Hundreds of people with ALS and caregivers submitted comments to the FDA regarding its draft guidance for industry during the designated comments period which ended in April.
Now the ALS Association is holding a "workshop" to cover the same ground, and they asked for questions and comments to be presubmitted. Below are my questions and comments for the workshop.
I hope that they will be discussed openly and candidly with the FDA representatives at the workshop... and that some action will follow the lights and camera.
_______________________________________
Risk Benefit – Question
We have seen far too many ALS clinical trials where the participants have been treated as guinea pigs rather than valuable human test pilots.
Trial designs often do not provide any access to the real therapy for people who were stuck in the placebo group.
They often fail to provide any continuing access to the therapy for people who tested the actual therapy and found the therapy to be helpful.
The excuse we get from sponsors is cost. In my opinion, if you cannot afford to provide the real therapy to the most important people on your project team, then you cannot afford to do a clinical trial.
Please, FDA, will you provide guidance that will set an expectation to include some access to therapy for all trial participants?
Risk Benefit – Comment
We seem to have lost some sense of ethics in a frantic pursuit of companion biomarkers.
If a trial has a washout period to see if a biomarker tracks as the patient crashes, that seems to me to be cruel.
I hope that the FDA will not approve such trial designs and will say that in its guidance.
Outcomes – Question
Thanks to the FDA for the swift approval of Radicava. I am glad for that.
As with most therapies, we know that the drug doesn't work for everybody.
Since Radicava got approval for the broad ALS indication, there is absolutely no incentive for the drug company to figure out who the responders really are.
If we end up with several more therapies (and I hope we do) that do something for a subset of people with ALS, we need to know more about who the responders really are.
Without that, we have an expensive and time-wasting pickle for patients and payers.
Will the FDA consider putting some conditions on such future approvals for post-market studies that can shed light on which patients are actually getting the results everyone desires?
Design – Comment
Last December at the International Symposium on ALS MND, we saw two presentations where overachieving placebo groups spoiled the results for the investigators’ therapies. There were going to be two more trial do-overs to see if the therapy was actually superior to placebo.
They described the placebo groups as having done "better than expected."
“Better than expected.”
“…expected.”
That's a vague reference to an historical control, folks.
What you expected in the control group is based on experience and data on how ALS typically proceeds.
Why not use historical controls themselves rather than kid ourselves that a placebo group is superior to historical controls?
We can't afford the do-overs to get control groups in RCTs that behave "as expected."
And now the recent fad of “enrichment” where trials seek fast progressors may have as much to do with finding a placebo group that declines (as expected) as it does about finding people with ALS who respond to the therapy.
Design – Question
As the FDA issues more and more guidance documents, the problem of consistency becomes apparent to me.
There is inconsistency in guidance among diseases (e.g. acknowledgment of ethical concerns about placebo in cancer trials but not in ALS).
I also fear inconsistency in two pieces of guidance that a therapy developer may use for an ALS trial. One guidance may promote innovative statistical models for control groups while ALS-specific guidance may reject that. In such a case, I guarantee that a sponsor will go with the more conservative path, and a disease like ALS needs the more innovative path.
At some point will the FDA review guidances for consistency and help us promote the most innovative and quickest paths to the scientific truth for ALS?
Overall – Comment (And the most important thing I have to say.)
During the FDA comments period for the guidance, hundreds of people with ALS and caregivers and drug developers stepped up (frankly, without any help from the ALS Association) and made cogent comments regarding the guidance.
I hope that this workshop does not diminish or distract from the comments of the many who got their homework in on time and gave their thoughts on the draft guidance at regulations.gov.
