Hoje, o The New York Times (texto completo para registrados) aborda a questão "Avandia" verificando os critérios utilizados para concluir se um medicamento é útil ou não. Essa é uma das aulas básicas nos curso de epidemiologia:"ensaio clínico". Há tratamentos que nunca foram e nunca foram testados, como por exemplo o uso de penicilina para tratar pneumonia, porque a sua eficácia e efetividade foram tão evidentes que dispensou qualquer ensaio comparativo do antibiótico com um placebo. No entanto, quando entramos nas era das doenças crônicas com duração prolongada, a capacidade de observar se houve melhora ou não somente pela observação médica se reduziu. Surgiram então os ensaios clínicos que testam um medicamento versus placebo ou um medicamento contra outro com critérios rigorosos independente do médico. E, nesse caso há um desfecho (outcome) a ser alcançado. Aí, na definição do desfecho que surgem os problemas. Como foi abordado por Nissen no artigo mais discutido, mas não tão lido - da última semana: é um erro aprovar medicamento para diabetes somente com o desfecho "redução da glicemia". Afinal, o objetivo principal é reduzir a carga de doença cardiovascular no diabético e, não a diminuição "cosmética" da glicemia. Um exemplo com mais de 30 anos: um medicamento foi lançado por reduzia o colesterol, diminuia o número de infartos do miocárdio e , da mesma forma a mortalidade cardiovascular.Ótimo, não? Não, porque aumentou a mortalidade por outras causas, por isso não vingou. Ou seja não adianta verificar se o medicamento afetou parte do mecanismo fisiopatológico, mas sim se houve um ganho efetivo para quem dele se utiliza. Abaixo, parte do texto do NYT com outros exemplos e também o custo da extensão dos ensaios clínicos dos surrogate outcomes para os hard outcomes.
By DENISE GRADY Published: May 29, 2007
People with diabetes have too much sugar in their blood, so a drug that lowers blood sugar ought to be a good treatment, right? Maybe not. Consider the diabetes drug Avandia, or rosiglitazone, which was approved in 1999. It lowers blood sugar, and about a million people in the United States have been taking it for Type 2 diabetes, the most common form of the disease. But last week, doctors reported that Avandia might increase the risk of heart attacks. ...... Avandia was approved because it lowered blood sugar, and seemed safe in clinical trials. But the real test of whether a drug is any good is, How are the patients? Not their blood tests or X-rays or EKGs, but the people themselves, and not after just six months, but after years, especially if they have a chronic disease and will be taking medicine for the rest of their lives. Are those taking the drug more or less likely than people not taking it to have heart attacks, die or develop heart disease or other illnesses?
The problem is, it can take a long time and a lot of patients — and, therefore, a lot of money — to get a real picture of health and survival. That is especially true for something like heart disease, which develops slowly and is so common that it may be hard to detect a small increase in risk. Studies might have to go on for years instead of months, and include far more than the few thousand patients in whom drugs are typically tested before they get approved. So instead of waiting to see if people die or have heart attacks, drug companies have looked for other traits that seem to correlate with health and survival and that could stand in as a yardstick — objective measures like blood pressure, cholesterol levels, blood sugar or tests of heart function. Researchers call these measurements “surrogate endpoints,” and the F.D.A. has encouraged companies to find surrogates that could reliably predict how patients would fare. These kinds of tests are seen as a way to streamline the drug approval process. But reliable surrogates are hard to find. There are plenty of endpoints that in theory should do the job, but do not. Tumor size, for instance: there are drugs that can shrink tumors without prolonging a patient’s life. Bone density is another example. Fluoride can increase it in people whose skeletons have thinned from osteoporosis, so fluoride should prevent fractures. But it doesn’t. In fact, it makes fractures more likely, because it turns bones brittle. Heart rhythm can also be deceptive. Certain medicines can stabilize dangerous, abnormal heartbeats in people who have had heart attacks — and yet have been found to increase their odds of dying. Cholesterol levels do not always tell the whole story, either. Hormone treatment in women after menopause can raise HDL, the so-called good cholesterol, and so was expected to prevent heart disease — but does not. Similarly, researchers had high hopes for an experimental drug that raises HDL, but instead of preventing heart attacks the drug wound up increasing the risk. Part of the problem is that surrogate endpoints do not always reflect what’s happening to the whole patient. The disease being treated may be too complicated to gauge with just one tool, and the drug in question may have many more effects than the one being measured. ......
People with diabetes have too much sugar in their blood, so a drug that lowers blood sugar ought to be a good treatment, right? Maybe not. Consider the diabetes drug Avandia, or rosiglitazone, which was approved in 1999. It lowers blood sugar, and about a million people in the United States have been taking it for Type 2 diabetes, the most common form of the disease. But last week, doctors reported that Avandia might increase the risk of heart attacks. ...... Avandia was approved because it lowered blood sugar, and seemed safe in clinical trials. But the real test of whether a drug is any good is, How are the patients? Not their blood tests or X-rays or EKGs, but the people themselves, and not after just six months, but after years, especially if they have a chronic disease and will be taking medicine for the rest of their lives. Are those taking the drug more or less likely than people not taking it to have heart attacks, die or develop heart disease or other illnesses?
The problem is, it can take a long time and a lot of patients — and, therefore, a lot of money — to get a real picture of health and survival. That is especially true for something like heart disease, which develops slowly and is so common that it may be hard to detect a small increase in risk. Studies might have to go on for years instead of months, and include far more than the few thousand patients in whom drugs are typically tested before they get approved. So instead of waiting to see if people die or have heart attacks, drug companies have looked for other traits that seem to correlate with health and survival and that could stand in as a yardstick — objective measures like blood pressure, cholesterol levels, blood sugar or tests of heart function. Researchers call these measurements “surrogate endpoints,” and the F.D.A. has encouraged companies to find surrogates that could reliably predict how patients would fare. These kinds of tests are seen as a way to streamline the drug approval process. But reliable surrogates are hard to find. There are plenty of endpoints that in theory should do the job, but do not. Tumor size, for instance: there are drugs that can shrink tumors without prolonging a patient’s life. Bone density is another example. Fluoride can increase it in people whose skeletons have thinned from osteoporosis, so fluoride should prevent fractures. But it doesn’t. In fact, it makes fractures more likely, because it turns bones brittle. Heart rhythm can also be deceptive. Certain medicines can stabilize dangerous, abnormal heartbeats in people who have had heart attacks — and yet have been found to increase their odds of dying. Cholesterol levels do not always tell the whole story, either. Hormone treatment in women after menopause can raise HDL, the so-called good cholesterol, and so was expected to prevent heart disease — but does not. Similarly, researchers had high hopes for an experimental drug that raises HDL, but instead of preventing heart attacks the drug wound up increasing the risk. Part of the problem is that surrogate endpoints do not always reflect what’s happening to the whole patient. The disease being treated may be too complicated to gauge with just one tool, and the drug in question may have many more effects than the one being measured. ......
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