Obsessed with surrogates?

Not really something you should tell your partner, that you are obsessed with surrogates. But it seems to me, we should all be pretty anxious about the rise in the use of surrogate outcomes in clinical trials over the last decade. Indeed, if the pharmaceutical industry could, they would make them mandatory for all primary outcomes, now, and in the future.

It would be the end of hard outcomes; throw in a few patient reported outcomes as well, and there you go, a ready made regulatory approved treatment to go.

Therefore it was with interest that I read  the article in the BMJ, by John Yudkin, Kasia Lipska, and Victor Montori, which argued that our obsession with surrogates is damaging patient care.

It was a relief to see there are other folk out there, implying that there is a widespread problem affecting healthcare worldwide –  might even need to declare it a pandemic.

This is what they say: ‘overinterpretation of surrogates can lead to misinterpretation of the evidence,’  as well as posing the important question: ‘why have doctors become so invested in surrogate markers?’

If you are wondering what surrogates are, and to get you up to speed, then read Healthy Skepticism’s collection of misleading surrogate end points.

Anyone, though, might think the problems with surrogates are a new issue. Yet, in 2000 Ralph D’Agostino was debating ‘The slippery slope of surrogate outcomes’ 

At the time this is what he concluded:

‘Surrogate outcomes are frequently used in cardiovascular disease research. A concern is that changes in surrogate markers may not reflect changes in disease outcomes. Two recent clinical trials (Heart and Estrogen/Progestin Replacement Study [HERS], and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]) underscore this problem since their results contradicted what was expected based on the surrogate outcomes. The current regulatory policy to allow new therapies to be introduced onto the market based solely on surrogate outcomes may need to be reviewed.’

This year, Larry Huston reported, the “FDA is actually seeking to make it easier for manufacturers of one therapeutic category, antihypertensives, to claim cardiovascular benefit for their drugs despite the absence of evidence to support most of these drugs.”

And further to this, the FDA was heavily criticised this year, for its reliance on surrogate  markers in the approval of a tuberculosis drug. Pharmalot reported earlier this year that ‘an essay in the Journal of the American Medical Association notes that the pivotal Sirturo trials were small and produced troubling data. Ten of 79 patients given the drug died, compared with two of 81 in the control group. And five of the 10 deaths were due to TB, indicating treatment failure. The trials measured the ability of the drug to convert a patient’s sputum culture from positive to negative.’

I can hear your thoughts: how do you exactly get to approval of Sirturo on sputum culture? Obviously, through over reliance on surrogates.

What has therefore changed in the last decade? Surrogates are used more, they are relied on more for regulatory approval, and less effective drugs are coming to the market.

Therefore let me ask you, who is it then, that is obsessed with surrogates?