"Unimed Paulistana vira caso de polícia": uma pena

O Estadão divulga com essa manchete problemas na Unimed Paulistana. É uma pena, mas trata-se de problemas que os cooperativados precisam resolver comparecendo às assembléias deliberativas e exigindo balancetes periódicos compreensíveis. Nunca fui cooperativado, mas considero o sistema Unimed (a Unimed Paulistana é independente das demais) ser um dos grandes pilares da asssistência médica no Brasil, principalmente no interior de São Paulo e, cidades como Vitória, ES (27% da população). Espero que os problemas da Unimed da capital sejam solucionados pelos seus cooperativados. A atuação da UNIMED é fundamental para parcela considerável da cidade de São Paulo onde há mais de um milhão de asssociados

A importância econômica do setor saúde.

O Ministro da Saúde ocupa a página 3 da Folha de S.Paulo para descrever vários aspectos do setor saúde. Ele parte para o ataque contra a visão estúpida das equipes econômicas - desse governo e passados e, de todas as esferas de governo - que somente lamentam os gastos do setor saúde, embora seus membros adorem uma mordomia nos hospitais públicos para si, familiares e amigos. Destaca o desaparelhamento da indústria, já citado nesse blogue como sendo o grande problema da atualidade no setor saúde. Acrescentaria a esse texto, a não desprezível atividade econômica do "turismo da saúde" com a ocupação de hotéis, por familiares, por exemplo que se dirigem a centros de excelência. Abaixo, parte do texto de José Gomes Temporão e Carlos Grabois Gadelha.

O entendimento dessas atividades como ônus ao orçamento público é cego. O segmento contribui para cidadania, investimentos, inovações, renda, emprego e receitas ao Estado. A cadeia produtiva representa entre 7% e 8% do PIB (R$ 160 bilhões). Emprega, com trabalho formal, 10% da população e é a área em que os investimentos públicos com pesquisa e desenvolvimento são os mais expressivos no país. O mercado farmacêutico brasileiro movimenta R$ 22 bilhões, equipamentos médico-hospitalares, R$ 6 bilhões, e vacinas, reagentes e hemoderivados, R$ 3 bilhões. São indústrias que geram 300 mil empregos diretos. Na prestação de serviços, 77 mil estabelecimentos de saúde empregam 1,6 milhão de pessoas (mais da metade com nível superior e alta qualificação). Por ano, o SUS realiza 2,8 mil transplantes renais, 215 mil cirurgias cardíacas e 9 milhões de procedimentos de rádio e quimioterapia, refletindo capacitação do sistema que se destaca entre países com grau semelhante de desenvolvimento. Há, porém, enorme fragilidade econômica e tecnológica. As indústrias perderam competitividade internacional ao longo da década de 90. O déficit acumulado cresceu de US$ 700 milhões ao ano, no final dos anos 80, para US$ 4 bilhões, sendo 60% concentrados na área farmacêutica. Um país desenvolvido requer base produtiva forte para atender a inclusão social e atenuar as desigualdades. O Brasil apresenta grande possibilidade de superação dessa vulnerabilidade. Nossa base produtiva, ciência, recursos humanos qualificados e sistema de saúde universal conferem ao Estado elevado poder de compra de bens industriais, com financiamento de longo prazo pelo BNDES. Fatores singulares na realidade latino-americana. Significa que a saúde é frente de expansão e janela de oportunidades ao padrão de desenvolvimento humanizado, equânime e solidário. (restante da matéria para assinantes da Folha)

A tecnologia insuperável: a observação humana.

A Folha de S.Paulo publicou uma matéria excelente de Marcelo Coelho questionando a propalada biodiversidade amazônica e, a importância estratégica para a indústria farmacêutica. O Centro Biotecnológica da Amazônia é um fracasso. Ponto final. Os novos medicamentos virão muito mais da beira do leito, dos consultórios e pronto-socorros associados aos laboratórios de pesquisadores básicos localizados em grandes centros urbanos. A base para as novas descobertas será a tecnologia mais desenvolvida até o momento: a observação humana. Como dizia, um filósofo popular americano - equivalente ao nosso Vicente Matheus - o jogador de beisebol Yogi Berra: "you can see a lot of things watching".

Uma consulta à página na internet do Centro de Biotecnologia da Amazônia, em Manaus, revela que os 12 mil metros quadrados da instalação contêm espaço para 25 laboratórios, mas abrigam só nove doutores e, ao todo, menos de cem funcionários. Se a Amazônia fosse de fato o Celeiro de Genes do mundo, o Pulmão Molecular do planeta, seu Eldorado Tecnobiológico, como explicar que permaneça vazio o elefante branco no Distrito Industrial da Zona Franca de Manaus?Há muitas explicações, decerto, a começar pela carência de recursos humanos qualificados na região. No passado, em 2000, também fracassou um acordo entre a iniciativa BioAmazônia e a empresa Novartis, firmado à revelia do governo federal e por ele anulado. Havia sido moldado em acordo similar firmado uma década antes, e dado como paradigma da bioprospecção, entre a empresa Merck e o INBio, do governo da Costa Rica, pela quantia de 2,8 milhões de dólares, do qual hoje ninguém mais fala.Do acordo brasileiro se pode dizer que naufragou por impróprio e por força da saudável reação social aos seus termos e condições. Mas o que dizer dos parcos resultados colhidos pelo INBio e, provavelmente, do futuro acanhado do CBA?Com certeza, que a bioprospecção não tem rendido nem uma fração do que prometia em 1992. Naquele ano se negociou no Rio de Janeiro a versão final da Convenção-Quadro das Nações Unidas sobre Diversidade Biológica, consagrando o generoso princípio da repartição de benefícios pelo uso de saberes tradicionais. O objetivo, aqui, é precisamente este: questionar a idéia feita de que a Amazônia represente uma espécie de Paraíso Genético, imagem fadada a se desfazer, assim como se desfizeram as do Pulmão Verde do mundo e do Celeiro de Alimentos. (assinante da Folha clique aqui).

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: um erro conceitual

Há um erro importante na discussão sobre o Avandia tem passado despercebido até por epidemiologistas envolvidos na questão de segurança de medicamento. Trata-se da afirmativa de que o risco da rosiglitazone seria pequeno em provocar um infarto do miocárdio. A nota das sociedades brasileiras repete o mesmo equívoco. A consultora do FDA exemplificou que se um diabético teria 1% de possibilidade de infarto do miocárdio em um determinado período de tempo, o uso do medicamento aumentaria para 1,4%. Isso seria o aumento estimado em 43% estimado na metanálise de Nissen. Nenhum reparo ao ao exemplo e ao cálculo. A discordância é conceitual. O diabetes de tipo 2 é ao mesmo tempo uma doença com sintomas – bem menores do que aqueles decorrentes do tipo 1 – motivados pela glicemia elevada e ao mesmo tempo, um fator de risco cardiovascular, decorrente da aceleração da aterosclerose em diabéticos. Ainda não há comprovação de que reduzir a glicemia implica em reduzir o risco cardiovascular. Por outro lado, há vários estudos mostrando que reduzir radicalmente a pressão arterial e o nível de colesterol reduz em muito o risco de novos eventos cardiovasculares em diabéticos. Diabéticos têm um risco de morte cardiovascular 3 vezes maior do que um não diabético. Isso posto, o objetivo principal no tratamento de um diabético tipo 2 é diminuir o risco cardiovascular, secundado por reduzir a glicemia. Por isso, não deve haver possibilidade de risco nenhum de infarto do miocárdio decorrente do uso de medicamentos para reduzir a glicemia em diabéticos. Pequena, média ou alta, o risco é indesejável e, condena o medicamento em definitivo.

Para compreender esse conceito há outro exemplo vindo do tratamento da aids cujos objetivos são exatamente opostos. Os medicamentos utilizados com o objetivo de impedir a replicação viral e a progressão da doença aumentam os níveis de colesterol e, com grande chance aumentam o risco de infarto do miocárdio. Nesse caso, o risco cardiovascular é secundário a um objetivo maior, o de evitar a replicação do HIV. Em outras palavras, trocaria a morte certa pela aids, por um infarto do miocárdio, tratável na maioria dos casos.

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.

Política de saúde (aids ) e política industrial (medicamentos)

Uma pausa no caso Avandia. Agora, voltando ao caso efavirenz que motivou uma reportagem de Valor Econômico (25/05/07) que conseguiu ir no âmago da questão: a contradição do progama da aids. Excelente na assistência, deficiente na sustentação econômica. O Estado brasileiro está correto em desenvolver sua política de saúde pública com autonomia para reduzir dano a sua população. Fez isso de forma no caso da aids. Por outro lado, o Estado brasileiro foi incorreto ao não desenvolver a política industrial na área de medicamentos. Com isso, o "Estado brasileiro que está correto" foi penalizado pelo "Estado brasileiro que foi incorreto". Aí entram, os pescadores de águas turvas com soluções para hoje que foram as causas do erro do passado. Qual erro? Considerar três nuncas: (1) nunca poderíamos competir com a Big Pharma. (2) nunca desenvolveríamos um programa de genéricos. (3) nunca teríamos um programa de saúde pública competente. Essa inapetência pelo poder global (e, claro conflito imenso de interesse com a Big Pharma) fez com a Índia passasse na nossa frente e, conseguisse dar muita dor de cabeça à Big Pharma. Por outro lado, a política indiana para aids é pífia.

A solução agora, não é comprar remédios de indianos, não é xingar a indústria farmacêutica multinacional (nem adulá-la) mas sim desenvolver a rede de incorporação de tecnologia na área de medicamentos, oferecendo muitas vantagens para entrada no Brasil do capital da........Big Pharma acoplado a incentivos a indústria local desde que tenha perspectiva do mercado mundial. Insisto muito, que o Brasil pode ser a plataforma da Big Pharma na área não só de genéricos como de química fina.

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.

Avandia: Public Citizen se manifesta porque o risco seria conhecido há 5 anos

Letter Demonstrating that the FDA Knew About Avandia Dangers, Urging Action (HRG Publications #1812) May 22, 2007 Andrew von Eschenbach, M.D., Commissioner U.S. Food and Drug AdministrationFood and Drug Administration5600 Fishers Lane Rockville, MD 20857 Dear Dr. von Eschenbach: We have obtained an internal FDA memo dated almost five years ago concerning heart failure from Avandia and Actos (the other widely-prescribed glitazone drug for diabetes). The July 16, 2002 memo from FDA staff in the Division of Drug Risk Evaluation evaluated cases of heart failure reported to the FDA during the first two years of marketing that were serious enough to require hospitalization.[1] Their analysis of these adverse reaction reports found 47 cases in which the use of Avandia (25 cases) and Actos (22 cases) resulted in hospitalization for heart failure. In the majority of these cases, the heart failure improved with the cessation of treatment with these drugs, further evidence of their role in causing heart failure. In their memo, the FDA scientists recommended that both labels “should include mention of these postmarketing reports.” They also recommended “a Phase IV cohort study to evaluate possible increased risk of incident CHF” [congestive heart failure]. At the time of this memo, the labeling for these drugs merely stated that: WARNINGS Cardiac Failure and Other Cardiac Effects: AVANDIA [or ACTOS], like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. AVANDIA [or ACTOS] should be discontinued if any deterioration in cardiac status occurs.[2] Despite this 2002 recommendation to mention post-marketing cases of heart failure and the fact that there are now a total of 1182 cases reported to the FDA with these two drugs (689 for Avandia, 493 for Actos; 803 involving hospitalization—415 for Avandia, 388 for Actos)[3], the current labeling for the drugs still starts with the identical warning.[4] There continues to be no mention of the large and increasing number of post-marketing reports of heart failure, which was the explicit recommendation in the 2002 internal FDA memo. The importance of the relationship between heart failure and heart attacks (myocardial infarction) is discussed in the New England Journal of Medicine article posted yesterday: “Rosiglitazone and other thiazolidinediones are known to precipitate congestive heart failure in susceptible patients. Congestive heart failure is a physiological state that is associated with an increased intravascular volume…In susceptible patients, an increase in myocardial oxygen demand could theoretically provoke ischemic events [such as myocardial infarctions].”[5] The failure of the FDA to act on the recommendations made almost five years ago by its Division of Drug Risk Evaluation is yet another example (e.g.,Rezulin, Vioxx) in which the conclusions of employees engaged in post-market drug safety review are not taken seriously enough or addressed soon enough. As a result, millions of people are prescribed drugs, to the detriment of their health, whose risks are dangerously understated. Thus, instead of being prescribed safer, equally or more effective alternative drugs, patients’ lives continue to be put at risk. The magnitude of this problem can be seen in the enormous number of prescriptions for these drugs. The total number of prescriptions filled for Avandia and Actos in 2006 was 22 million (11 million for each).[6] The current amount of data demonstrating cardiovascular risk of Avandia and Actos is certainly sufficient to at least label the drug as a last choice treatment and require a black box warning about the risks to the heart. Serious consideration should also be given as to why these drugs, which are supposed to decrease the cardiovascular complications of diabetes, are on the market at all since they actually increase these life-threatening problems. Until this post-marketing drug safety part of CDER is made independent within the FDA of the rest of the Center for Drug Evaluation and Research, these life-taking mistakes will continue to occur. Such legislation was introduced by Senators Dodd and Grassley but is not included in the package of legislative reforms that have passed in the Senate and are likely to pass in the House. We look forward to a prompt response to this letter. Sidney M. Wolfe, MDElizabeth Barbehenn, Ph.D.Health Research Group at Public Citizen cc: Congressmen Waxman, Dingell and Senators Grassley, Dodd [1]Green L, Shaffer D, and Swartz L. Adverse Event—Congestive Heart Failure Requiring Hospitalization: Pioglitazone (Actos) , Rosiglitazone (Avandia) July 16, 2002. [2]PDR, 2002, page 1493 [3]FDA AERS Data Base as of 9/30/06 [4]PDR, 2007, page 1387 [5] Nissen SE, Wolski K Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes N Engl J Med 2007;356. [6]Drug Topics, Retail prescriptions filled during 2006.

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.

Pesquisa experimental em Olinda

O Secretário Municipal de Olinda se realizou pesquisa - auto-hemoterapia - em contrariedade ao estabelecido pela sociedade de especialidade, CRM e ANVISA. Se ele realizou sem autorização de Comissão de Ética em Pesquisa estará em péssima situação em todas as esferas na qual ele for julgado. A reportagem poderia ao menos informar se houve ou não autorização por alguma CEP autorizada pelo Conselho Nacional de Ética em Pesquisa do Conselho Nacional de Saúde. A sua defesa no texto foi pífia.