With an assumption that Adu gets approved (which is less than 50/50), I'm not sure the FDA will clear a non-inferiority pathway for other drugs. I think at least one of the two typical AD trials will need to be against placebo (beating placebo in one and being non-inferior in another might be ok). As it is, placebo in AD usually means donepezil or other AChEI.
For comparison: Relapsing MS studies over the last 8 years have mostly been against active comparator as there is overwhelming evidence that a 2 year delay in treatment leads to more disability later in life and is thus unethical (i.e. drugs are disease modifying not just treating a symptom). Ocrelizumab/Ocrevus, Ozanimod/Zeposia, ponesimod/Ponvory, ofatumumab/Kesimpta approved during the last few years all beat an existing drug (either Aubagio or Rebif). Mayzent/siponimod is one exception as they were going for a SPMS indication (no approved drugs for inactive/nonrelapsing SPMS) but the FDA approved them for RMS (which includes active/relapsing SPMS) and Ocrevus for PPMS is another as no FDA approved treatment for PPMS existed before Ocrevus. So all drugs approved by standard 505b1 pathway either beat placebo or beat a comparator. Vumerity which used the 505b2 pathway for approval was the only non-inferiority approval (compared to Tecfidera in short study done more for marketing than for the FDA). But the active ingredient (monomethyl fumarate) is the same with both drugs. This allowed the short cut approval.
Companies will need to get a little creative to enhance recruitment. This can be as simple as reimbursing patients better but more likely to be a change in design. Another simple method is to increase the ratio of treated to placebo to 2:1 or 3:1. Definitely offering open label drug after a set time helps.
I would favor a staggered start design. Lets say there are 1000 patients in a 2 year study. 250 start drug at entry and are on drug x 24 months in blinded fashion, 250 are placebo x 6 months then start treatment for 18 months, 250 are placebo x 12 months then drug x 12 months and 250 on placebo x 18 months then drug x 6 months. This allows true blinded placebo comparison x 18 months and also allows determination whether the drug is just a treatment or is disease modifying (if just a treatment the delayed start group will be about the same at 24 months as the initial group; if disease modifying, the delayed group does not catch up). It also allows earlier treatment for many patients. Of course, all should be offered at least another year or more of OLE.
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