Ex Big da Big Big Pharma desagrava epidemiologistas. E, agora speakers?

Imperdível a reportagem no The IN VIVO Blog sobre a saída de JP Garnier da Glaxo Smith Kline. Os pontos apresentados por ele decorrentes de vários problemas, mas principalmente do Avandia mostram o quanto a Big Pharma errou. Epidemiologistas estamos sendo desagravados pelo CEO da maior Big Pharma do ataque constante dos speakers da própria Big Pharma.

Há décadas que se critica o abuso dos "surrogate end-points". Leiam abaixo a opinião de Garnier sobre o uso da hemoglobina glicada como desfecho em oposição a um evento clínico como gangrena ou infarto do miocárdio. (clique aqui para ler a reportagem completa)

Expect to do more outcomes studies.“There will be more demands for outcome studies. People are even questioning whether hemoglobin A1c is a good indicator for diabetes. It is very easy to say well why don’t you do outcome studies and show us that over five or six years you can reduce the rate of gangrene and heart attacks and the like. Well, if we have to do that, it is going to be a long time before the product can hit the market. So we’re going to have to deal with this issue.”Once again, it is not just Avandia that supports that argument. Look at ENHANCE.

Steven Nissen, novamente no holofote

Se você não aguenta mais o caso Avandia descrito aqui em detalhes, passe adiante, mas se quiser recapitular clique aqui. Abaixo, mais um capítulo centrado na figura de Steven Nissen.

The New York Times descreve nesse domingo (artigo completo para registrados no site) as atividades de Steven Nissen, o pesquisador que mostrou os problemas de segurança com o Avandia. Muitos dizem que ele tem como objetivo dirigir o FDA. Apesar do rigor do artigo publicado no The New England of Journal , Nissen cometeu deslizes como afirmar que Avandia mataria mais gente do que o 11 de setembro. Questiona-se também o fato de que Nissen procura ativamente financiamento da indústria, mas sempre afirma que o dinheiro é distribuído para instituições de caridade. Nas quais se incluem entre outras, American College of Cardiology e o Cleveland Museum of Art, onde trabalha sua mulher.

Tudo isso é perfumaria e bobagem perto da afirmação que após ter sido o responsável principal pela derrubada do Vioxx, Nissen está trabalhando em ensaio clínico com o Celebrex, também um inibidor da COX-2, do mesmo grupo farmacológico do Vioxx.

Desfecho: a palavra-chave no caso Avandia e outros.

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. ......

Avandia: editorial do NYT (25/05/07)

Começando a semana, com o tema da semana passada: Avandia. Abaixo, reproduzo o editorial do The New York Times da última sexta-feira que passou despercebido.. Ele faz a síntese desse episódio. A Glaxo e o FDA estão com a palavra para responder aos fatos do artigo publicado no The New England Journal of Medicine e das declarações confusas da empresa e da própria agência.. Vamos ver o que ocorrerá na semana que entra. Infelizmente não poderei acompanhar porque estarei fora para reunião do Estudo Longitudinal de Saúde do Adulto que ocorrerá em Belo Horizonte, quinta e sexta-feiras e, preparando participação em evento no exterior na próxima semana. Mas, novamente citando o beisebolista americano Yogi Berra (um Vicente Matheus local) It's like déjà vu all over again.
Editorial Ignoring the Warnings, Again?
The latest findings on Avandia, a top-selling diabetes drug, raise concerns both about its safety and about the way the manufacturer and the Food and Drug Administration have responded to signs of danger. It would be rash to make definitive judgments until the F.D.A. completes a detailed analysis. But the handling of this case bears disturbing resemblances to the Vioxx debacle, in which early warning signs were ignored by its manufacturer until the evidence of serious harm became inescapable and the drug was pulled from the market. Avandia was approved for sale in 1999 based on studies showing that it could lower blood glucose levels in patients suffering from Type 2 diabetes, also known as adult-onset diabetes. The assumption was that the drug could alleviate some of the most damaging effects of the disease, such as heart attacks and other cardiovascular ailments. But a paper just published in The New England Journal of Medicine suggests that Avandia may instead increase the risk of a heart attack by 43 percent and perhaps the risk of cardiovascular deaths as well. The study — an analysis of the combined results of 42 previous studies that compared people who took the drug with people who did not — is not definitive, and the absolute risk to any given patient is small. But the study points to a risk that could potentially harm thousands of patients a year. Its lead author was Steven Nissen, a cardiologist at the Cleveland Clinic, who blew the whistle on the cardiovascular risks of Vioxx, which adds to the sense of déjà vu.What’s most troubling is the possibility that early warning signs were not adequately heeded.Seven years ago a leading diabetes doctor warned the F.D.A. of “a worrisome trend in cardiovascular deaths,” two years later a safety monitoring group within the agency expressed concern over cases of heart failure in patients taking the drug. In late 2005 and again in August 2006 the drug’s manufacturer — GlaxoSmithKline — informed the F.D.A. that its own combined analysis of various studies showed a 31 percent increase in adverse cardiovascular events. But the company also cited studies that it said showed no evidence of harm, and the F.D.A. concluded the findings were too mixed to take immediate regulatory action.Now, prodded by Dr. Nissen’s article, the agency has issued a safety alert, is completing its own safety analysis and will convene a panel of experts to review the data. The best hope for a definitive answer may lie in a clinical trial that won’t finish monitoring all enrolled patients until late next year. If the verdict goes against Avandia, the F.D.A. and Glaxo will have a lot to explain. Congress will need to probe hard to determine what risks the agency and the manufacturer were aware of and what they did — or didn’t do — to mitigate them.

Avandia: a cavalaria não chegará em tempo RECORD

A defesa da Glaxo Smith Kline para a metanálise apresentada por Nissen (e, ao que parece pelo FDA também) viria dos resultados parciais do estudo RECORD. Porém devido à publicação do artigo de Nissen, os participantes do RECORD estão abandonando o ensaio clínico. Sinceramente, não dá para entender a preocupação da empresa, afinal, ela afirma que os resultados parciais quando adicionados aos demais mostraria exatamente o oposto ao publicado, ou seja um fator cardiovascular protetor da rosiglitazone.

Test of Drug for Diabetes in Jeopardy
By STEPHANIE SAUL Published: May 26, 2007
A large clinical study meant to test the heart safety of the diabetes treatment Avandia may be in jeopardy as a result of recent reports of the drug’s risks, according to an executive at its maker, GlaxoSmithKline.
Dr. Ronald L. Krall, the medical director for GlaxoSmithKline, said in a telephone interview yesterday that some of the 4,450 patients enrolled in the drug trial, called Record, have dropped out this week because of safety concerns about Avandia. Dr. Krall said he did not yet know how many patients have withdrawn, but said Glaxo was now worried about whether it could complete the drug trial, which has been scheduled to run through next year. The company has been counting on a successful outcome from the study to dispel widespread concerns that Avandia carries a higher risk of heart attacks than other diabetes drugs. Now, though, the independent research committees overseeing the study “are concerned about the ability of the study to continue” and are “considering what to do to prevent people from dropping out of the trial,” Dr. Krall said. The safety concerns were ignited by an analysis published Monday in The New England Journal of Medicine suggesting that Avandia, used to treat Type 2 diabetes, carries an increased risk of heart attack, estimated at 43 percent, compared with other diabetes drugs or placebos. In response to the medical journal article, the Food and Drug Administration, issued a safety alert for Avandia and advised patients who take it to consult their doctors. Avandia, which was approved by the F.D.A. in 1999, has been used by an estimated seven million people, six million of them in the United States. Yesterday, the F.D.A. said its own recent analysis of more than 40 clinical studies of Avandia seemed to confirm the findings in The New England Journal of Medicine’s study, whose lead author was the influential Cleveland Clinic heart specialist Steven E. Nissen. But an agency spokeswoman yesterday urged caution in interpreting those results. “Dr. Nissen’s meta-analysis and the F.D.A.’s meta-analysis both arrived at a similar figure of 40 percent” the F.D.A. spokeswoman, Julie Zawisa, wrote in an e-mail message. “But this alone, is not conclusive of anything. What it does mean is that we need to try to reconcile the meta-analysis finding with clinical trial data that DO NOT show this increased risk.”People with Type 2 diabetes are already at risk of heart attacks, facing a 20.2 percent chance of such an attack over seven years. One of the main reasons for controlling blood sugar in diabetic patients is to manage that risk. But if Dr. Nissen’s analysis is an accurate reflection of Avandia’s increased risk, it appears the drug would do more cardiovascular harm than good. Diabetics taking Avandia would run a 28.9 percent chance of heart attack over the same seven-year period, according to his analysis.
GlaxoSmithKline’s own meta-analysis, submitted to the F.D.A. last August, showed a slightly lower 31 percent increased risk of heart attack. A meta-analysis, which involves comparing the results of disparate clinical trials, is not considered as definitive as a uniform, controlled patient study of the sort GlaxoSmithKline has been counting on with its Record trial. Both GlaxoSmithKline and the F.D.A. have said that the meta-analyses indicating a heart risk with Avandia are contradicted by an interim look at Record, as well as data from an analysis of more than 20,000 patients enrolled in a UnitedHealthcare plan.But neither GlaxoSmithKline nor the F.D.A. has released results from that interim assessment of Record, which was conducted within the last month. The F.D.A. has received heavy criticism this week from Capitol Hill, where members of Congress have suggested that Avandia is shaping up as another Vioxx — a painkiller that became a bestseller, despite periodic questions about its safety, before being taken off the market in 2004 when its heart risks became irrefutable. The F.D.A. plans to ask an advisory panel to review the Avandia data. Such panels, if they find safety risks with a drug, can recommend that the agency require a stronger warning label or ban the drug altogether. Avandia is Glaxo’s second-largest selling drug, with more than $3 billion in sales last year worldwide. The company’s American depository receipts fell nearly $5 this week on news of safety concerns about the drug. The shares closed yesterday at $52.43. GlaxoSmithKline has urged regulators and the public not to rush to judgment based on the New England Journal of Medicine article and has said that the Record trial, which began in 2000, would be a more reliable way to estimate the drug’s cardiovascular risks. In that study, half of the 4,450 patients are being treated with Avandia in combination with another diabetes drug, while the others are being treated with two other drugs. The trial is designed to determine whether patients taking Avandia are more likely to have a range of cardiovascular problems, including heart attack and stroke

Avandia: posição Sociedade Brasileira de Diabetes e da de Endocrinologia e Metabologia.

Comparem o texto abaixo - transcrito na íntegra - com o que já foi noticiado nesse blogue sobre o tema Avandia.

Rosiglitazona e Risco de Infarto do Miocárdio e Morte Cardiovascular
Diretoria SBD e SBEM - 25/05/2007 12:02 Posição conjunta da SBD e da SBEM

No dia 21 de maio corrente foi publicada uma meta-análise no The New England Journal of Medicine intitulado "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes”. As conclusões da análise deste estudo sugerem que a Rosiglitazona, droga utilizada para o tratamento oral do Diabetes Mellitus tipo 2, aumenta o risco de Infarto do Miocárdio e morte por causa cardiovascular. Os autores, Steven Nissen e Kathy Wolski, cometam a dificuldade destas conclusões pois não tiveram acesso aos dados completos dos pacientes. O editorial da NEJM, publicado no mesmo dia, segue nesta mesma direção. A American Diabetes Association, American College of Cardiology e American Heart Association se posicionaram em conjunto e comentam que embora o risco pareça baixo é necessário considerar cautelosamente estes dados. A FDA (Food and Drug Administration), em seu posicionamento, liberado recentemente em nota, se preocupa com os dados, mas que os resultados publicados e não-publicados em estudos de longo prazo questionam estes achados. A FDA comenta, ainda, que os dados carecem de significado clínico e que, considerando o risco de mudança de medicação para pacientes diabéticos, afirma que a agência não está solicitando ao fabricante (GlaxoSmithKline) que estabeleça qualquer ação neste momento. O estudo RECORD, desenhado especificamente para analisar os desfechos cardiovasculares, trará, após sua análise completa, dados definitivos acerca do tema. A SBD e a SBEM (Sociedade Brasileira de Endocrinologia e Metabologia) recomendam aos seus associados que discutam com seus pacientes os resultados e eventuais mudanças de conduta. Reafirmam que para o tratamento do diabetes é necessária a participação efetiva do médico e do paciente na busca do controle estrito da glicemia e dos outros fatores de risco cardiovasculares associados.

* Os Drs. Marcos Tambascia e Ruy Lyra são os presidentes, respectivamente, da Sociedade Brasileira de Diabetes e Sociedade Brasileira de Endocrinologia e Metabologia

FDA também "acha" que Avandia aumenta o risco cardiovascular.

Voltando ao tema "Avandia". Despacho dessa tarde (25/05) da Reuters é reproduzido abaixo na íntegra para revelar a absoluta confusão reinante no órgão regulador americano. Para quem acha há despreparados e incompetentes somente abaixo do Equador, ao menos um consolo. Entidades científicas estão pedindo avaliação por pares sem conflito de interesse com o tema.

FDA review also shows Glaxo diabetes drug risk

WASHINGTON (Reuters) - A U.S. Food and Drug Administration preliminary analysis found a level of heart-attack risk with GlaxoSmithKline Plc's diabetes drug Avandia similar to what was reported in a study earlier this week, the agency confirmed on Friday.
FDA spokeswoman Julie Zawisza stressed that other data conflicted with that finding, and officials still were weighing whether to take any action.
A Cleveland Clinic analysis released Monday said the drug increased the chances of having a heart attack by 43 percent. Speaking on the Senate floor late on Thursday, Republican Sen. Charles Grassley of Iowa said preliminary findings from an FDA analysis of Glaxo's clinical trials found a 40 percent increased risk, while the company puts the figure at about 30 percent. "Those numbers seem like a high enough threshold to me for the FDA to warn the American people of the possibility of a problem," Grassley said. The FDA's Zawisza confirmed that the agency's evaluation of Glaxo's clinical trials found a higher risk of about 40 percent. But she said "this alone is not conclusive" and officials are trying to reconcile that with clinical trial data that did not show an elevated risk. "We don't have the scientific data upon which to make any conclusions or decisions yet," she said via e-mail.
If a 40 percent risk were confirmed, it would mean that a person with diabetes who does not take the drug has about a 1 percent risk of having a heart attack or other, similar problem, while someone who takes the drug would have a 1.4 percent risk, Zawisza said.Grassley also said some FDA scientists recommended months ago that Avandia carry the strongest possible warning, a "black-box," about heart-attack risk. Zawisza said she could not comment on "ongoing regulatory matters" such as whether staff had recommended a black box. Grassley also said it had been reported to him that the incidence of heart attacks with Avandia could be as many as 60,000 to 100,000 from 1999 to 2006. He did not cite the source of the numbers, and experts say it is difficult to make such estimates across a broad population. The FDA's Zawisza said a relationship between Avandia and that number of events had not been established. "We don't have data to support such a conclusion," she said. GlaxoSmithKline spokeswoman Mary Anne Rhyne said Grassley's use of the estimate was "irresponsible." "They are extrapolations of extrapolations, and do not reflect reality. If these numbers were true, we would have seen them clearly" in long-term studies and databases of real-world use, she said. Glaxo has said Avandia's cardiovascular safety is similar to other oral diabetic drugs, and the benefits of treatment outweigh the risks. The FDA is continuing to review data on Avandia and plans to ask an advisory panel of outside experts for input. The Union of Concerned Scientists and several consumer groups wrote the FDA on Friday urging officials to chose advisers with no financial ties to Glaxo for the past 36 months. "By staffing the Avandia advisory committee with scientists from diverse specialties who are non-conflicted, you will send a message that the FDA cares about avoiding conflicts of interest and evaluating drugs on the basis of unbiased scientific findings," the letter said.

Avandia: the Empire strikes back

The Wall Street Journal (ver parte do texto abaixo) mostra o contra-ataque da Glaxo Smith Kline e a situação aflitiva dos propagantistas farmacêuticos. O interessante não é bem o risco causado aos pacientes, mas a queda das ações da empresa. Em negrito, as mudanças da bula que na Europa já indicava risco de infarto do miocárdio.
Glaxo Courts Doctor Support of Avandia
Similar Consumer Ads Aren't Yet Planned But Won't Be Ruled Out
By JEANNE WHALEN and ANNA MATHEWS May 25, 2007 GlaxoSmithKline PLC, under pressure to protect its diabetes drug Avandia, is reaching out to physicians to defend the drug's safety but isn't currently planning a similar ad campaign for consumers.In meetings with doctors, Glaxo sales representatives are focusing on data from a large clinical trial called A Diabetes Outcome Progression Trial, or ADOPT. "We are reassuring physicians about the safety data we have, particularly looking at ADOPT," said Alice Hunt, a Glaxo spokeswoman. (…..)
Dr. Nissen's analysis led to a sharp drop in Glaxo's stock price, and some analysts have predicted Avandia sales could be cut in half because of physician and consumer concerns. The Glaxo spokeswoman said the company isn't planning consumer ads defending Avandia but won't rule them out, either. "At the moment, there is an information vacuum, and GSK may need to step into the void," she said. (…….)
When Avandia was approved, its label held a mild precaution noting that in animal studies, there had been signs of plasma volume expansion and heart hypertrophy, signals of a heart-failure risk. It also noted that while LDL, or "bad cholesterol," went up in Avandia patients, HDL, or "good cholesterol," ended up rising, as well. Later, the drug's label got a new warning that Avandia, like similar treatments, might exacerbate or lead to heart failure. The warning also noted that when taken with insulin, such drugs may "increase the risk of other cardiovascular adverse events." Last year, the Avandia label warning got beefed up a bit, saying patients with heart failure who took Avandia had a higher risk of cardiovascular events. The Glaxo analysis showing potential heart-attack risk hasn't been placed in the U.S. label, although it is mentioned in the European label. On Internet sites popular with drug-industry sales representatives, people claiming to work for Glaxo have been posting hundreds of messages this week bemoaning the difficult position Dr. Nissen's study has put them in.

Avandia: publish or publish

O lema da academia americana: "publish or perish", está sendo agora focado para a imprensa médica. Questiona-se se o The New England Journal of Medicine deveria ou não publicar o artigo sobre o rosiglitasone. Eu não tenho dúvida do acerto em publicar. Agora, estou observando a reação ao estudo. Estou no aguardo das revistas semanais para ver quem ficará com o " ZecaPagodinho quesito diabetes" Ou seja, defender quem o paga, com pouco ou nenhum conteúdo, somente desqualificando o autor do artido ou projeto que contraria o seu patrocinador, tal como o cantor fez com o Ministro da Saúde.

Porém, ninguem chegará perto de Steven Haffner, de San Antonio, Texas. Ele se considera o dono da epidemiologia do diabetes e, adora o sensacionalismo quando a seu favor. Ele transformou o diabetes no paraíso da indústria, por forçar cada vez mais definição de diabetes, que um dia atingirá toda da população. Abaixo, a opinião de diabetólogos americanos, publicado no Heartwire, um noticiário do Medscape. Vejam a declaração de Haffner e, concluam. Destaquei também parte da declaração de David Natham sobre o papel da Glaxo Smith Kline nessa questão.
Dr Steven Haffner (University of Texas Health Science Center, San Antonio), who was involved in the ADOPT study of rosiglitazone, said the paper needed to be published, but it should have undergone a more extensive review, and there should have been a different editorial with more emphasis on the flaws of the study. “The NEJM was irresponsible to go to [Drs Bruce] Psaty and [Curt] Furberg for the editorial--they were always going to emphasize concerns about drug safety; that’s what they do," he commented. “But I’m not surprised this paper was published like this. The three major medical journals are becoming more like British tabloid newspapers--all they lack is a bare-chested woman on page 3," he jibed.
Dr Brian Strom (University of Pennsylvania, Philadelphia) agrees. “Drugs are given because they have benefits. Where there’s a scare, people stop taking them. So you can do more harm than good if the scare is not based on correct information. I do believe this meta-analysis should have been published, but a less sensational editorial would have been better," he told heartwire.
Dr Robert Califf (Duke University, Durham, NC) made the point that news reporting should follow scientific discussion on drug-safety issues, not precede it. “It would be better if we had a system of postmarketing signal detection in which signals were vetted scientifically rather than splashed over TV and newspapers. I can't help but wonder if the NEJM is functioning more like the mainstream press than a scientific journal at this point, since many potential peer reviewers seem to feel that Dr Nissen's analyses are missing key elements that could have been added."
Dr Darren McGuire (University of Texas Southwestern, Dallas) commented to heartwire: “All the sensationalism surrounding this observation has created unnecessary chaos and confusion at the patient level."

Dr David Nathan (Harvard Medical School, Boston, MA), who was one of the reviewers of the NEJM paper, is not so sure that people have overreacted. “Yes, this was an imperfect analysis. It can’t be looked at as definitive, but at the same time the findings shouldn’t be ignored," he told heartwire. “GlaxoSmithKline had the opportunity to collaborate, and they chose not to. They say they have more data, but why have they not published it? If they can produce convincing data, we can become more relaxed about this drug. But for the moment all we have is Nissen’s analysis," he added. “I’m advising patients to discuss this with their doctors--there are other choices for the treatment of diabetes. It certainly doesn’t make much sense to me to use a drug that is potentially cardiotoxic in a condition that causes heart disease. Given the choice of all the drugs available I would be very cautious about using this medicine," Nathan said.

Nissen sob o foco dos admiradores.

Destaquei a relação das 100 pessoas mais influentes da atualidade pelo Time magazine onde figurava Steven Nissen. Depois do caso Avandia, ele está novamente no foco da mídia e, também de seus "admiradores". Vejam, os comentários abaixo retirado do Heartwire, um boletim do Medscape.

Nissen: A public safety net?
Other media coverage surrounding the rosiglitazone saga has focused on Nissen himself. The WSJ chronicled the background to the current study, noting that Nissen first became interested in rosiglitazone after finding that cardiovascular side effects were an issue with a related drug, muraglitazar. After publishing these findings, he received an email from a diabetes expert suggesting that rosiglitazone may have similar issues. Then last year, after seeing signs of cardiovascular problems in the DREAM and ADOPT studies, he started searching for more data, which he found on the FDA and GlaxoSmithKline websites. Cleveland Clinic statistician Kathy Wolski, who helped Nissen with the analysis, describes him in the WSJ article as “a dog with a bone" in his determination to investigate this issue.
As Nissen was also involved in the downfall of Vioxx (rofecoxib, Merck), he is gaining somewhat of a reputation as a drug watchdog. An Associated Press report describes Nissen as a “public safety net," adding: "As criticism of the FDA mounts, Nissen, aided by powerful medical journals and government officials, has become a de facto drug regulator." But one blogger on the WSJ site has a less charitable take on Nissen’s actions, noting that his unfavorable studies are focused on drugs and companies that are not supporting large trials with the Cleveland Clinic [5]. “Wake up pharmaceutical companies. . . . If you don’t hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and company," he jests.

Transparência e Inteligência: a fase dos dados públicos

No episódio do mensalão, um dos envolvidos tornou célebre a frase: “transparência demais é burrice”. No caso Avandia, parece que esse foi o caso, com uma tinta de ironia, por favor. Explico, depois de uma disputa judicial com o o Estado de Nova Iorque, a Glaxo Smith Kline comprometeu-se a divulgar os resultados de todos os estudos relativos aos seus produtos. A partir desses dados foi possível, o cálculo do risco do medicamento. Ao contrário da frase cínica acima reproduzida, o fato mostra a importância da internet e do controle social sobre produtos de interesse coletivo, que não eram questionados tão rapidamente como agora. Que se torne obrigatória a divulgação de todos os resultados de pesquisas na web, incluindo os da indústria, como os originados por fundos públicos. Nesse último caso haveria um período de tempo para que os dados fossem publicados em revista com revisão por pares. Abaixo, artigo do The New York Times explicando o ocorrido entre os dados da Glaxo e a publicação no The New England Journal of Medicine.
For Drug Makers, a Downside to Full Disclosure
When GlaxoSmithKline settled a lawsuit three years ago with the State of New York over the antidepressant medication Paxil, the company agreed to take an unusual step: publicly disclosing the results of its clinical trials for Paxil and other drugs. The company, which was criticized at the time for failing to publicize all pediatric trials of Paxil, not just the positive ones, made good on its promise. The first posting on a new Web site was about 65 studies involving its popular diabetes drug, Avandia. This week, GlaxoSmithKline learned what that greater disclosure could mean. A cardiologist at the Cleveland Clinic, Dr. Steven Nissen, stumbled onto the Glaxo Web site while researching Avandia last April. He and a colleague quickly analyzed the data, and on Monday, The New England Journal of Medicine released its finding that Avandia posed a heightened cardiac risk. “It was a treasure trove,” Dr. Nissen said about the Web site. GlaxoSmithKline has disputed the journal’s interpretation. Officials with the Food and Drug Administration said they were reviewing whether to take any action on Avandia. Whatever the drug’s fate, the episode is likely to fuel efforts by some medical experts, including Dr. Nissen, to persuade lawmakers to require makers of drugs and medical devices to disclose study results publicly. Currently, producers are not required to do so, but Congress is considering legislating a requirement. Many companies besides GlaxoSmithKline already post results from some studies or trials on their Web sites, or one operated by the Pharmaceutical Research and Manufacturers Association, a trade group in Washington. Dr. Bruce M. Psaty, a cardiologist at the University of Washington, said that having such information can play a critical role, as the case of Avandia suggests, in spotting signals of a drug’s possible dangers. Other experts have argued that the relative efficacy or cost of competing drugs can be compared only when all study results, rather simply those that a company chooses to publicize, are available. Studies have found that the vast majority of drug and medical device studies are never published in medical journals. “The more information, the better,” Dr. Psaty said. Dr. Ronald L. Krall, chief medical officer for Glaxo, said his company sharply disputed the methodology of Dr. Nissen’s study, and a top F.D.A. official said that the agency had previously informed doctors about Avandia’s heart risks. Dr. Krall said his company was aware when it created its database of study results a few years ago that it might lead to controversy. Other scientists might look at its data or choose to analyze it differently than company officials did, he said. “We are committed to the principle of transparency,” Dr. Krall added. “But we knew that when starting this, by putting the data in the public, many things could happen, some of which could be trouble.” Some experts also believe that releasing the results of hundreds of studies involving drugs or medical devices might create confusion and anxiety for patients who are typically not well prepared to understand the studies or to put them in context. “I would be very concerned about wholesale posting of thousands of clinical trials leading to mass confusion,” said Dr. Steven Galson, the director for the Center for Drug Evaluation and Research at the F.D.A.

Avandia: EMEA e FDA não estão surpresas

A EMEA - agência européia equivalente ao FDA americano e ANVISA brasileiro - manifestou-se sobre o caso Avandia, informando que não há surpresa no publicado e, que o medicamento encontra-se sobre vigilância da agência, que reconhece o aumento de doença isquêmica cardíaca.

Reproduzo, a seguir , em negrito a declaração da EMEA:
When rosiglitazone was first authorised in the EU in 2000, it was contraindicated in patients with a history of cardiac failure. Since then, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has kept rosiglitazone under close surveillance for cardiovascular effects (cardiac failure and other cardiac disorders including myocardial infarction). The majority of the studies included in the NEJM paper have already been assessed by the CHMP. The EU product information was updated in September 2006 with information about the risk of cardiac ischaemic events.

Pergunto porque a agência não se manifestou anteriormente?

O FDA também se manifestou com declaração contraditória onde ora afirma que novas análises do estudo DREAM e de outro em andamento não revelaram risco (o DREAM não tinha revelado risco, não entendi essa menção) ou então declara que já mudara a bula do Avandia devido ao seguinte fato relatado pela própria empresa

Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes. The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease.

Repercussão do caso Avandia

Finalmente, mais de 24 horas depois de ter tido acesso ao artigo e editorial referente ao risco cardiovascular da Avandia consegui ler ambos. Apesar de não ser fanático por metanálise, o artigo é consistente. O editorial é um verdadeiro torpedo contra o FDA pela aprovação sem critérios mais rígidos. Assisti entrevista com Steve Nissen onde ele afirma que os dados obtidos não eram os melhores (explico abaixo), somente uma síntese publicada e disponível na web. A Glaxo há três anos foi acusada de esconder dados de medicação psiquiátria e, partir daí passou a mostrar todos os estudos referentes aos seus medicos. A origem dos dados desse trabalho vieram daí. Por isso, intriga muito aos editorialistas - e, também a mim - porque a empresa com dados mais fortes (explico abaixo) não os publicou? E, porque o FDA não exigiu que isso fosse feito.

Quanto ao prêmio Zeca Pagodinho, quesito diabetes, vários leitores de blogues americanos concorreram, mas somente brasileiros são elegíveis. Vamos ver os jornais de amanhã. Porém, paro por aqui porque acho que haverá nada mais significativo.

explicação técnica: a melhor forma de calcular risco é saber não somente o número de participantes que sofreram infarto ou morreram, mas também por quanto tempo o fizeram. os dados disponíveis não mostram o tempo de exposição, por isso considerei que Nissen trabalhou com informação mais fraca, o que para ele foi uma força.

Avandia: leia The Wall Street Journal e vote no prêmio Zeca Pagodinho quesito diabetes.

A melhor cobertura sobre o tema encontra-se em jornal especializado em economia pelo motivo simples: a queda nas ações da Glaxo Smith Kline.

O tema Avandia já foi tratado aqui em 16.9.06 analisando o estudo básico para o Avandia. "Dream: o óbvio é comprovado para o diabetes". Nas próximas semanas, médicos que não têm a mínima idéia como organizar uma meta-análise, mas sabem muito bem como agradar uma empresa farmacêutica estarão dando entrevistas, fazendo palestras e outras coisas sobre a "segurança da Avandia". Aguardem a saraivada de intrigas contra Steven Nissen. Uma no blogue do WSJ diz que ele será o commissioner da FDA em um provável governo Hillary Clinton.

Aqui, no Brasil vamos ver quem vencerá o prêmio "Zeca Pagodinho" no quesito diabetes.