendments from 1962. As recently as April 25, 2016 you have the director of the FDA Center for Drug Evaluation and Research (CDER) saying that greater uncertainty is tolerated under Accelerated Approval. The deputy director repeatedly stated that trials using external controls can be considered “well-controlled”. The FDA for decades has maintained that the effectiveness standard is discretionary and that they understand that different diseases have different needs. Yet there is very little in this document that takes advantage of the tools at our disposal that not only fall well within the FDA’s current guidelines and are used to fight other diseases, but that also coincide with the leadership’s public statements. The FDA isn’t the problem here. Our lack of creativity and cowardice is. Or maybe we are just not willing to have the serious discussion required to justify anything new?
Efficiency and Single-arm trials.
The goal of a clinical trial is to figure out whether or not a treatment works. In ALS, this is especially difficult for a number of reasons that are well spelled out in the document. The disease manifests itself differently across patients. Patients progress at different, ever-changing rates. Our current measurement techniques are fairly imprecise. Many times we do not have a good idea on who a treatment will likely work for. Lastly, a relatively small number of patients have the disease and will be able to survive a long, drawn out trial. This implies that it is hard to get a signal of the underlying effectiveness of a treatment because of the degree of statistical noise due to all of these factors. Constructing trials that efficiently utilize data to inform us of the likely effect of a treatment is paramount in ALS.
Yet, in the discussion of an adequate control group, there is boilerplate language on the unbiased nature of RCTs, but absolutely nothing addressing whether or not this should be our primary concern given the specific nature of ALS. Even when addressing the rarity of the disease and the need for small clustered trials, the document only goes so far as to discuss when RCTs might not be feasible, but fails to state when they may not be advisable relative to other techniques. Multiple sections contain detailed discussions of the degree of heterogeneity in this disease and our limited ways of measuring progression. However there is no serious discussion of the importance of efficient trial design. I do not see how we can not have any real discussion of the trade-offs between bias and efficiency in this setting. We simply ignore everything else that we have stated regarding natural history when it comes to selecting an appropriate trial design. Our recommendations make almost no distinction between 500 patient trials and 20 patient trials. This is insane. We are not doing our job.
One of the most direct and cost-effective ways to increase the explanatory power of a trial is to use external controls. For example, in an early phase, 50 person double-blinded randomized controlled trial, you provide treatment to 25 patients and then give the 25 others a placebo in order to establish a baseline for what the treated patients would look like on average over time. You use half of your data to reestimate a baseline, ignoring everything we have learned from the past. In a single-armed trial using external controls, you can use thousands of observations from existing datasets to estimate a more precise baseline and then can use all 50 patients to try and get a sense of whether or not the treatment works. Same number of patients. Same timeframe. Four times the explanatory power. If we are serious about trying to increase the signal to noise ratio in our trials so that we can make definitive determinations on whether or not to proceed with potential treatments, we have to be open to utilizing these types of techniques. The FDA has repeatedly stated that external controls can be used to generate and “adequate and well-controlled” trial. Our document currently says no. So while the ALS Association is publicly praising, and generously funding, the work of groups like Origent, we put down in writing that only RCTs can provide “conclusive evidence”.
The most positive thing we have to say about this technique is that we mention that it can be used to provide supplemental analysis in the Risk/Benefit section. The Clinical Trials section takes a much more negative stance.
As I read the section on historical controls under Clinical Trials, it struck me as being grossly outdated and based on examples from generations old textbooks. If you look at the citations in this section (426-429) they are from 1972, 1974, 1972, and 1976. There is anecdotal evidence from (430) 2012 and from a fifty-year overview of multiple myeloma from 2005 that is tangentially related (432), as well as a survey (431) from 1983.
Yet curiously there is no mention of Monzon et al. 2015, (http://www.sciencedirect.com/science/article/pii/S0959804915007790) that compared 270 single arm and 66 randomized controlled phase 2 cancer trials conducted between 1998 and 2012. The authors found that subsequent phase 3 RCTs were no more likely to be successful when resulting from a positive RCT than from a positive single arm trial. If it was the case that single-arm trials were prone to excessive bias and were unreliable (as was found in the trials from the 1960s and 1970s in the Sacks 1983 paper), then you would expect that subsequent phase 3 trials based on their results would likely fail. However, receiving a positive signal from a single-armed phase 2 trial was equally as informative as receiving a positive signal from a phase 2 double-blinded randomized control trial.
Again, I am dumbfounded that the ALS community seems willing to rest on what was commonly accepted in textbooks in the 1970s and 1980s, while other areas, like oncology, have moved forward and currently make great use of externally controlled trials. The 1983 survey, used to argue against the use of historical controls, also pointed out that RCTs are problematic as well. We completely ignore that best practices for using historical controls obviously have changed over the past 30 or 40 years, yet we are quick to dismiss the concerns over RCTs by saying that we should just relax our evidentiary requirements.
If trials are constructed carefully and you make sponsors ex ante identify and justify their choice of controls, external controls would be one of the most direct and effective ways of trying to increase the efficiency of our trials. If we are worried about missing data, isn’t it at least worth mentioning that single-arm trials may improve retention? Are we going to disregard an approach, supported by the FDA and frequently used in other disease spaces, that would increase the power of our data by 4x because we do not want to move beyond what was commonly accepted 40 years ago or have to think seriously about establishing best practices? Are we going to ignore the fact that the most consequential failed trials in this space have followed double-blinded phase 2 trials?
The final line of this section stating that only RCTs can provide “conclusive evidence” is patently false and I believe is a huge red flag indicating that we do not want to think seriously about improving on the status quo. It is complete fiction. Has oncology been built on pseudoscience? Has the FDA been permitting a sham method since they established the “adequate and well-controlled” requirement in 1970? For all the focus on making this a scientifically justified document, there is in no way we should be inserting this myth into our guidance.
Lastly, I will not lower myself to seriously consider the idea that single-arm trials are inherently unethical (p. 72). This is being marketed as a “Patient-focused Guidance” and this is the single instance in the document where we are going to choose to discuss ethics? I speak for one patient who would never even hint at this kind of absurdity. I don’t care what esoteric references are used to justify it.
Dexpramipexole and Ceftriaxone.
Efficiency is not some obtuse statistical concept not relevant to ALS studies. It played and an enormous role in the Dexpramipexole trial. In the phase 2 study, whose results led to a failed, $50M+, 1,000 patient phase 3 study, it was crucial. That study compared patients on three different doses to patients in a small placebo arm. They found that fewer patients receiving high doses of Dexpramipexole had a six point decline in ALSFRS-R than in the placebo group over three months. 33% of patients on placebo declined by six points are more. Patients on higher doses of Dexpramipexole incurred six-point declines 15% and 8% of the time. However, if you look at historical data from placebo patients in the Pro-Act database using similar exclusion conditions, roughly 14% of them decline by six points or more over three months. So it was not that the dex patients were progressing slower than expected, it was that placebo patients in the trial happened to progress faster than normal. The dose dependent response is much less convincing when you add in historical placebo data that mirrors the high dose patients. Perhaps if the treated patients had simply been compared to representative external controls instead of to a small number of concurrent patients on placebo, the money and time spent on a 1,000 patient trial could have been deployed elsewhere. Even though this was perhaps the most important trial in the history of ALS, there is no discussion in this draft on what we should learn from its failure.
Along the same lines there are no mentions of the failed ceftriaxone trial. There were a number of unique motivations that contributed to the stage 1-3 adaptive design of this trial. However, lessons should be learned about how and why it progressed to a 448 patient stage 3 phase based on results from 45 treated patients and 21 patients on placebo after a 20 week stage 1-2. The published articles following this trial only included the difference in the decline of ALSFRS-R between treated and placebo patients, so it is unclear whether this positive signal was due to unexpectedly slow progressing treated patients or unexpectedly fast progressing placebo patients. Either way, there is no discussion of these results relative to data from other sources. Therefore the decision to add 448 patients and extend the trial was dependent on a baseline generated from only 21 patients.
The use of external controls may or may not have impacted the preliminary results of these studies that led to the two largest and most expensive (and failed) ALS trials in recent history. However, the fact that they were based on results from “gold standard” double-blinded randomized trials must at least be discussed. We are content to cherry pick misleading anecdotal results from trials in other disease spaces to rationalize not using external controls, but we ignore misleading results from “gold standard” trials in ALS which led to incredibly expensive dead ends. At a bare minimum, we must acknowledge that according to the recommendations that we are currently making, decisions to expend an enormous amount of scarce resources on phase 3 trials will continue to hinge upon the very noisy progressions of a handful of patients who randomly end up in the placebo arm of a preliminary trial.
Biomarkers, Surrogate Endpoints, Accelerated Approval.
The biomarkers section describes a number of promising areas and techniques. While it stresses the need to find usable biomarkers, I believe it could go further in providing guidance to sponsors on how to get there. In the discussion of identifying and using biomarkers, the FDA’s concept of “surrogate endpoints” must be addressed. There is currently one single sentence on this issue on the last page of the section. If we truly want to provide sponsors with a way to get effective treatments to patients in a manner that reflects the urgency needed, we must provide them with true guidance on the regulatory vehicles at their disposal.
According to the FDA, “A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.”
Part of the permitted “uncertainty” with regards to Accelerated Approval is on the connection between a surrogate endpoint and the desired clinical benefit. For decades cancer used objective response rate (ORR) as a surrogate for survival before it was ever empirically validated to predict clinical benefit. It was only recently that researchers began to do this and there have been conflicting results across different forms of cancer (Chen et al. 2000 vs. Buyse et al. 2000).
It will take decades to definitively validate any surrogate endpoint. To truly do it, we would need multiple effective treatments that could manipulate the surrogate and then we would need to track patients for years to verify that changes in the surrogate were correlated with clinical benefit. This process will take decades at best. This is exactly why the FDA uses ambiguous language about surrogate endpoints needing to be “reasonably likely to predict” clinical effect. Then given this added level of uncertainty, the FDA requires post-approval trials to verify anticipated clinical benefits.
Again, why are we not playing a role as thought leaders on this subject? Refer to documents like this (http://www.hpm.com/pdf/blog/Subpart%20H%20Analysis%20-%20FDA-2013-D-0575.pdf) to help sponsors understand how the FDA makes determinations on the validity of surrogates. Discussing the severity of the disease in the natural history section and in the introduction of other sections is not sufficient. Our “guidance” must be tailored utilizing the FDA’s protocols that were specifically established for diseases like ALS. The Public Policy section contains no description of Accelerated Approval and only discusses preapproval expanded access programs.
Given the statistical difficulties in generating conclusive results in ALS, the severity of the disease, and the number of patients who will die or lose significant physical abilities while large and lengthy trials are conducted, there is urgent need to get effective treatments to patients as quickly as possible. Sponsors must be encouraged to utilize the FDA’s Accelerated Approval program and we must be providing them guidance as to what this program entails and its evidentiary standards. We need to do a better job breaking out Accelerated Approval in a distinct fashion and stress to sponsors that we as a community and the FDA believe this is an important and appropriate regulatory route to take in finding an effective treatment for ALS.
In addition to Accelerated Approval, the FDA has three additional programs intended to expedite development and review for new drugs that address unmet needs for serious or life-threatening conditions. Of the 21 new drugs approved by the FDA for rare diseases in 2015, 18 utilized one or more of the expedited pathways. These programs obviously were put in place specifically for diseases like ALS, yet we devote one sentence to their existence on the second to last page of the document. If our goal is to help sponsors get drugs through the FDA as efficiently as possible, we must inform them on how to navigate these different programs. Shouldn’t this be central to “Guidance for Industry Drug Development for Amyotrophic Lateral Sclerosis”?
Survival as an Outcome Measure.
The discussion of the use of Survival as an outcome measure must address the fact that even if you have the resources to conduct a trial of sufficient duration, by definition you would need to wait for a significant number of patients in the placebo arm to die before you could make a determination of efficacy. (This point was discussed at length on the only substantive call for the PCAC, yet no changes have been made.)
So just to clarify, the document currently states that it is unethical to give a treatment to every patient in a trial. However, there are no ethical issues with a design that by construction requires standing by while a certain number of patients in the placebo arm die before you can statistically see an effect. If the treatment is effective, you only sacrifice the placebo patients. If it doesn’t work, you sit and watch an equal number from each arm die. Where is the patient voice here?
Even if we suspend disbelief regarding the point above, it speaks to the broader issue that using inefficient designs means we need bigger, longer trials. That means patients in the placebo arm have to wait longer until they get access to the treatment and everyone who was excluded from the trial must wait longer as well. For a frame of reference, a 6 month delay will lead to over 2,000 unnecessary deaths in the US alone. Before disregarding anything new, we must be honest about what the status quo implies.
Linearity of ALSFRS-R.
Where is the citation justifying that ALSFRS-R declines linearly over the course of a year? I believe it is inaccurate and counterproductive to suggest to sponsors that ALSFRS-R follows a linear trend in any way. Origent recently changed their methodology to avoid assuming a constant slope for this exact reason. Sure, you can draw a line through any set of points, but that does not mean that the relationship is truly linear or that assuming linearity will improve your trial. Even if we believe progression follows a somewhat constant pattern, ALSFRS-R does not. Yet, you still see trials set up measuring “deviation from trend” or “change in slope”. We think this makes intuitive sense because we know patients progress at different rates, and so tracking patients for a couple of months gives you different individual baselines. The problem is that individual progressions simply do not follow linear patterns and analyzing “deviation from trend in ALSFRS-R” can introduce more bias due to unbalanced arms than simply assuming that everyone will progress at the same rate.
One of the most striking things that I have found looking at the PRO-ACT data is that of the 20% of observations that had the smallest average monthly decline in ALSFRS-R over a three-month period, 100% of them experienced larger average monthly declines over the following nine months and only 47.1% continue to decline at a slower rate than the overall population average. The same holds at the other tale and when examining FVC. Crudely using a three-month lead-in does not identify “slow progressors” it identifies who progressed slowly over the first three months. In no way does the data support assuming linearity over 12 months in a trial. Suggesting ALSFRS-R follows a linear trend is not only incorrect, but applying that incorrect assumption makes our trials worse.
On page 13, in reference to the prevalence figure from the 2014 Registry report, the word “definite” should be in quotations. This usage comes from a specific definition of “definite ALS” related to the methods in that paper to passively identify ALS cases from government administrative databases based on items like prescription records. It has no connection to how the term is typically used in the ALS community related to diagnostic designations within the El Escorial Criteria that is discussed at length in the Natural History section.
Also, the 12,000 figure is the number of patients who self-enrolled in the registry along with selected cases from government databases. A large number of patients are not captured through either source. At the Collaboration For A Cure meeting last year, the consensus was that this number needed much more work before it should be published. “After a robust discussion among members of the group, it was determined that the data is not sufficient to support currently reported numbers of people living or diagnosed with ALS.” http://www.alsmndalliance.org/collaboration-for-a-cure/ Without controlling for enrollment decisions, this number should not be used as an estimate of prevalence and does not merit inclusion in this document.
My main concern is that in too many sections of the paper we are not seriously tailoring our recommendations to the specific nature of ALS and the urgent need to identify and provide patients access to effective treatments. We are not taking into consideration the limitations and drawbacks of current methods and techniques when looking at potential improvements. Instead we are relying on decades old norms, that other disease spaces have left in the past, to justify the status quo. Whether it is in the discussion of biomarkers, new measurements, exclusion criteria, single-arm trials, or Accelerated Approval, simply noting why a new method might not work perfectly does not mean that it still is not better than the status quo. It is unacceptable to me that we are writing a document that takes a much more cautious tone than the FDA’s recent public statements and current policies. If we are truly writing “guidance” to sponsors then I do not see how we can avoid seriously examining whether imperfect new strategies may be superior to imperfect old strategies. We must base our guidance on the disease and the needs of patients. We must do better.
 “The accelerated approval program includes a requirement for confirmatory studies for efficacy. So, as you heard from the sponsor, they have to do further studies to explore and confirm effectiveness. An inherent presumption in this program of accelerated approval, which is written in the preamble of our regulation about it, is that more uncertainty is going to be tolerated initially and that in fact sometimes we will collectively get it wrong. Otherwise accelerated approval will have no different standards than regular approval.” – Dr. Janet Woodcock, Director of CDER, 4/25/2016 Sarepta AdComm.
 “Our regulations since 1970 have said that a historical controlled trial can be adequately and well controlled study. The question here goes: Under the circumstances do you think it was? Do you think the way they selected patients, the way they analyzed them, was good enough to make it an adequate and well-controlled study? That’s the question. Historically, historical-controlled trials have been the basis for approval — sometimes in sort of obvious cases and sometimes in cases that quite aren’t so obvious.” – Dr. Bob Temple, Deputy Director of CDER, 4/25/2016 Sarepta AdComm.
 “The standard is adequate and well controlled trials, OK, that’s what is in this statute, but we are instructed to have flexibility on how we interpret that based on medical need.” – Dr. Woodcock, 4/25/2016 Sarepta AdComm.
 We are also ignoring efficiency when we recommend that sponsors explore the dose range even in early trials. Typically this involves further segmenting the small number of observations into more than two arms. Therefore efficacy is judged based on a comparison of the treated patients to an ever smaller sample of patients in the placebo arm.
 Using unbalanced allocation ratios actually further reduces efficiency. For instance, if you used a 2:1 randomization, or a 1:1:1 with two different doses and a placebo arm, your baseline would then be determined by the 33 random patients who ended up in the placebo arm.
 In the Sarepta case, the issues were not the use of historical controls, they were with how the trial was designed and conducted. “The ways the controls were selected and analyzed didn’t meet the threshold that I would consider to be adequate and well controlled,” said Caleb Alexander, an associate professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health and chair of the advisory committee.
 If you hold some concept of “conclusive evidence” so closely to your heart that you do not believe a single arm trial could ever meet your standards, then if you are truly intellectually honest, you have to concede that no RCT (especially in as small and heterogeneous population as ALS patients) would ever be able to provide “conclusive evidence”. This is a false construct made by someone who fundamentally does not understand science and the uncertainty that goes along with anything that is empirically based.
We recently got home from spending five days at Disney World. We drove down last Friday and came back Tuesday night. The four of us in the car together, in a hotel room together, at the parks together. Plus there was food and drink available around the clock in the lobby right off our room. So once the kids went down, we could sneak out to have a glass of champagne and a cupcake together. It was a special few days. We got to meet characters, see shows, ride roller coasters, drink champagne.
We knew the kids would have a blast. James is about to turn four (he PROUDLY wore his birthday boy pin the whole time and made sure the characters took notice) and Mary Adair is five. They love a bunch of the Disney movies (have you ever heard of Frozen?) and TV shows. I was a little nervous about James on the roller coasters though. Mary Adair is typically up for anything, but James is the one who gets scared during movies and turned off by spicy food. Somehow this led me to believe that he would be skittish on the rides.
Not only were they the perfect ages for the trip, but in many ways this was the right time for me to go as well. With a scooter I can get around pretty well. With a bit of help, I can get on and off rides if I’m careful. My neck is weaker, but it is still strong enough to handle the rides that Disney has to offer. I’m not sure if that will be the case in a year’s time, but it is true today. Last December we went to the Bahamas and spent a couple of days at a waterpark. I snuck off a few times to go down the big slides. I was nervous at first climbing the steps and sitting down at the top of the slide, but after doing it once, I realized I could handle it. I also realized whenever the next time came, that might no longer be the case. So I did it over and over again. I loved sitting at the kiddie pool watching the kids play on the jungle gym’s etc., but any excuse I had, I wandered past the big slides and took one more ride. A year later I don’t think I could do it. I don’t think climbing the steps would be a good idea, and I don’t see how I could sit myself down. In the grand scheme of things, it doesn’t bother me at all, but I am glad that I took the opportunity when I could.
In some ways this Disney trip was the same. As long as I was careful, and used the scooter to get around, I could still be a participant and not just an observer. So the first time James and Mary Adair rode a roller coaster I was sitting there with them. James and I in one row and Mary Adair and Cara in the next. As we went down the first hill I couldn’t quite tell how James was reacting. I heard him making noises, but I couldn’t initially see the expression on his face. When I leaned over to get a better look, he was grinning from ear to ear, squealing with delight. His expression didn’t change through the rest of the ride. When we pulled into the station and got off the ride, I asked Cara how Mary Adair did. Mary Adair proudly exclaimed that she had her hands up the whole time. After one ride, they were hooked. We were a roller coaster family. The four of us. Me included.
Going into the trip I had not considered what it would have meant if James or Mary Adair decided they were too little for the roller coasters. It may have meant that we never would have had the chance to experience that thrill together. Again, in the grand scheme of things that wouldn’t have been a big deal, but once it clicked, it was incredibly special to me. The four of us riding over and over and over again. We debated whether we liked Snow White or Big Thunder Mountain more and went back and forth from ride to ride using our fast passes and disability return pass to navigate the lines. One time I would ride with Mary Adair and James with Cara and then we would switch. One time we would sit in the front, and then one time in the back. Each and every time James grinned from ear to ear. Each and every time Mary Adair held her hands up to the sky. Each and every time I got to be the annoying dad yelling “Hi Hoooo” in their ears over and over again.
Of course ALS always manages to present complications. Through a couple of days we thought that complication was having to figure out how to get me off the Winnie the Pooh ride when it stopped working. But that wasn’t it. At the end of a fun day at Hollywood Studios, I fell getting off of the Buzz Lightyear ride. Since my arms don’t really work, my forehead took the full blow. As I lay facedown on the ground, unable to speak because it knocked the wind out of me, and with blood seeping from a gash in my head, Cara was left to figure out if I was okay while also dealing with the kids. One more impossibly hard situation that got thrown in her face. There is never really a break. I don’t remember much from the incident, but I know how incredibly scary and stressful it must have been for her. After an ambulance ride to the hospital, a CT scan, a handful of stitches, and two new stuffed animals and lots of candy for the kids, we shrugged it off and continued our trip. I still am feeling the effects of banging my head and ribs, but we still managed to get in a couple more great days at the parks. It meant that Cara got to take them on Splash Mountain by herself, but otherwise we pressed on. Together.
Afterwards we were kicking ourselves, because if I had just asked her to give me a hand as I got off the ride, maybe we would’ve come through the trip unscathed. It’s a fine line between being safe and letting stuff get in our way. For the most part I think they are pretty good at it. Sure I would have preferred not to have fallen, but still we spent our days riding roller coasters, nights at the parks wrapped up with the kids in our laps watching the fireworks, and for five days we laughed and played and slept and ate and loved together. It was a magical trip.
Recently, a number of close friends have reached out to me and asked how I am doing. People who I love and respect and do not see nearly often enough. People for whom a simple, “I am doing great. How are you?” does not do justice to how I feel for them or to what they are really asking. But I find that is hard to put into words how I AM doing. It is not that I have any hesitation sharing, it’s more that I have a hard time figuring out what the right perspective is for an email. It’s complicated.
In so many ways, I am doing great. That is the honest answer. I have two happy, healthy and silly kids. Mary Adair loves kindergarten and all things learning. She is in ballet and skips around the house doing all sorts of poses and routines. When we were decorating the Christmas tree, James chucked one of my glass balls across the room shattering it. Without prompting, she wrote on her Christmas list (that she was so proud to do all by herself) that she wanted Santa to bring her an ornament so that she could give it to me. Santa obliged by bringing her a “World’s Best Papa” ornament. She (and Santa) are pretty great.
James loves superheroes and all his stuffed animals. He probably sleeps with 20 stuffed animals and can give you a long winded back story on each of them and their families. Cara’s mom gave him a set of tools for Christmas and my parents just brought him my old workbench and he loves pretending to be a working man and he loves giving his Papa snuggles. I am involved with a bunch of different ALS projects and am still happy at South Carolina. Cara likes her job and we are all getting settled into our new house.
Almost 3 years after my diagnosis, my progression continues to be slow. Compared to how most folks with ALS typically do, I am still way out on the good side of the curve health-wise. Three years in, I can still walk, talk, breathe, swallow, etc. If there was an ALS basketball team, I’d probably be a first round pick (my game in high school was strong to quite strong. What I lacked in height and skill I more than made up for in fouls.) In so many ways, “great!” is the honest answer.
But to friends outside of the ALS community, that still doesn’t quite capture everything that is going on. It’s complicated. I am so very thankful that I am doing much better than we could have hoped for a couple of years ago. That’s just not to say that my progression doesn’t continue. The other day at the zoo Mary Adair asked me how strong elephants were. I told her they were stronger than 20 people and she responded, “20 strong people or 20 people like you?”
I now need her to help me get shirts and socks on and off. I have grown a beard because shaving is exhausting. I am in a constant search for the ideal pair of pants with an elastic waistband. I have a sweet pair of puffy Velcro sneakers that I wear with my orthotics. Yes Matt Bellina, I am quickly becoming a beer swilling hobo.
I can’t cut my own food. If we are going somewhere where we will be on our feet, I will either take my scooter (think rascal not razor) or wear my leg braces. I am still driving, but may have to give that up in a few months. My breathing and swallowing are still normal, but my speech is starting to be affected. If I speak for an extended period of time, it gets harder and harder. I am in the process of “banking” my voice, which involves sitting at the computer and repeating 1600 sentences. This way I will have phrases recorded and even will have a computer generated synthetic voice based on my recordings whenever I need it. Most of the sentences are pulled from the Wizard of Oz or Little Women, but every now and then they’ll be a phrase like “I have ALS and this machine speaks for me.” I am doing great, but this is the reality of what I am facing. This is the reality of what Cara is facing. This is what Mary Adair and James are facing.
Cara is constantly running around like crazy trying to keep our family going. Anything that’s needs to get done is on her. We continue to add more help around the house, but she still is taking out the trash, fixing meals, putting together flatpack furniture, wiring light fixtures, making liquor drinks, etc.
So yes, it is complicated and it is not easy for any of us. How do we look at it? In general, we take my health as a matter of fact and in many ways it doesn’t affect how we are “doing”.
Great new house. Weekly trips to the zoo. Two crazy kids. Trip to Disney World at the end of the month. A wife I love more today than 10 years ago when I proposed.
I am doing great, how are you?
Here is my response to the and published in the Washington Post on November 19. https://www.washingtonpost.com/opinions/the-21st-century-cures-act-could-be-a-harmful-step-backward/2015/11/19/919ace5e-8e27-11e5-acff-673ae92ddd2b_story.html
While it is admirable that the authors aim to protect women and the elderly from unanticipated side effects from sleeping pills, arthritis medication, or hip transplants, they are also advocating for greatly increasing the cost of trials and time-to-market for potentially life-saving drugs. Testing therapeutics against every conceivable subgroup is incredibly expensive and will add years to the already cumbersome trial process. Increasing the cost of trials decreases incentives for pharmaceutical companies to invest in the rare disease space. It means fewer potential treatments will be tested in patients. Increasing the time-to-market means that my friends die while we tried to protect them from unknown side effects.
Three years ago, between my son’s first birthday and my daughter’s third, I was diagnosed with Amyotrophic lateral sclerosis, or ALS. I was told I had 2 to 5 years to live and that I would progressively lose my ability to walk, to speak, to eat, and to breathe. According to President Barack Obama’s Council of Advisors on Science and Technology, “Over the past 50 years, the time from drug discovery to drug approval has nearly doubled from 8 years in the 1960s to roughly 14 or more years now.” That means if a cure for ALS was found today, at least three generations of patients would die before it reached the market. Make no mistake, authors are advocating for the lengthening this process.
While we should not rollback regulations to levels from the early 20th century, we should also not insist on using data in the same ways we have done so since the 1950s. The 21st Century Cures Act gives the FDA flexibility in interpreting data. If a doctor believes that an approved drug is still risky, she should have a frank discussion with her patient. However, it does not mean we should prohibit all patients from accepting those risks. We should be empowering doctors and patients to make informed decisions.
Every single day I see a friend pass away from ALS. Every single day I grow slightly weaker and hugging my kids and speaking to my wife becomes more difficult. Every. Single. Day. Days matter.
Protecting patients from unknown side effects must be weighed against protecting them from disease. It is the 21st century. We have new tools to construct smaller, more efficient trials and interpret new forms of data. Let’s use these new tools and not put our heads in the sand and protect me and my friends to death.
Dr. Stephen Finger is an economics professor at the University of South Carolina’s Darla Moore School of Business. He is on the board of the Every90Minutes Foundation and HopeNowForALS, and is an ardent supporter of the ALS Therapy Development Institute.
While the awareness around ALS has changed over the past year, the urgent need to find a cure has not. Every day I see friends pass away from this disease. Kids lose parents. Husbands lose wives. Parents lose children. I see friends who a year later can no longer walk. Can no longer speak. Can no longer breathe. I feel my own body breaking down. The other night I dozed off on the sofa and when I woke up the first thing that caught my eye was a school picture of Mary Adair and James. Arm and arm on a bench, smiling, excited to take on the world together. I just laid there a while looking at it, smiling back at them, but then when I struggled to generate enough momentum to sit myself up, all I could think of was what else they were going to have to face together. Why do these two amazing, happy-go-lucky kids have to face this situation? Same for their mom. There are things I can come to grips with with ALS, and there are things I will never be able to.
I hope you will join Sarah Coglianese’s #whatwouldyougive campaign benefiting ALS Therapy Development Institute (https://www.classy.org/events/whatwouldyougive/e82638). If you are friends with me on Facebook, you know how incredible she is. Two years ago Cara and I loved getting to meet her and Rob at ALS.net’s gala and I selfishly need a cure to be found so we can be friends for a long, long time. What else will I do at work if I don’t have her blog to read?
Her campaign is off to an incredible start. For one day give up an ability that those of us living with ALS have to do without. Rely on someone else to drive you around, to cook for you, to cut your food, to get you dressed, or to brush your teeth. Use a text to speech app on your phone to communicate. If you don’t want to impose on those around you, then act as a caregiver (cALS) and be at someone’s beckon call. Serve them all their meals. Clean up after them. Do their chores. Watch them every minute to make sure they can still breathe. #whatwouldyougive for a loved one to avoid this fate?Sign up at https://www.classy.org/events/whatwouldyougive/e82638 and get your friends to support you.
However you wish to do it. support families living with ALS. Support research to end this disease. Support ALS.net.
May is the first ALS Awareness Month since the Ice Bucket Challenge. That silly, organic, viral campaign did more for ALS awareness than years of marketing by any organization could have ever done. Millions of people created videos last summer. Millions of people talked about ALS and looked up what it is. Over $220 million was donated to ALS charities worldwide. This money didn’t miraculously appear though. Hundreds of thousands of people chose to donate. It was not Internet “slacktivism”. It was Internet activism at its best: People became aware of an issue and tried to make a difference. My hope is that some of these people will continue to actively support the ALS community. Every 90 minutes someone in the US is still being diagnosed with ALS and someone else is passing away from the disease. With continued, concerted effort, we have the power to change that.
My family did not have the luxury of forgetting about ALS once the videos stopped popping up on Facebook last year. I was diagnosed with ALS in 2013. Shortly after my son James’s first birthday and before his sister Mary Adair’s third birthday, I was told what I thought was a minor hand ailment was a neurodegenerative disease that would progressively rob me of my ability to write, to walk, to speak, and to eventually breathe. No cure, no treatment, and an average life expectancy of 3 to 5 years. The prognosis is essentially the same today, a year after the Ice Bucket Challenge, as it was for Lou Gehrig when he was diagnosed 75 years ago.
The Ice Bucket Challenge hasn’t slowed my progression. My hands and arms are very weak now. I haven’t buttoned a pair of pants in over a year. Showering and drying off sap all of my energy. Walking is getting more difficult. Yet over the past two years, I have been very lucky that my progression has not been faster. I have seen friends get diagnosed and pass away in the time I have had ALS. Friends, who within months of their diagnosis, can no longer speak or can no longer walk. Since I’ve been diagnosed, James has learned to walk, talk, and get himself dressed (mostly). He has become a big three-year-old, taking on the world in his rain boots because those are the shoes that are the easiest for him to get on and off by himself. He beams with pride when he actually puts them on the right feet. Mary Adair is now playing soccer, taking ballet lessons, has learned to read, and can fill out the numbers on the check for me when we go out to eat. In many ways, they are still growing up faster than I am progressing. But when I start to do the math, it just doesn’t add up. For all his development, James is still only three. So in two more years Mary Adair tells me he will be five. I don’t see them carrying me to the beach or driving themselves to school at ages 5 and 6. It doesn’t get easier from here. One summer is not enough to change our future. It will take continued action to change the course of this disease for families like mine.
Already I see what it means for my wife. Because my arms are weak and getting around is enough of a challenge on its own, I can’t help with much around the house. She is left to do the work. My wife has excelled at everything she has ever done. This month we will attend her class reunions at the University of Virginia and at Harvard Business School. Going forward, though, the house we live in, the city we live in, the job she takes, will all be dictated by her choice to push our family forward the best she can in the face of this disease. I am in awe of her strength and am humbled by her commitment to our family. I have the greatest partner to live with and to fight this disease with. But make no mistake, she has ALS just as much as I do.
People who did the ALS Ice Bucket Challenge need to remember that they were helping families. They were trying to change our future. Ice Bucket funds have improved the research landscape. I am taking part in a Precision Medicine study at the ALS Therapy Development Institute (als.net) that was made possible by a surge in funding last summer. The ALS Association received the lion’s share of donations and has been able to triple their annual research spending, as well as increasing funding for patient services and building relationships with other ALS organization that share a common goal. They must continue to put these funds to work investing with the urgency this situation requires.
The success of the Ice Bucket Challenge, which did not come out of any one organization, but from patients themselves, has reiterated to individuals the kind of impact they can have, and has shown the community what it is capable of when people rally together. For example, Medicare’s arcane reimbursement policies for speech generating devices (SGDs) currently have a drastic impact on patients’ quality of life, restricting their access to technology that allows them to communicate with loved ones and stay connected to the outside world. However, Steve Gleason, one of the most visible and inspirational ALS patients, has been instrumental in getting these policies reversed. Along with the Center for Medicare Advocacy, he has led the community in advocacy efforts that caused the Centers for Medicare and Medicaid Services to rescind some of their most restrictive policies. In addition, the Steve Gleason Act of 2015 would permanently fix these problems and has already been passed by the Senate. Now we need the House to quickly pass the companion bill so that we can put this issue behind us. Please encourage your representative to sign on as a co-sponsor and quickly bring this bill to a vote. Patients are continuing to find their voices and engagement by the broader public is making a significant difference.
Recently, a small pharmaceutical company tried to utilize an expedited approval mechanism within the FDA to speed patients’ access to their experimental treatment. Given the current lack of treatment options, over 700,000 people signed a patient-led petition urging the FDA to grant Accelerated Approval to the investigational treatment. Without the awareness generated by the Ice Bucket Challenge, I do not believe that would have been possible. While the FDA declined the request, patients and their families had their voices heard and are continuing to work with the FDA and pharmaceutical companies so that expedited pathways are utilized to bring treatments to patients as quickly as possible. HopeNowforALS.org sprung out of this campaign as the ALS community recognized that all agencies, foundations, associations, and researchers, must approach this disease with the urgency needed to truly change the status quo.
In accepting a Webby Award as one of the creators of the Ice Bucket Challenge, my friend Pat Quinn said “Every August until a cure”. Whether it is dumping ice on their heads again, through donations, or through other means, my hope is that the millions of people who gained a glimpse into this community through the Ice Bucket Challenge continue to be engaged. In the past year, we have seen how their generosity and advocacy efforts have impacted the ALS community. Small acts go a long way. Small donations add up. $220 million alone will not cure ALS, but continued efforts from people now aware of the disease will make a difference. Maybe it is time to graduate from ALS Awareness Month to ALS Action Month.
This past week I went to Washington DC to speak at a rally urging the FDA to grant Accelerated Approval for GM604. I saw old friends, made new friends, connected with many families in the ALS community, and met with members of Congress.
While we do not yet know how effective GM604 will end up being, Accelerated Approval was specifically designed to allow patients access to treatments, that have been shown to be safe, for serious conditions with limited therapeutic options.
Please note that Accelerated Approval does not come at the expense of good science. Data will continue to be collected and full approval will not be granted until results of a confirmatory trial prove efficacy. There are simple statistical techniques that can be used to control for placebo effects even in single-armed trials.
Here is the text of my speech in which I lay out why I believe Accelerated Approval should be granted:
March 25, 2015
Hello, my name is Stephen Finger. It is an incredible honor to speak here today in front of so many families involved in this fight. I grew up across the river in Arlington, VA, but never anticipated coming to DC for this reason.
Two years ago I was diagnosed with ALS. Between my son James’s first birthday and his sister Mary Adair’s third, I was told, what I thought was a minor issue with my hands, was a disease that would rob me of my ability to play catch, to play tag, to walk, to speak, to eat, to breath.
My family’s lives where forever changed and if one thing was clear, it was that time was of the essence. And just as we recognized the need to live urgently; to hug today, to laugh today, to live today, to love today. We also recognized the need to act urgently, to act today. That is why we are here. Team Gleason says “Not quietly”. The ALS Association says “The time is now”. We are here telling the FDA that the status quo is not good enough and they need to do everything in their power speed the search for a cure. We are here urging our members in Congress to remind the FDA to work with the flexibility and urgency needed to fight this universally fatal disease.
I have now been a part of this community long enough to see patients who were diagnosed with this disease after me lose their fight. Last year, I had the pleasure of meeting Trickett Wendler in the halls of Congress. A young mother with three kids, a wife, a friend, a relentless advocate, she was diagnosed in the summer of 2013 and passed away in less than 2 years. Always one to speak her mind, she has asked her friends to continue to fight. So we are all here on her behalf. On Tony Conway’s behalf. On so many other great people’s behalf, who have been lost to this disease that we know can be solved.
We are not just here acting in their memory, we are here inspired by the way they fought this disease. Everything we do must be done with the recognition that every 90 minutes another mother, another father, another daughter, another son, another friend will be lost.
It is with that urgency that we are here today asking that the FDA grant GM604 Accelerated Approval. Let’s not force it to go more of the traditional trials that will take years to complete. Based on the results of the Phase I and II trials, let’s make it available immediately to patients who desperately need it, while we gather confirmatory data required of full approval. We are not asking today to rewrite any laws. We are not asking for a special exception. We are asking that the FDA uses the tools at their disposal to make this treatment available to as many people as possible in the shortest amount of time.
Accelerated Approval is not a new program. It has been around for over 20 years, specifically designed for situations like this. Congress has provided them with the ability to act with the urgency this situation merits. The 2012 Food and Drug Administration Safety and Innovation Act, with near unanimous support in both the House and Senate, I quote: reiterated the “Agency’s longstanding commitment to regulatory flexibility regarding the evidence required to support product approval for the treatment of serious or life-threatening diseases with limited therapeutic options”.
That is us! Here is their chance to live up to their own directives. Today! We are simply asking that they use the tools at their disposal to act with the urgency Congress told them to act with. The urgency deserved by the families in this fight. No ALS treatment has been granted Accelerated Approval before, so here is an opportunity to show a new way forward. The status quo is not good enough.
In GM604, we have a drug meets the FDA’s own criteria for Accelerated Approval. Its safety has been demonstrated according to traditional standards. Over 50 patients have received GM604 with no adverse events, consistent with the preclinical work. Surrogate endpoints for efficacy have been reached. Even in a small trial, GM604 had a significant effect on Forced Vital Capacity, which we know is a predictor of survival. Because ALS is a complex disease and progressions vary, meeting traditional standards of efficacy will require additional large and lengthy trials. Well we don’t have time for that and Accelerated Approval was specially designed to address this. While we wait for confirmatory data, let’s give current patients a fighting chance. That is the directive Congress has given.
Now sure after Phase I and Phase II trials there are still risks, but there will still be risks after Phase III and more importantly, we all know what the risk of inaction is. Accelerated Approval does not mean we enter the wild, wild west. Data will still be collected and approval could still be revoked if confirmatory trials do not go our way. But given the safety data, given the suggestion of efficacy, given the prognosis of the disease, given the urgency of the situation, isn’t that a risk we are willing to take? Isn’t that a risk the FDA is supposed to take? Given the evidence from the competed trials, doesn’t that make more sense than telling current patients to sit tight for two years until another trial can be completed? We won’t sit here quietly. Too many people have already been lost. Too many people have shown us the importance of acting today.
The FDA has recognized that different conditions require different acceptance of risk. They have granted Accelerated Approval status to cancer drugs, to HIV treatments. They have this tool at their disposal specifically for situations like this. Just because ALS is not communicable does not mean that we can be complacent.
So we are telling the FDA to act urgently, to act today, to act for the families in this fight, to grant Accelerated Approval to GM604.
If you have not done so, please sign the White House petition requesting that the President urge the FDA to grant Accelerated Approval to GM604.