Thank you for inviting me, it was great to hear about your important work! Great effort to develop methods for using real world data in drug development for #ALS #MND, including synthetic controls with the potential to reduce placebo & trial duration!

Yes as prognostic factor it works great, could be used as eligibility criteria to leave out slow progressors, but correlation NFL - progression is not 1 to 1 and comparative data is sparse yet how well this works (and how much better it is than simpler methods based on FRS/clinics).

Regarding NFL, most programs include it as secondary objective now. I have some reservations still around NFL as probably small effects like Riluzole will not show a large change and would be difficult to assess in non-randomised studies.

You are right, the riluzole example is an RCT for patients who can't participate in the main RCT, which I believe is similar for EAP (only those not eligible for trial?). Think you need some control to make the data insightful.

Thanks! I would be interested in the starter pack as well!

Maybe redesign how we use EAPs. I like the approach riluzole used - they did a controlled EAP study, which provided useful data (pubmed.ncbi.nlm.nih.gov/12021952/): "The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel."

Good points; EAP could evaluate safety and tolerability, but it is difficult to determine drug benefit in EAP. OLE (or ATE - active treatment extension - as I was told over the weekend) holds value to get some efficacy data, especially if there is a delayed effect, but doesn't replace a placebo.