Questioning Medicine

Question What is the strength of association between surrogate markers used as primary end points in clinical trials to support Food and Drug Administration (FDA) approval of drugs treating nononcologic chronic diseases and clinical outcomes?

often surrogate markers are used as primary end points in clinical trials to support FDA approval of drugs

I get it

Surrogate markers offer the advantage of reducing the duration, size, and total cost of trials

n 2018, the Food and Drug Administration (FDA) publicly released an Adult Surrogate Endpoint Table of more than 100 surrogate markers that may be used as primary end points in clinical trials that form the basis of traditional or accelerated approval of new drugs or biologics.

The authors evaluated Thirty-seven surrogate markers listed in FDA’s table of markers that can be used as primary end points in clinical trials across 32 unique nononcologic chronic diseases.

Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.
https://jamanetwork.com/journals/jama/article-abstract/2817850

The full podcast -- not sure why the last one cut off early.
Question and answer from ACOI

https://pubmed.ncbi.nlm.nih.gov/38945140/
The primary outcome was a composite of myocardial infarction, revascularisation, hospitalisation for heart failure, stroke, or death from cardiovascular causes

The mean systolic blood pressure throughout the follow-up (except the first 3 months of titration) was 119·1 mm Hg (SD 11·1) in the intensive treatment group and 134·8 mm Hg (10·5) in the standard treatment group.

During a median of 3·4 years of follow-up, the primary outcome event occurred in 547 (9·7%) participants in the intensive treatment group and 623 (11·1%) in the standard treatment group (hazard ratio [HR] 0·88, 95% CI 0·78-0·99; p=0·028).

primarily driven by a reduction in the risks of stroke, heart failure, and death from cardiovascular causes.

Serious adverse events of syncope occurred more frequently in the intensive treatment group (24 [0·4%] of 5624) than in standard treatment group (eight [0·1%] of 5631; HR 3·00, 95% CI 1·35-6·68).

INHALE-3, a randomized trial, 123patients with type 1 dm that compared the efficacy of an inhaled insulin regimen (Afrezza) plus degludec insulin (Tresiba®) against usual care over 17 weeks

The study's primary endpoint was a change in HbA1c levels, a critical marker of long-term blood glucose control.

More participants using the inhaled insulin regimen experienced significant improvements in HbA1c levels compared to those on usual care.

21% of those on inhaled insulin had an HbA1c improvement of greater than 0.5%, while only 5% of those with standard care.

21 – 5 that is an absolute difference of 16% (NNT of 6.25)

And they found a bunch of things when they went back like more people with a1c >7 reached their goal—which was not their end point they just found it and like to talk about

inhaled insulin and degludec was not for everyone: and everyone is missing this—we know how many people had an improvement in their a1c by 0.5% but how many had a worsening???

well 26% of the patients in the inhaled insulin group had a worsening of HbA1c greater than 0.5%

compared with only 3% with standard care.

26-3== 23 100/23== 4.3 NNH

So out of 100 people that still have to give themselves insulin

This doesn’t remove insulin

But we now add inhaled insulin we should expect to see 16 people out of the 100 have a 0.5% improvement in their a1c at 4 months

And we would expect to see 23 poeople have a 0.5% worsening in their A!C

That math don’t math—people are excited about this and all I can say is maybe they are getting paid by the drug company maybe they don’t understand number needed to treat and number needed to harm but this makes no sense.

The problems with observation data is real—

randomized trial, U.K. researchers identified 519 patients (mean age, 68) with mostly moderate COPD (mean forced expiratory volume in 1 second [FEV1], 50%), ≥2 exacerbations during the previous year, and no cardiovascular (CV) indications for β-blockers.

Patients were randomized to receive the cardioselective β-blocker bisoprolol (initially 1.25 mg daily, titrated to 5 mg if tolerated) or placebo.

At 1 year, no significant differences were noted between groups in incidence of COPD exacerbations or in other important benefits or harms.

Cardioselective β-blockers remain appropriate for COPD patients who have valid cardiovascular indications for their use, but taken these two studies together suggests that COPD patients without such indications should avoid bblockers—even cardio selective beta blockers
https://jamanetwork.com/journals/jama/article-abstract/2819083