RE:AA requires proof of enrollment N0taP00p ... For AA, you have to look at the specific 2018 FDA
bladder document to the industry to have more insights. See in
blue below (on what differentiates us from non-pivotal Ph. 2) and also in
green (on why the design of our clinical trial could lead to marketing application). So the
green could the explaination behind the "commercial revenues (projected)" advanced to early 2023. It seems to fit perfectly what our Ph. 2 has been designed for. We'll see in due time, as we're still dependent upon a FDA decision. But so far to me, it's might be the missing piece of what I was looking for.
AA gives the opportunity to get revenues from the drug before FDA approval. So that's something that should logicially interest all BCG-unresponsive biotechs. In the bladder indication, apart from Roche that got it in 2016, why none got it, I don't know!
Below, is the FDA 2018 guidelines to the industry regarding BCG-Unresponsive.
In the Table of Contents, note this section 10 (10. Accelerated Approval (Subpart H and Subpart E) Considerations)
A development program that assesses complete response rate in a single-arm trial may be appropriate for regular approval, or it may require a confirmatory trial after approval. 5 A confirmatory, randomized trial in the same population often is not possible (e.g., patients with BCG-unresponsive NMIBC). Sponsors may be able to provide confirmatory evidence of effectiveness in a different patient population. Potential trial designs include randomized trials comparing the investigational drug to BCG in treatment-nave high-risk disease or as add-on therapy to BCG (BCG plus/minus investigational drug) in patients who recur after an initial induction course of BCG. The need for a confirmatory trial and its design can be discussed at a separate, end-of-phase 2 meeting held during the conduct of a single-arm trial. On occasion, long-term follow-up from the same trial can satisfy a confirmatory study obligation under accelerated approval.
There's also this to consider and I think this is why TLT oftenly stress "long duration" response.
9. Statistical Considerations
For single-arm trials of patients with BCG-unresponsive NMIBC in patients with CIS that use complete response rate as the primary endpoint, the lower bound of the 95 percent confidence interval around the observed response rate should rule out a clinically unimportant complete response rate. The median duration of complete response is also important. A high complete response rate is not meaningful if the response duration is short. The sponsor should discuss with the appropriate review division the minimum duration of response at the time of NDA or BLA submission. Patients participating in the trial should continue to be followed for the development of a complete response and for duration of complete response. Sponsors can use either early phase evidence of effect size or data from historical controls to calculate the sample size of the single-arm trial; however, the FDA does not require or recommend a prespecified response rate. The natural history of CIS is well understood, and the complete response rate is negligible in the absence of therapy.
But I know the following in yellow is what we followed. And interestingly, the FDA must be extremely impressed that we get these results, via intravesical, when she's recommending systemic, despite admitting higher risks! Could this be what could land us Accelerated Approval or is this also because they expect PDT to give instant results, and even more, when combined with the potency of our molecule???
II. DEVELOPMENT PROGRAM
A. Early Product Development (that's pretty much our preclinical with UHN and Ph. 1b work)
Sponsors should conduct nonclinical studies to assess toxicity in animal models (see section II.C.2., Nonclinical Safety Considerations). We also recommend that sponsors conduct nonclinical studies to demonstrate antitumor activity in NMIBC and to determine the optimal dose and schedule of the investigational drug. Although six weekly instillations of intravesical therapy have become a standard dosing regimen for the treatment of patients with NMIBC, few data are available to support this approach. Once sponsors complete the animal studies, we recommend that sponsors examine antitumor activity as well as the optimal dose and schedule in an early phase clinical trial. One option is to assess antitumor activity in patients with marker lesions that can be safely left in place after resection of other areas of NMIBC. Sponsors developing investigational drugs for BCG-unresponsive NMIBC should also consider assessing antitumor activity in a small number of patients who are awaiting radical cystectomy for BCG-unresponsive NMIBC. With this approach, only a limited window of time is available for observation of antitumor activity because surgery should not be delayed. In addition, these trials should not interfere with the use of neoadjuvant systemic chemotherapy whenever appropriate.
B. Late Phase Development
1. General Considerations
Whether the patient has active disease at the time of trial enrollment is a key consideration for the recommended trial design and endpoints used to evaluate the effectiveness of an investigational drug treating NMIBC. For patients without active disease (disease was resected at or before trial entry), FDA recommends a randomized, controlled trial design using a time-to event endpoint such as recurrence-free survival. In contrast, patients with carcinoma in situ (CIS) at trial entry can be studied in either a randomized, controlled trial or a single-arm trial. In the absence of pharmacologic intervention or cystectomy, BCG-unresponsive CIS (a type of NMIBC), with or without resected disease, will persist and progress. In BCG-unresponsive NMIBC, a single-arm clinical trial with complete response rate and duration of response as the primary endpoint can provide primary evidence of effectiveness to support a marketing application. Sponsors can include patients with completely resected lesions and no evidence of CIS in these single-arm trials but should not include them in the evaluation of the primary efficacy endpoint. However, sponsors should include these patients in the safety analysis. The use of systemic, as opposed to intravesical, therapy has been proposed for the treatment of patients with BCG-unresponsive NMIBC. Given the potential for the increased risks associated with the use of systemic therapies, sponsors should limit early phase trials to patients with few treatment options. Patients with BCG-unresponsive NMIBC are appropriate because their treatment options are limited and the current alternative is cystectomy.