@Mozzarc @39KPIts all very interesting.... We have PAR saying...

@Mozzarc @39KP

Its all very interesting....
We have PAR saying the DM studies can be done within our P3 studies (incorporated into 002 stage 2 or 003).
We have Kraus saying that "Biomarkers now exist in OA that are reasonably likely to predict important benefits to patients" (thanks for the reminder @Dungiven )
Its almost hard to imagine a scenario where FDA doesn't agree to surrogate endpoint(s) that if met would enable AA.

[There is a question here in that the FDA definition for AA is that a surrogate endpoint needs to predict a clinical benefit, or is reasonably likely to predict patient reported otcomes of interest or overall survival. I fully get that DMOAD is the goal, but these difinitions seems to form a slightly lower bar (there have been numerous successsful AA approvals, but not all of them would have disease modification potential). So DMOAD would/should mean AA, but AA could happen wihout DMOAD I guess?]

Anyway the bible on this seems to be this 2019 paper by Kraus you can read HERE
"Proposed study designs for approval based on a surrogate endpoint and a post-marketing confirmatory study under FDA's accelerated approval regulations for disease modifying osteoarthritis drugs"

Its quite a read!

This is the framework
- the Grey box is a pre-approval trial with patient reported outcomes (WOMAC) and Surrogates
- the Black box is the longer term Post Marketing Approval (PMA) trial which relies on PRO plus other Observed Outcomes



A few choice sections..


One of the key attributes of AA seems to be to help fund new drugs by gving the sponsors access to early revenues to assist with the longer term trials. Pretty important statement (agreeing surrogates will really indicate the FDA believes they can be met). But it gets better....




Now I'm interpolating here, but what I think it means is that if we demonstrate succesful readout of an agreed surrogate marker, FDA would agree there is reasonable liklehood of DMOAD which should then facilitate AA.... but importantly we would get DMOAD (even though its only 'reasonably likely') on the label upon granting of AA and not having to wait until after a longer PMA trial. At least I think thats what it infers?

The paper is full of a ton of other interesting things like...
- how hard it is to have a placebo arm in a PMA because patients wouldnt take the risk of getting placebo if the drug is already approved.
- other data which may assist a PMA, such as real world evidence (RWE - remember we have hundred through the SAS already)
- using other data to show there is a long term benefit such as electronic patient records, quality of life, mobility (using fitness devices) and even associated prevalence/incidence of diabetes (due to reduced mobility).