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BIOLOGICI E BIOSIMILARI: LA DIFFERENZA CON I GENERICI
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Articolo in lingua italiana
QUANTO SONO CREDIBILI I MARKER INDIRETTI DELLE PATOLOGIE?
15/04/2008
Di: Nicola Ferraro

In quale misura è lecito curare le cause presunte di una patologia che potrebbe svilupparsi nel tempo? Oggi, ad esempio,  si cura l’ipertensione arteriosa perché si crede in modo condiviso che questa condizione favorisca l’insorgenza dell’infarto miocardio e dell’ictus. Per queste due patologie l’ipertensione arteriosa si configura quindi come “surrogate marker”, marker indiretto, si potrebbe tradurre.
Questo modo di procedere però in oncologia a volte non funziona: la somministrazione di farmaci approvati sulla base di una loro azione su un marker indiretto di un certo di tipo di tumore non sempre ha effetti positivi sulla mortalità.
Questo dato ha reso nuovamente attuale un dibattito che si trascina da decenni: il rapporto ipertensione –infarto e ictus era per esempio molto acceso una quarantina di anni fa. Un contributo importante alla discussione arriva da un recente articolo pubblicato da Nature il 1° aprile scorso; lo riproponiamo ai nostri naviganti nella stessa forma in cui era in libera consultazione sulla Rete.

Published online 1 April 2008 | Nature 452, 510-511 (2008) | doi:10.1038/452510a
News

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.”
Nobody is saying that surrogate indicators should be abandoned altogether. Many well known drugs on the market today, including the breast cancer drug Gleevac (imatinib) and HIV fighting antiretrovirals, were approved based on surrogate endpoints, and scandals are rare. “You don’t want to deprive the public of a drug that possibly works,” says Arthur Schatzkin, chief of nutritional epidemiology at the National Cancer Institute in Bethesda, Maryland. “On the other hand, you don’t want to put something on the market that is harmful. This is the kind of thing that people at the FDA [Food and Drug Administration] tear their hair out over.”
One difficulty is the struggle to show that a surrogate is causally related to disease out come, rather than merely a correlate. Just because patients with flu have a fever, for example, doesn’t mean that treating the fever will clear the infection. Absolute confidence in a surrogate requires complete knowledge of the pathways leading to disease. “The surrogate outcome would have to be involved in all pathways that might link the treatment to the clinical outcome,” says Ross Prentice, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, Washington. “Really we aren’t ever in a position to know whether those conditions are strictly satisfied.” That is particularly true of complex conditions, including cardiovascular disease and diabetes.
Regulatory bodies such as the FDA in some cases allow drugmakers to bypass long-term safety studies, and conditionally approve a drug based on small studies using a surrogate marker, on the basis that future studies will be done to establish its clinical efficacy and safety. The fear here is that unanticipated side effects are missed. “Wait long enough, and you’re going to find that all surrogates eventually fail due to these off-target effects,” says Steven Nissen, a cardiologist at the Cleveland Clinic in Ohio.
And the FDA has a poor history of enforcing post-marketing trials — a 2007 report noted that drug companies had started only 29% of the post-marketing safety studies they had agreed to as part of a drug approval decision. By dragging their feet on the required clinical trials, drug companies can make billions of dollars on a flawed drug. “If the drug withstands the test of time, then that’s wonderful,” says Maha Hussain, an oncologist at the University of Michigan Health System in Ann Arbor. “But you have to actually collect the data on survival.”
It is unclear whether the current scrutiny of surrogate endpoints will affect how drug-approval agencies view them; the field has weathered scandals in the past. For now, at least, the FDA has not announced any plans to change its policies. In February, Senator Charles Grassley (Republican, Iowa) requested an investigation into how the FDA uses surrogate endpoints in drug approvals.
The issues are likely to become more pressing as projects to collect biomarkers of disease bolster the collection of potential surrogates. There is intense interest in finding surrogates for clinical trials of drugs for diseases such as cancer or Alzheimer’s. “If you’re trying to prophylax against some dreadful disease that won’t show up for 20 years,” says Robert Temple, director of the FDA’s Office of Medical Policy in Rockville, Maryland, “you almost don’t have a choice.”

References

    • Nissen, S. E. & Wolski, K. N. Engl. J. Med. 356, 2457-2471 (2007)
    • Kastelein, J. J. P. N. Engl. J. Med. 358, 1431-1443 (2008)
    • Prentice, R. L. et al. Am. J. Epidemiol. 163, 589-599 (2006)
    • Cardiac Arrhythmia Suppression Trial Investigators N. Engl. J. Med. 321, 406-412 (1989)
    • Cardiac Arrhythmia Suppression Trial II Investigators N. Engl. J. Med. 327, 227-233 (1992)
    • Temple, R. J. in Clinical Measurement in Drug Evaluation (eds Nimmo, W. S. & Tucker, G. T.) (Wiley, New York, 1995)

 


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