http://www.nature.com/news/2008/080401/full/452510a.html
Drug markers questioned
A recent spate of worrying clinical-trial data has researchers
questioning drugs approved on the basis of how they affect biomarkers
rather than clinical endpoints. Heidi Ledford looks at surrogate
markers.
Heidi Ledford
Forty years ago, a debate raged among cardiologists over the nature of
the link between high blood pressure and heart disease. Some believed
high blood pressure was a causal factor in producing heart attacks and
strokes. But others argued that the body raised blood pressure as a
way of mitigating poor vascular health. The stakes were high: if
increased blood pressure was a coping mechanism, then drugs that
lowered it could be harmful.
After dozens of clinical trials, millions of people now take drugs to
treat their hyper tension. High blood pressure has become an accepted
surrogate marker for cardiovascular disease, meaning that a fall in
blood pressure can be used as an endpoint in clinical trials for drug
approval. An advantage is that blood pressure can be measured quickly
and cheaply, so a drug can be approved for use without the need to
wait for its effect on distant and infrequent clinical outcomes such
as heart attacks.
Drugs that lower blood pressure are now regularly approved for
cardiovascular disease on the basis of their ability to fight
hypertension alone -- in the United States and Europe, for example,
regulatory agencies do not require additional clinical trials to
determine whether such drugs also reduce heart attacks or strokes.
Drugs for other conditions, from cancer to diabetes, are also often
approved on the basis of such surrogate outcomes as reduced tumour
size and a drop in blood-sugar levels.
But a recent spate of disquieting clinical trials involving high-
profile drugs such as Avandia (rosiglitazone) is prompting researchers
to re-evaluate this reliance on surrogate markers (see 'Surrogates
under suspicion'). "It's been a watershed year," says Harlan
Krumholtz, a cardiologist at Yale University. "It's shaking
assumptions about how we should be evaluating these drugs."
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Luke
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