RE:RE:RE:RE:RE:RE:pre-BTD and BTDFrom the start the protocol of the trial was 2 treatments - one at 3 months and one at 6 months.
The primary outcome of the trial is efficacy evaluated by CR at any time,
The secondary outcome of the trial is duration of CR at 12 months post initial CR.
There is every reason to think that these are the efficacy criteria the FDA will use to judge whether or not our treatment has demonstrated sufficient efficacy to warrant approval.
I don't think it would be reasonable on the part of the FDA to demand a longer duration of response than 12 months past initial CR for BTD or AA when this will not be required for full approval.
The FDA judged the Adstiladrin trial based on exactly the same outcomes as our frial. They granted Adstiladrin full approval based on CR at any time and duration of CR at 12 months post initial CR. This is despite the fact that Adstiladrin was administered every 3 months for 12 months. All of the Adstiladrin patients who were CR at any time had their initial CR at 3 months. This means that at their 15 month durable CR assessment most (if not all) of these patients had received a treatment only one month before. And it was on this basis that they were granted full FDA approval.
This is from an FDA Clinical review memo:
"The effectiveness claim of this original BLA is based on, rAd-IFN-CS-003, a single-arm trial that enrolled patients with high-grade, BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). The study population included patients with CIS only, Ta/T1 high-grade disease with concomitant CIS, or Ta/T1 high-grade disease without concomitant CIS. Only patients with CIS with or without concomitant Ta/T1 tumors were considered evaluable for complete response at any time, the primary endpoint of the study. The key secondary endpoint was the durability of CR in patients in the CIS cohort who showed CR at any time after the first administration of nadofaragene firadenovec.
A total of 107 patients with CIS were enrolled onto rAd-IFN-CS-003 of whom 103 were considered to have had adequate prior BCG therapy to be considered BCG-unresponsive per FDA guidance. Fifty-five patients had a CR at the first disease assessment (three months after the treatment start), leading to a CR rate of 53.4% (95% CI: 43,63%). No patients experienced a CR subsequently. The median duration of response was 9.7 months (95% CI: 9.9, 13.9 months). As of the November 15, 2019 data cutoff, the applicant reported that all study subjects had completed the Month 15 efficacy assessment visit and thus all patients in CR had been followed for at least 12 months following response. Of the 103 patients with BCG-unresponsive CIS who were treated with r-Ad-CS-003, 24 remained in CR for at least 12 months after the response was achieved. This corresponds to 44% of responding patients and 23% of all treated patients. Of note, random biopsies, which may capture occult CIS thereby improving the reliability of the durability results, were performed at the 12 month follow-up visit. Thirty-two patients with CIS with either no CR or CR followed by recurrent disease underwent subsequent cystectomy. Progression to muscle-invasive disease (T2) was seen in 3 of these 32 patients (9.3%), which is not higher than expected based on historical controls in the literature."
DJDawg wrote:
I'm not really sure. My area of work doesn't work with FDA but we do recruit for thyroid cancer trials.
My personal gut feeling is that frequent communication with the FDA seems a bit fluffy. The FDA is a beauracracy so when I read that I don't know if I imagine a dedicated phone line back and forth. My hunch is that the BTD review committee is its own silo and they can just look at things and say what the personally want in the applications. And then the companies have to dig around for those details.
I'm not ever sure that the 15 m timeline was a mistake that just happened. Didn't they start the study doing just one treatment and then modify it for a 2nd maint treatment at 6m after the first 12? I can't recall the timeline. If so, then the original one and done protocol would have mean that they would have had follow up for 15m from last/only treatment. With the 6 m protocol for a second treatment it now means that the 15 m follow up is only 9 m from last treatment.
I'm guessing completely.....