@Coit[Please note that in my response, I am taking the input from @UpsideDownAndUnder as FACT]!
# 1. Who defines the Reference Standard?
Its the trialists (Clarity and its researchers) who define the Reference Standard (its part of the design of the trial). This design has to be based on the highest available scientific evidence.
Now: if the design is done incorrectly, the regulators will reject the study: imagine the costs! That's why it helps to get guidance from that target regulator in advance.
Whats interesting in the story being told, is that, it sounds like Clarity proposed doing something that has the highest level of scientific validity and robustness, while the FDA were willing to accept a lower standard! The reason this can happen is precedent: the FDA's previous approvals!
# 2. Why is SOC PSMA PET (Illuccix, Pylarify) not acceptable as the Standard of Truth?
These scans miss cancer too often (as we now know - thanks to COBRA), so using them as a "truth" risks missing disease when it exists (FALSE NEGATIVE) - in the process, labeling Clarity's more sensitive Cu6 tracer as wrong, when it is actually detecting real disease.The bottom line is: you should not evaluate a new diagnostic tool against an imperfect existing tool! Worse still, the real standart of truth, histopathology (biopsy) exists! So, why compromise?
3. Does insisting on biopsy make the trial impossible?
No. Even without biopsy, Clarity could show equivalence to SOC in as far as picking up lesions is concerned. They just need to pick up all lesions picked up by SOC. Same day scanning will do that. The next day scan will cause a lot of trouble - by picking up more! Very strange situation. So, Clarity want to demonstrate this superiority, which requires knowing the true disease status.Without histology, true detections by 64Cu-SAR-bisPSMA will be misclassified as false positives — harming both the product and patients.
4. Patient safety and scientific integrity!
# False negatives delay care and worsen outcomes!
# False positives lead to unnecessary toxic treatments!
# Histopathology tells the truth, avoiding both errors and ensuring patients get accurate diagnoses.
5. Is there precedence?
One of many examples is the Kuten et al study; a head-to-head that directly compared 68Ga-PSMA-11 versus 18F-PSMA-1007 PET/CT imaging, using histopathology and immunohistochemical analysis as the reference standard. What a shame they did not have 64Cu-SAR-bisPSMA! The study was published in 2020.
The point is: what Clarity want to do, can be done.
The difference is that, the Kuten et al study does not appear to have been linked to any planned FDA approvals for any product (although I do not know for certain if it was later used or not for any approvals, considering that some of these products got approvals based on historical studies (studies done by others, for the sole purpose of generating or expanding knowledge)).
Anyhow: the point is - Clarity’s request is not only scientifically sound, but there is precedent on both accounts: head-to-head, and histology!
6. Is the St Vincent’s head-to-head trial meaningless?
Not at all. Even if the FDA does not require a head-to-head or biopsy results, Clarity can still submit these data as supporting evidence. FDA decisions are made by expert committees, and require a vote. Strong evidence speaks for itself. “You can't unsee what you've seen, even if you didn't want to see it.” If the results are as expected, the St Vincent's data will be powerful and persuasive in demonstrating 64Cu-SAR-bisPSMA's performance.
7. Why so much trouble if an approval won't issue gold medals?
While the FDA might approve all who make the grade, meaning that Clarity is wasting time and resources, superiority in trials (as opposed to equivalence), confirms Best In Class status, which is useful for market dominance. With all other things equal (access: availability and cost), patients and their doctors will choose a test that gives them the truth, and if not possible, one that is closest to the TRUTH!
8) And for the KICKER: A biopsy gives access to the truth (histopathology), but it is a real pain! Only 9 out of about 50 in COBRA had a biopsy! A damnig statistic, we might say!
Well, thats exactly the point! Why have a biopsy, when a 64Cu-SAR-bisPSMA powered scan can give you a result that is close to a biopsy obtained truth?That is the reason why it's so important to know the TRUTH, and if it hard to verify it, we need to have the best and closest surrogate of the truth.
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REF
Kuten, J., Fahoum, I., Savin, Z., Shamni, O., Gitstein, G., Hershkovitz, D., & Even-Sapir, E. (2020). Head-to-Head Comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and Immunohistochemical Analysis as a Reference Standard. Journal of Nuclear Medicine, 61(4), 527–532.
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