21 Comments

I wonder if Sensible Medicine would discuss the recent announced use and distribution of retroviral vaginal rings in Sub Saharan African countries. Data suggests compliance with antiretroviral treatment is better with the vaginal ring versus oral treatment, but as best I can tell the only data currently available is on safety. I do not see data on efficacy on this type of delivery but it is being touted as a game changer for HIV prevention.

The Lancet HIV DOI:https://doi.org/10.1016/S2352-3018(23)00227-8

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I can find no data which indicate that was ever the case. What is your source for your claim that before 1990 drug development was conducted primarily in universities and funded by the government?

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Good one John! Keepin' 'em honest! 👏

"More events to count helps sort out signal from noise" also increases the odds of spurious "positive" statistical findings.

Back in my day, "peeking" at the data before the study was completed was a definite No-No. We can protect the validity of clinical research by (1) requiring PI's to file their research design before starting the trial (2) prohibiting pre-completion design changes and (3) requiring PI's to bank their research data for future review/analysis.

Standards matter.

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Apparently it's hard to get a negative trial published, so there's a push to find something positive in every trial. Beyond that, having invested in the drug trial, why would the drug company want to publish a study that says it doesn't work?

What ought to happen is that studies should proceed according to the approved research protocol, and they should be published regardless of whether they show the desired effect or not.

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It seems these days as a matter of routine, investigators are “surprised” by lower event rates than they had banked on in their power calculations. This occurs across all domains in cardiology. At some point, that has to stop being a surprise.

Perhaps trialists should simply account for this fact, and plan to enrol more than they think they might need to. And if they happen to luck out and event rates are higher than expected, then the DSMB can step in if efficacy crosses stopping boundaries. Hopefully this will help us avoid clinically meaningless endpoints.

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Apparently sales weren't going well so a "study" was cooked up in order to generate some positive marketing. What is the biological plausibility that a drug designed to inhibit glucose reabsorption in the proximal renal tubules would have any significant benefit for patients with MI? Adding new endpoints that do have something to do with the action of the drug and inventing a new statistical procedure to generate some positive numbers plumbs new depths of scientific dishonesty.

By the way, all cause mortality is the only truly hard endpoint. Cardiovascular death may be semi-hard but a number of autopsy studies have shown that CVD as a clinical diagnosis may not be accurate 1/3 to 1/2 of the time. Hospitalization for heart failure may be due to a range of reasons and is, therefore, somewhat soft.

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Thank you for sharing.

All your points are well taken. But, if the investigators had used a 99.7% CI, this would really not have been a "positive" study.

(Of course, we would have missed an opportunity to learning about importance of circumspection about "positive" results with little clinical impact and the problems with adding end-points that might not really be meaningful.)

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Will we ever get a totally independent trial that does not try to fudge the data and outcome? In other words, we can look at a trial and not have to dig under the hood to discover the truth and results are far from advertised.

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John-

Always enjoy your cogent analysis. It’s truly a great mini-journal club for all of us. Thank you-

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"The problem was that hard clinical endpoints like death, CVD, HHF, MI, and even all-cause hospitalization were not different. .. The primary endpoint was driven by softer endpoints like new diagnoses of diabetes and weight loss—both of which are way down the hierarchical scale."

Slam dunk!

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John -- Good observation.

I note that the study was funded by Astra Zeneca, so my BS radar is immediately put on flashing red. My take home is that this is yet another way the drug companies use to move the goal posts CLOSER to get a positive result from a trial.

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