"... if cu64 is capable of detecting tumours as small as 2mm, that an individual with 10s or 100s of cu64-detected tumours is not going to have all of their tumours biopsied for ethical reasons..."
"... Is it possible that a patient has a scan, their doctor learns enough from the scan to decide on a course of treatment and then the patient decides not to go through with the biopsies? Hard to blame a cancer patient for not wanting to be a voodoo doll ..."
TRIAL PROTOCOLS 1) Learning from COBRA (whose full trial protocol is publicly accessible): The initial intended management plan for the patient was made according to SOC. The treating doctor was then given the Cu64 scan report and asked to "document whether a change to the initial intended management plan may be warranted due to the 64Cu-SAR-bisPSMA PET/CT finding". About 50% said they would change. 2) Back to CLARIFY: The fact that the patients recruited for this trial (CLARIFY) are already on the journey towards surgery, I think its likely that the Cu64 scan has no role in the decision making. The Cu64 scan is experimental, so (like COBRA), SOC must guide management, until after approval. 3) If the patient somehow finds out that the cancer is too far gone, and withdraws (rightly so - for the patient), they will clearly no longer be able to provide the trial end points. The trial could fall apart if too many such cases (protocol violations) happen. The FDA should be getting rolling submissions so one assumes such things will be seen early - at which point the protocol could be revised. Also, the fact we have trialists who have been in the trenches for a long time should be comforting.
ETHICS CONCERNS! a) Ethics are not breached when you do not have conclusive evidence that the drug or test that you are evaluating is superior to another. In theory and for ethics purposes, the investigators are all in equipoise: they don't know which is better. In the interview with Michael Frazis, Louise Emmet covers this quite a bit. She still does not know if Cu64 scans are better for patients - even though she produced the early evidence that convinced all of us that they are! Only with enough evidence, will management of patients change! b) In fact, it would be unethical for doctors to influence patients decisions by revealing the results of an experimental drug to them. First do no harm: What if its harmful? And, what if it doesn’t work? c) OPT-302 was a wonderful drug that was supposed to beat SOC by 5 miles (5 letters), until SOC loaded itself with carrots, multivitamins, and also started visiting the gym a lot - and boom, it was victorious! Or did SOC drink some Redbull!
SAMPLE SIZE CLARIFY aims to establish sensitivity and specificity against a gold standard (histopathology).These trials generally require larger sample sizes to ensure statistical power for both:Sensitivity (true positives), AND Specificity (true negatives). AMPLIFY trial details are not yet known but if its a shoe in with COBRA (as we expect it to be), the aim will be to establish either of Non inferiority or superiority to SOC. The main determinant of the sample size here is the expected gap between intervention and control. Cu64 was far much better than SOC PSMA tracers in COBRA, so we need a relatively small sample size to prove that. However, some other factors are factored in, including inflators so as to get results that are generalisable, and to account for potential dropouts or data that can not be interpreted. Many here will be aware of trials that have terminated early when interim analyses showed compelling evidence of effect! DISCO (SARTATE in NETS) did that - 45 recruited instead of the planned 63. It wasnt a Phase 3, but it matters - it finished early, and will have saved some money!! I don’t think CLARIFY can do that though coz of its design, but its very possible with AMPLIFY, depending on who SOC is gonna be! But lets not forget OPT-302, may he/she Rest in Peace! A slam-dunk that never was!
MULTIPLE CLARITY TRIALS: Costly for sure, but could there be a silver lining? It's a cup half-full versus cup half-empty situation! I wont talk about the cup half-empty situation: its depressing. The cup half-full: For clinical adoption of new drugs, 2 is better than one, and 5 is better than 2! A statement like '...Only one trial has ever been done on this product ....' creates doubts in clinicians' minds! Repeatability an confirmation is important. I hope CLARIFY and AMPLIFY get on to show the results that Clarity investors want - so that the message moves from an indication (patients before prostatectomy only, or BCR only) to Prostate cancer in general! A bit like Googling! The SAR, the bis, and the Copper! If the Cu64-SARTATE and Cu64-BOMBESIN trials do their part: Copper will reign supreme.
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