Should regulatory authorities approve drugs based on surrogate endpoints?
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n2059 (Published 16 September 2021) Cite this as: BMJ 2021;374:n2059Linked Analysis
Raising the bar for using surrogate endpoints in drug regulation and health technology assessment
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Dear Editor
The Regulatory Authorities appear to have lost their souls.
In India, a DNA based vaccine has been approved without full assessment. Here in the West, we are treating Covid-19 as if it was a plague; although we do not have reliable tests.
Competing interests: No competing interests
Dear Editor,
There is an even more recent example of the use of a surrogate endpoint in drug trials than that of aducanumab for Alzheimer's.
It appears that the FDA decision to approve it is based on the reduction of amyloid plaques, with the proposition that, if it does this, it must produce clinical benefit.
An exact parallel is the recent NICE approval of Inclisiran as an adjunct to statins for reducing cardiovascular risk (CVR). It is based on the similar-in-principle assumption that as it lowers LDL-C far better than statins, it must reduce CVR to a greater extent.
There is no clinical evidence for this whatever, nor for the extraordinary claim that its use will save 30,000 lives, as reported in the lay press. The drug company's own trial was terminated early, having failed to prove a reduction (indeed it has been suggested that had it continued to term it would have shown an increased risk). As Lenzer and Brownlee point out, clofibrate caused cholesterol to go down, but non-cardiovascular mortality went up - perhaps the first indication that lowering cholesterol might have its drawbacks..
If statins reduce CVR (a bit) and reduce LDL-C (a bit), while Inclisiran reduces LDL-C a lot, but does not reduce CVR, the only conclusion possible is that the benefit of statins is independent of its effect on LDL-C and is due to another factor. We know that statins are mildly anti-inflammatory (and Inclisiran appears not to be) . This effect is far more likely to be the reason why they work (though I repeat not a lot).
Using the lowering of LDL-C as a surrogate endpoint for decision-making with Inclisiran is therefore scientifically invalid. NICE should withdraw its approval for Inclisiran, not least because the cost of using it is substantial and we have no idea what the long-term consequences of such a huge reduction in LDL-C might be. I would suggest further that any new analysis of the matter should be done by experts with no conflicts of interest - which would exclude all those funded directly by the drug manufacturers, and all those who work for or represent charities and organisations that receive substantial financial support from the same sources.
Competing interests: No competing interests
Dear Editor,
The task of regulatory authorities in matters of drug approval is intricate and complex. The question raised can have two adjudicatory responses:
a) approval on the basis of surrogate end points can at best be exceptional/rare, with most important/significant justifications being cited (and never appearing as general consideration)
b) confirmatory trials need to be conducted in a time bound manner, and outcomes submitted to authority as a necessary part of follow-up for consideration.
The load of Alzheimer's disease and such degenerative conditions is so high that patients/families wait for 'breakthrough' with enormous hope. The mere 'possibility' of probable relief carries high stakes.
Prof Murar E Yeolekar, Mumbai.
Competing interests: No competing interests
Re: Should regulatory authorities approve drugs based on surrogate endpoints?
Dear Editor
I am grateful as ever to Dr Anand [1]. In this regard I recall an Indian news report of 2018 which reported the Drugs Controller General S Eswara Reddy [2]:
“He said media reports that during last 7-8 years, 25,000 patients died during clinical trials in India while the fact is that only 5 percent of these deaths are actually due to clinical trials.”
I think one might still be concerned that 1,250 deaths from clinical trials could be acceptable.
[1] JK Anand, ‘ Re: Should regulatory authorities approve drugs based on surrogate endpoints?’, 21 September 2021, https://www.bmj.com/content/374/bmj.n2059/rr-1
[2] ‘Drugs Controller to come out with vaccine specific regulatory policy’, News. Web India 19 May 2018, https://news.webindia123.com/news/Articles/Health/20180519/3347418.html
Competing interests: AgeofAutism.com, an on-line daily journal, concerns itself with the potential environmental sources for the proliferation of autism, neurological impairment, immune dysfunction and chronic disease. I receive no payment as UK Editor. I also moderate comments for the on-line journal ‘The Defender’ for which I am paid. I am also a member of the UK Medical Freedom Alliance