From a science standpoint, we don’t know what causes 90 percent of the cases. We suspect there may be subsets of ALS with different pathologies driving progression in different patients at different times, but we have no good way to identify these. We do not typically have pharmacodynamic biomarkers telling us we are hitting our targets with the doses and routes of administration we chose. The outcome measures we do have are clinical, things like disability questionnaires, breathing volumes, muscle strength testing. These are noisy and slow to change. There is disagreement over what a clinically meaningful change on these measures looks like. ALS trials enroll slowly for a variety of reasons, and so it can be years between the first patient enrolled and the availability of results. Given all this, it is hardly surprising that replication (one of the fundamental principles of good science) is rare in ALS trials. Either no confirmatory trial is done, as in the case of Radicava, aka edaravone, or the follow-up trial fails to replicate the previous “positive” result, as in the case with lithium, dexpramipexole, and NP001.
From a humanitarian standpoint, ALS is still the worst disease I have come across in all my years in medicine. One of my patients described it as follows: “You put me in a box with this diagnosis, and every day it gets smaller on all sides, further restricting what I can do. Eventually it will get so small and tight that it will crush me to death.” Given this, it is easy to see why people living with ALS (PALS) are frustrated, sometimes angry, that after more than 100 years of ALS research we do not have better treatments. They have channeled these emotions into impressive advocacy efforts, and through these have changed laws. I suspect these advocacy efforts also played a major role in the 2017 FDA approval of Radicava, which occurred after just one small, short-duration trial showed a marginal signal on a single clinical outcome measure.
So how can we reconcile the scientific need for replication in ALS trials with the humanitarian need for more treatment options? I see three possibilities. First, we can approve new ALS drugs with just one positive trial and call for “real world” follow-up studies as we have here with Radicava. The problem is, even a well-designed “real world” study, like this one by Witzel and colleagues, cannot provide the same degree of proof as a trial would. I personally doubt Radicava’s efficacy even more after this real-world study, but without another randomized, double-blind, placebo-controlled trial, I will never truly know whether it works or in whom. The 2017 FDA approval removed incentive for the company that owns it to ever sponsor another trial.
Second, we could use “conditional approvals” for ALS drugs, as was recently done with aducanumab. This way we could get a drug with preliminary evidence of safety and efficacy into the hands of those who need it, while at the same time requiring a confirmatory trial. A question I have about this option is, if the drug is widely available, how well will that second trial enroll?
Finally, we could require replication before any kind of approval, but, once safety is established in the first trial, utilize large, expanded-access programs to make the drug available to those who cannot qualify for the trial. I personally like this last option best. There certainly are challenges to creating expanded-access programs at the level of the sponsor and the treating physician, but new financial resources, such as Act for ALS, and educational resources, such as those being assembled on the NEALS Website, should offer solutions.
Comments
Duke University
Drug development in ALS is not easy.
From a science standpoint, we don’t know what causes 90 percent of the cases. We suspect there may be subsets of ALS with different pathologies driving progression in different patients at different times, but we have no good way to identify these. We do not typically have pharmacodynamic biomarkers telling us we are hitting our targets with the doses and routes of administration we chose. The outcome measures we do have are clinical, things like disability questionnaires, breathing volumes, muscle strength testing. These are noisy and slow to change. There is disagreement over what a clinically meaningful change on these measures looks like. ALS trials enroll slowly for a variety of reasons, and so it can be years between the first patient enrolled and the availability of results. Given all this, it is hardly surprising that replication (one of the fundamental principles of good science) is rare in ALS trials. Either no confirmatory trial is done, as in the case of Radicava, aka edaravone, or the follow-up trial fails to replicate the previous “positive” result, as in the case with lithium, dexpramipexole, and NP001.
From a humanitarian standpoint, ALS is still the worst disease I have come across in all my years in medicine. One of my patients described it as follows: “You put me in a box with this diagnosis, and every day it gets smaller on all sides, further restricting what I can do. Eventually it will get so small and tight that it will crush me to death.” Given this, it is easy to see why people living with ALS (PALS) are frustrated, sometimes angry, that after more than 100 years of ALS research we do not have better treatments. They have channeled these emotions into impressive advocacy efforts, and through these have changed laws. I suspect these advocacy efforts also played a major role in the 2017 FDA approval of Radicava, which occurred after just one small, short-duration trial showed a marginal signal on a single clinical outcome measure.
So how can we reconcile the scientific need for replication in ALS trials with the humanitarian need for more treatment options? I see three possibilities. First, we can approve new ALS drugs with just one positive trial and call for “real world” follow-up studies as we have here with Radicava. The problem is, even a well-designed “real world” study, like this one by Witzel and colleagues, cannot provide the same degree of proof as a trial would. I personally doubt Radicava’s efficacy even more after this real-world study, but without another randomized, double-blind, placebo-controlled trial, I will never truly know whether it works or in whom. The 2017 FDA approval removed incentive for the company that owns it to ever sponsor another trial.
Second, we could use “conditional approvals” for ALS drugs, as was recently done with aducanumab. This way we could get a drug with preliminary evidence of safety and efficacy into the hands of those who need it, while at the same time requiring a confirmatory trial. A question I have about this option is, if the drug is widely available, how well will that second trial enroll?
Finally, we could require replication before any kind of approval, but, once safety is established in the first trial, utilize large, expanded-access programs to make the drug available to those who cannot qualify for the trial. I personally like this last option best. There certainly are challenges to creating expanded-access programs at the level of the sponsor and the treating physician, but new financial resources, such as Act for ALS, and educational resources, such as those being assembled on the NEALS Website, should offer solutions.
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