A voz do dono: entrevista com o CEO da GlaxoSmithKline

Abaixo, segue entrevista com o CEO da GlaxoSmithKline publicada hoje no The Wall Street Journal. Destaquei algumas opiniões como de que o risco da Avandia já era conhecido pela empresa - obviamente, em magnitude menor - e que há países que preferem comprar metralhadoras a vacinas.

Glaxo's GarnierIs Taking the Heat Defending Safety of Avandia Preoccupies,But Doesn't Consume, Drug Company's CEO By JEANNE WHALENJuly 9, 2007; Page B1 Jean-Pierre Garnier, chief executive of GlaxoSmithKline PLC, has been in the hot seat since May, when an article in the New England Journal of Medicine raised concerns about the safety of the diabetes treatment Avandia, his company's second-biggest selling drug. In the article, cardiologist Steven Nissen analyzed 42 past clinical trials of Avandia -- an approach known as a meta-analysis -- and concluded that patients taking the drug may be at a higher risk for heart attacks than patients taking other drugs. Since then, Avandia prescriptions have fallen sharply, and Glaxo's stock price has plummeted. Dr. Garnier is now trying to fight research with research. He says Glaxo performed its own meta-analysis of Avandia before Dr. Nissen's -- and also found a risk of heart attack. But the risk was very slight, and was outweighed by other evidence showing that Avandia is as safe for the heart as other diabetes drugs, Dr. Garnier says. The Food and Drug Administration is now carrying out its own meta-analysis and will convene a panel of medical advisers on July 30 to weigh the evidence. Dr. Garnier has faced safety crises before. In 2004, medical experts raised concerns that Glaxo's Paxil and other antidepressants could induce suicidal thinking and behavior in children, leading the FDA to add strong warnings to the drugs. In an interview in Glaxo's Philadelphia office, Dr. Garnier discussed such topics as managing the Avandia crisis, the pricing of HIV drugs, serving poor communities and what he wants to accomplish before stepping down as CEO in May 2008. Excerpts follow. WSJ: Has Glaxo done everything it could to study Avandia and communicate its risks to the public? Dr. Garnier: We're not perfect, I'm sure. With 20-20 hindsight we could have done more. But I have to say in the case of Avandia, you see that we were diligent from the day of the launch to start to study the drug in some depth in [clinical] studies and then we did the meta-analysis a year ahead of Dr. Nissen. As soon as we found out that there was at least a question raised by the meta-analysis, we immediately did the epidemiology study with 30,000 patients that came out absolutely squeaky clean and supportive of Avandia. So you look at the totality, Avandia is by far the most studied diabetic agent on the market today. So sure, maybe we could do more, but frankly the record is very good. Not only have we studied this drug right, left and center, but also we have been transparent, informed everybody. WSJ: What feedback are you getting from doctors about Avandia? Dr. Garnier: Doctors are worried about being sued for putting patients on Avandia and things like this. But overall, they are staying behind Avandia. Very few patients actually are switching off their medication. But some have. WSJ: Are doctors more concerned about liability risk when putting new patients on the drug? Dr. Garnier: Physicians are naturally gun-shy about putting new patients on. The reality is, and we have the data, they're putting fewer new patients on it. We've just run a big survey of physicians, and they're playing back again the two key points: "Most of my patients have not switched, and I have no intention of switching them. However, as far as putting new patients on Avandia, I'm putting far fewer than before, and I'm waiting to see what the FDA has to say." WSJ: Does the safety flap take up your entire day? Dr. Garnier: Pretty much, 24-7. This is a very unpleasant event. But on the other hand this is not my first one. I've been there before. My job is to manage the company through the crisis. WSJ: How do you do that? Dr. Garnier: We have crisis-management phone calls every day. These things don't get done without a lot of coordination. WSJ: Glaxo recently donated 50 million pandemic flu vaccines to the World Heath Organization. What's the story? Dr. Garnier: It's probably the largest vaccine donation ever. The company could have sold possibly those 50 million units. They [Glaxo] decided to set them aside because frankly those countries are not going to buy any pandemic vaccine. Some of them have no commitment to health care. Let's call a cat a cat. They'll buy a lot of other things including Kalashnikovs before they allocate enough money for health care in their own countries. [Some] are committed to better health care but [pandemic flu] never makes their top 10 list because they have humongous problems. They have HIV, and they have this and that. So putting resources aside for a maybe problem doesn't work out to their top priority. WSJ: How has Glaxo changed its HIV-drug pricing in the developing world since you started running the company? Dr. Garnier: I always wanted to have access as part of the DNA of the company. I don't look at those things as philanthropic undertakings. Even Tykerb -- we just introduced this breast-cancer treatment in the U.S. It's a very expensive product for the average person. We provide funding and subsidies for people up to an income level of $100,000 per family. It's intertwined with the purely commercial pricing. I wanted that. I never wanted to just close my eyes to the fact that 80% of the population won't be able to afford the drugs. Because that's the truth -- 80% of the market for pharmaceuticals comes from 20% of the world-wide population. I'm not going to be CEO of a company that just works for rich countries. And even within rich countries, by the way, you have holes in the safety net that are part of the equation. WSJ: What has that meant in HIV? Dr. Garnier: To me, it became very obvious that we had to go much further than to give discounts [on drugs]. We had to make basically a philosophical statement that for the very poor countries of this world, we were going to sell our drugs without making a profit, completely not for profit. And overnight we did this. And that allowed the consumption of HIV drugs in Africa to increase dramatically, exponentially. Overnight we went from very little to hundreds and hundreds of millions of tablets. Then we went one step further and said, why don't we give licenses to generic companies [to make our drugs], particularly local companies. Maybe they can make it even cheaper. WSJ: What are the main things Glaxo has done to provide better access [to HIV drugs] and what's been the effect? Dr. Garnier: What we sell at this not-for-profit price corresponds to roughly a million patients being treated, mostly in Africa. We dropped the price, helped with access -- that is, we have a number of community support programs. Because treating people who have HIV is not a simple thing. WSJ: What are you doing? Opening clinics? Hiring doctors? Dr. Garnier: No, we don't own the infrastructure but we've supported clinics. Not just with money -- with advice, sending doctors. WSJ: Do you do much licensing for production of your drugs in middle-income countries like Thailand? Dr. Garnier: No, no, no. Middle-income countries should pay a fair price for our drugs. They certainly can use some of their resources to pay a fair price, which is clearly an intermediate price between the lowest and the highest -- we try to price according to standard of living. WSJ: You're retiring next year. What more do you want to do? Dr. Garnier: No. 1 is deliver the pipeline. We have a very exciting, high-quality, deep, dense, innovative pipeline of late-stage drugs. So let's make sure we deliver, and those drugs pass the last hurdle and get launched.

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: 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.

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, o Legislativo americano assume uma posição.

Estou ainda sem possibilidade de avaliar os textos do NEJM publicados ontem, mas estou publicando abaixo, o despacho da Reuters.

Lawmakers to grill Glaxo, FDA on diabetes drug By Lisa Richwine and Susan Heavey WASHINGTON (Reuters) - U.S. health officials and drugmaker GlaxoSmithKline Plc are likely to face tough questioning from lawmakers on Wednesday over their handling of data suggesting a heart risk with the widely used diabetes pill Avandia. A furor erupted last month when a Cleveland Clinic analysis linked Avandia to a 43 percent higher chance of having a heart attack. The Food and Drug Administration and Glaxo say other data provided conflicting evidence. Glaxo has said it gave regulators information in August 2006 that estimated a 30 percent higher heart-attack risk with Avandia. Some critics question why neither the FDA nor Glaxo alerted patients sooner. "The American people deserve to know why eight years after FDA approved Avandia, it's still unclear whether the drug is harmful or helpful," Rep. Henry Waxman, a California Democrat and chairman of the House Oversight and Government Reform Committee, said in a statement. Millions of patients take Avandia, known generically as rosiglitazone, and sales topped $3 billion last year. But analysts this week said prescriptions have fallen 16 percent since the Cleveland Clinic report as doctors switch patients to Takeda Pharmaceutical Co. Ltd.'s rival drug Actos. Glaxo released early findings on Tuesday from an ongoing company-funded study that was unable to show a link to heart attacks. It also defended itself and reassured patients in full-page advertisements in at least a dozen U.S. newspapers. "Patients and physicians should find these data reassuring," said a statement by Moncef Slaoui, London-based Glaxo's research and development chairman. Still, several experts said the new evidence still suggests a greater risk of heart attack. Waxman's panel is set to question Slaoui, FDA Commissioner Andrew von Eschenbach; cardiologist Steve Nissen, who wrote the Cleveland Clinic analysis, and others. CRITICISM OF FDA Concerns over Avandia have sparked an outcry from members of Congress who have blasted the FDA in recent years as being slow to respond to problems with other medicines, including Merck & Co Inc.'s withdrawn arthritis drug Vioxx. The controversy comes as Congress considers legislation meant to bolster the FDA's oversight of drug side effects. Some critics are seeking to use the Avandia case to push for tougher safeguards. Waxman said the House hearing would focus on whether the FDA is properly safeguarding the public and whether changes in the agency's authority, resources or leadership might be needed. The FDA is finishing its own Avandia analysis to better assess the heart risk but has not said when it will be completed. FDA officials have defended their actions, saying they had to weigh warning the public against concerns that diabetic patients could stop taking their medication altogether. "I believe we did it right with regard to Avandia," von Eschenbach told reporters last week. The agency has scheduled a July 30 public meeting to discuss the

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: em breve nos tablóides

Ainda não consegui ler os textos do NEJM sobre o Avandia, talvez no vôo de retorno a São Paulo se a a bateria permitir. Mas, conseguir ler o NYT reportagem sobre a ameaça o professor americano pelo senhor Yamada, hoje na fundação Bill Gates. O caso Avandia começou no The New England, foi para os jornais e em breve chegará aos tablóides.A má educação e arrogância de executivos de empresas que são contrariadas por acadêmicos é indescritível. Quem assistiu a um evento no Centro de Convenções Rebouças há uns dois anos pode se lembrar da grosseria e impertinência à crítica. Recentemente, recebi de dois anônimos uma resposta a um post de novembro que falava da Merck Sharp e Dhome, onde eu fazia um relato de reportagem de revista. Leiam o post e a resposta e o texto abaixo do The New York Times.

Doctor Says He Was Assailed for Challenging Drug’s Safety By STEPHANIE SAUL Published: June 7, 2007 WASHINGTON, June 6 — The business of developing and selling new drugs is fraught with peril and setbacks. Billions of dollars are at stake. Nerves are on edge. Tempers flare. Just ask Dr. John B. Buse, a medical researcher who testified at a House hearing on Wednesday about the safety of the popular diabetes drug, Avandia.Dr. Buse described name-calling and what he said was the veiled threat of a lawsuit by a high-ranking drug company executive in 1999 after he had criticized Avandia at a medical meeting. He said the executive called him a “liar” and “scoundrel” in criticizing him to his supervisor at the University of North Carolina medical school, where Dr. Buse was an associate professor and has since become the chief of endocrinology.Dr. Buse did not name the executive, but he was later identified at the hearing by another company official as Dr. Tadataka Yamada. In 1999 Dr. Yamada was the chief of research and development for Avandia’s maker, SmithKline Beecham, which is now called GlaxoSmithKline. Dr. Yamada is a well-known scientist who left GlaxoSmithKline in June 2006 to become director of global health programs for the Bill and Melinda Gates Foundation. A spokesman for the Gates Foundation, Joe Cerrell, said that Dr. Yamada was not reachable for comment. The committee released a letter Dr. Buse wrote in 1999 to Dr. Yamada in which he expressed anger and frustration. “Please call off the dogs,” Dr. Buse wrote. “I cannot remain civilized much longer under this kind of heat.” Some members of the Congressional panel, the House Committee on Oversight and Government Reform, said the company’s behavior toward Dr. Buse was inappropriate and unacceptable. “We cannot have a post-regulatory environment where manufacturers intimidate scientists,” said Representative John Yarmuth, Democrat of Kentucky. In documents and in a prepared statement, he said his problems with the company began in 1999, the same year Avandia was approved by the Food and Drug Administration, during a presentation at a meeting of the American Diabetes Association. Dr. Buse recalled trying to squeeze two hours of scientific data into a 25-minute speech to the group, in which he said the data suggested Avandia raised the risk of chest pain and heart attacks by 50 percent. “In the week that ensued,” Dr. Buse said in his prepared statement, “there were a number of phone calls from SmithKline Beecham. During these calls, it was mentioned on two occasions that there were some in the company who felt my actions were scurrilous enough to attempt to hold me liable for a loss in market capitalization.” He was referring to a decline in the company’s stock price. The company also contacted the chairman of medicine at the University of North Carolina, Dr. Fred Sparling. In his letter to Dr. Yamada, Dr. Buse wrote, “I was not upset when my chairman called me into his office to tell me that some in your company perceive me as being ‘for sale,’ as he knows me well enough to doubt it.” In testimony yesterday, GlaxoSmithKline’s current chief of research and development, Moncef Slaoui, who succeeded Dr. Yamada in that job, said that Dr. Buse made an error in the presentation he gave in 1999. Dr. Buse said he ultimately signed a statement clarifying his position about Avandia that the company could present to financial analysts. But in his letter to Dr. Yamada, he said: “I cannot change my opinions in the absence of new data or understanding, in large part because I am not for sale.” After the hearing, Senator Max Baucus, the Montana Democrat who is chairman of the Senate Finance Committee, and Senator Charles E. Grassley of Iowa, the ranking Republican on the committee, asked that GlaxoSmithKline and the University of North Carolina supply additional information about any retaliation against Dr. Buse

Avandia, mudança de bula e ameaças a médico.

O caso Avandia ainda rende: essa semana, o FDA obrigou a empresa a modificar a bula do medicamento com alerta para risco potencial de infarto do miocárdio. Hoje, The Wall Street Journal relembra das pressões sobre pesquisador de diabetes há 8 anos por causa de suas críticas ao medicamento.

Glaxo's Handling of Physician Criticized By JEANNE WHALENNovember 17, 2007 Over a period of several years, drug maker GlaxoSmithKline PLC was so concerned about a prominent physician's negative views of its diabetes drug that it engaged in a concerted effort to intimidate him and stifle his opinion, a report by the U.S. Senate Finance Committee found. The report offers a window into the rarely acknowledged practice among drug companies of monitoring and seeking to influence the opinions of leading physicians, who can make or break a drug's sales. The report alleges that Glaxo Chief Executive Jean-Pierre Garnier and former research chief Tachi Yamada were involved in the intimidation.The Senate Finance Committee released the report Thursday, after researching Glaxo's relationship with John Buse, a diabetes expert and professor of medicine at the University of North Carolina in Chapel Hill. In 1999, Dr. Buse began expressing concerns about the cardiovascular risks of Avandia, one of Glaxo's top selling drugs. The Senate Finance Committee investigated the matter because it has jurisdiction over Medicare and Medicaid and wants to ensure that they are paying for safe and effective medicines, the report says. The committee, led by Montana Democrat Max Baucus and Iowa Republican Chuck Grassley, didn't recommend any particular action. It said it feared the Avandia case was part of a "troubling pattern of behavior by pharmaceutical executives." "The effect of silencing [Dr. Buse's] criticism is, in our opinion, extremely serious," the report concludes, noting that patients may have needlessly suffered heart attacks during the period. "Had GSK considered Avandia's increased cardiovascular risk more seriously when the issue was first raised in 1999 by Dr. Buse, instead of trying to smother an independent medical opinion, some of these heart attacks may have been avoided," the report says. This week, the Food and Drug Administration forced Glaxo to add a strong new warning to Avandia's prescribing label about potential heart-attack risks for patients taking the drug. A Glaxo spokeswoman, Nancy Pekarek, said the company strongly disputes the committee's conclusions. She said Glaxo had tried to correct Dr. Buse's "inaccuracies" about Avandia but had never tried to intimidate or silence him. "People at the time were very passionate about this new medicine and could perhaps have handled the interactions with Dr. Buse better," she said. "We did apologize to Dr. Buse for the tone of some of the conversations, and he accepted that apology eight years ago." She said Dr. Garnier had no additional comment. Dr. Yamada, who is now president of the global health program at the Bill & Melinda Gates Foundation, was traveling Friday and unavailable for comment, his assistant said. In an interview last month with Nature magazine, Dr. Yamada said that he never pursued any "diabolical plot" against Dr. Buse. Dr. Buse was also traveling Friday and unavailable for comment.

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: as teorias conspiratórias

Abaixo, a descrição de teorias conspiratórias sobre o caso Avandia retiradas do heartwire.

Rosiglitazone meta-analysis continues to drive controversy in second week May 30, 2007Lisa Nainggolan New York, NY - The fallout continues from the publication in the New England Journal of Medicine (NEJM) last week of a meta-analysis of rosiglitazone (Avandia, GlaxoSmithKline [GSK]), which suggested it increases the risk of MI and cardiovascular death. As reported by heartwire, many experts have said the data were far from perfect and have expressed concern about the manner in which they were released. But new reports go one step further—suggesting that FDA whistleblowers coordinated with politicians critical of the agency and the study authors to get damaging data into the public arena before the FDA could issue a safety statement on rosiglitazone. And damage has certainly been done in the form of a battering of the stock of GlaxoSmithKline, as Avandia was until now a $3-billion-a-year drug. Shares of the company were today at their lowest level in two years, following the sixth drop in seven trading days. Prescriptions for Avandia have also plummeted, with its slice of new oral diabetes prescriptions dropping from 10% to almost zero in the two days following the NEJM report. As part of the company's response to the controversy, chief medical officer of GSK, Dr Ronald L Krall, has written a letter, published online in the Lancet today In support of the cardiovascular safety of rosiglitazone, he cites, among other things, the decision by the independent data safety monitoring board to continue the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, which is specifically designed to look at cardiovascular outcomes with rosiglitazone. However Krall told the New York Times last week that the RECORD study could be under threat because some of the patients have dropped out of the trial due to safety concerns following last week's events Conspiracy theories An in-depth feature in a biotechnology weekly newsletter relates the tale of who knew what and when with regard to the rosiglitazone saga. US politicians have "portrayed Avandia as the quintessential. . . . Washington scandal, complete with maverick outsider who exposes wrongdoers and alerts congressional guardians of the public health," writes Steve Usdin in BioCentury But according to an editorial by former FDA deputy commissioner Scott Gottlieb, published May 29, 2007 in the Wall Street Journal, the truth is that the study authors, the NEJM, and politicians with their own motives tried to upstage the FDA in an attempt to influence public debate.According to Gottlieb, lead author Dr Steve Nissen (Cleveland Clinic, OH) submitted his manuscript to the NEJM on May 1 and did not inform either the FDA or GSK. The journal expedited the review of the paper and commissioned a commentary from two well-known critics of FDA's drug safety record, Drs Curt Furberg (University of Washington, Seattle) and Bruce Psaty (Wake Forest University, Winston-Salem, NC). The paper and commentary were published online by the NEJM on May 21, a move Gottlieb says was "timed to get ahead of the FDA's more careful evaluation of the same issues." The FDA had planned to issue a safety statement about Avandia around May 23, according to an unnamed drug safety official cited in the article by Usdin. Following publication of the NEJM paper, the FDA issued a statement on May 21 saying that its analyses were ongoing and that it would convene an advisory committee on the issues as soon as possible. Gottlieb says the NEJM claims to have made the decision to publish quickly because of the medical importance of the research but, if that were the case, he wonders why it did not inform the FDA about its publication or the findings. "When it comes to the issue du jour, drug safety, no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval. Yet NEJM and other journals have tried on other occasions to upstage FDA investigations through well-timed but much less complete publications," he asserts. He adds that there was no mention in the NEJM paper or editorial of rosiglitazone's benefits or of how doctors should advise patients. Steven Galson (director of the FDA's Center for Drug Evaluation and Research) told Usdin: "Medical journals have to take their job seriously. They have a responsibility to patients and physicians to publish information in a responsible and balanced manner. I'm not sure that responsibility was adequately executed in this instance." But NEJM editor Dr Gregory Curfman told BioCentury that his journal is not responsible for the media reactions to the rosiglitazone paper and commentary: "We are a scholarly journal, not a news outlet. What happens in the media is beyond our control

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.

em recesso, Avandia: transcrição de outro blogue

IN VIVO Blog Update Who's Sorry Now? Not Feeling So Good Edition Posted: 30 Jan 2008 11:50 AM CST Nature reports today that a peer reviewer for the New England Journal of Medicine leaked to GlaxoSmithKline that big old Avandia meta-analysis that has been the bane of their existence since it was released in May 2006. (Our coverage of the Avandia debacle can be found here.) University of Texas Health Science Center professor of epidemiology Steven Haffner, MD, explained to Nature: "Why I sent it is a mystery. I don't really understand it. I wasn't feeling well. It was bad judgement." Brian Vastag writes in Nature that Haffner faxed the article 17 days ahead of publication to GSK's Alexander Cobitz, whom he had worked with on an earlier trial of Avandia. What happens from there is unclear--though it's not like GSK effectively got out in front of the news, the 17-days head start may have helped them provide a relatively prompt interim analysis of its RECORD study, which was published in the NEJM in June to try to stop the bleeding. We will likely have more on this later, once the dust settles. For now, we bring you another edition of "Who's Sorry Now?" Steven Haffner to NEJM: Sorry I leaked the Avandia study, but i had a serious cold that day. Senator Grassley's office to Nature: Sorry we broke your embargo on the Avandia news today, but we aren't feeling so hot today ourselves. American Heart Association and American College of Cardiology to patients: sorry we forgot to disclose our potential financial ties to Merck and Schering-Plough, but there's a wicked flu going around the office. Phillies to Mets: Sorry you're spending all that money on Santana, but you're still not winning the NL East this year. Cough. © Copyright 2008 Windhover Information Inc. www.windhover.com/blog

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.

Avandia: rumo ao precipício?

Do sempre bem informado blogueiro do WSJ.

Avandia Dips: Pothole or Cliff? Posted by Jacob Goldstein New prescriptions of GlaxoSmithKline’s Avandia dipped sharply last week after the New England Journal of Medicine published a study suggesting the diabetes drug raised the risk of heart attacks, according to pharma research shop ImpactRx. In a note to investors this morning, Deutsche Bank cited ImpactRx data showing that Avandia’s market share of newly prescribed diabetes pills fell from about 10% before the NEJM paper to roughly zero in the two days after the paper was published. The situation “is far worse than we had anticipated and suggests that there could be as much as 22% downside risk to GSK’s near term earnings,” the note said. But the data don’t support such a far-reaching prediction, ImpactRx CEO Richard Altus argued in an interview with the Health Blog. “It’s premature to draw any conclusions from our data with respect to the future script writing of Avandia,” he said, adding that he was “shocked” at Deutsche Bank’s interpretation of his company’s figures. GlaxoSmithKline and Deutsche Bank have both been clients of ImpactRx, but Altus said he was not acting at GSK’s request. The Health Blog couldn’t reach the London-based authors of the note Tuesday afternoon for comment.

Mudando de Avandia para Actos

The Wall Street Journal (assinante clique aqui) que médicos americanos evitam Avandia e, ao mesmo tempo prescrevem mais Actos (pioglitazone). Há uma grande chance que a maioria dos pacientes, ao invés da prescrição de um desses dois medicamentos se beneficiaria mais de outras condutas com redução radical de peso, aumento da atividade física, redução dos níveis de pressão arterial e de colesterol. Por isso, talvez não seja mudança adequada, somente conveniente a quem prescreve. Abaixo parte do texto.

U.S. Doctors Shun Glaxo MedicineIn Wake of Study LONDON -- Doctors in the U.S. have shunned GlaxoSmithKline PLC's diabetes drug Avandia since a study was published last week linking the drug to greater heart-attack risk, according to early prescription data. Market-intelligence group Impact RX said Avandia's share of the market for newly prescribed oral antidiabetics fell to around zero from around 10% in the two days after the article was published in the New England Journal of Medicine on May 21. At the same time, the rate of patients switching from one drug to another was three times the usual level. Takeda Pharmaceutical Co.'s rival drug, Actos, saw its share of the new-prescription market increased to 22% from 10%. The U.K. company played down the data, saying, "Two days of data is not enough to reach sensible conclusions on the trend for Avandia new prescriptions."

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. ......

Ah, esse monstro de olhos verdes..

Heartwire, o boletim do InfoHeart apresenta os problemas do foco na pessoa de Steven Nissen e, não no FDA e na Glaxo-Smith Kline no caso Avandia. O título acima é uma tradução tosca de Otello de Shakespeare, que os americanos popularizam como The Irish eyes of envy. Sim, a inveja é a aquilo que os caminhoneiros escrevem nos para-choques.

The media, the man, and his message: Nissen seeks to refocus scrutiny on rosiglitazone June 21, 2007Shelley Wood New York, NY - The first act appears to be over in the rosiglitazone (Avandia, GlaxoSmithKline) drama, but the media have not yet loosened their grip on the man who first sounded the alarm about the diabetes drug: Dr Steven Nissen (Cleveland Clinic, OH). Nissen's meta-analysis, published in the New England Journal of Medicine (NEJM) and reported by heartwire, propelled rosiglitazone into the spotlight, culminating in a congressional hearing earlier this month and an FDA hearing on July 30. Despite Nissen's repeated insistence that the focus should be on patient safety, not his methods or motives, newspapers and their editorialists—as well as alternative media—continue to take disparate views on the man in the middle of the maelstrom. Dr Steven Nissen An editorial in the Cleveland Plain Dealer insists Nissen is being victimized for championing the public good . "Nissen, and clinicians like him around the country, aren't sifting drug performance data so they can add to their scrapbooks of news clippings. They're doing it so they can add to the store of knowledge in the medical community, which can then improve care for patients," the Dealer asserts. "As it now stands, public-spirited doctors like Nissen, who are trying to save patients grief, can be accused of poking their noses where they don't belong. That's ludicrous." Other media outlets have profiled Nissen, emphasizing his lifelong activism in different spheres. A glowing portrait of Nissen on MedPageToday.com points out that he was a part of the college antiwar movement during the 1960s at the University of Michigan. "His years as a campus activist left him with an entrenched commitment to righting wrongs and a willingness to challenge the status quo, attributes that he has integrated into his medical career," Peggy Peck writes for MedPageToday. "And he never forgot the power of the press." Altruism not universally accepted Indeed, the mainstream media loves a whistleblower, but not all of the coverage of Nissen's role has accepted the notion of him as altruist. Earlier this week, the Wall Street Journal (WSJ) ran an editorial questioning the "larger political context" in which the rosiglitazone concerns were raised, noting that "Dr Nissen has a reputation as an adversary of the pharmaceutical industry" and that he "admitted that he consulted with several congressional committees" prior to the publication of his rosiglitazone meta-analysis. "Ostensibly serious medical research isn't supposed to be peer-reviewed by the Democratic majority," the WSJ editorial gibes. Nissen, for his part, has repeatedly rejected claims that politics had anything to do with it. "That's just not what happened," he told heartwire. "The scientific process proceeded in the usual way: the journal had the article reviewed by peer scientists, it was a very careful review, it was revised based upon those reviews, and it has absolutely nothing to do with politics, it was about patients. . . . If the reviewers had not recommended publication, I'm sure that the NEJM would not have published it." Other news coverage has implied that Nissen had a different, more personal, political agenda. On June 5, Boston Globe staff reporter Diedtra Henderson quotes critics who claim Nissen's motives stem from a desire to run the FDA, a charge Nissen flatly rejects. "I'm not running for anything," Nissen is quoted in the Globe. "I've got a great job here [at the Cleveland Clinic], and I'm not going anywhere." Nissen reiterated this point to heartwire: "Speculation about the FDA is a very common topic. I am very happy as the chair of CV medicine at the Cleveland Clinic: I have no interest in going anywhere else; I have my hands full. I'm certainly not interested in running for an office like the FDA commissioner, I don't know where that comes from, it certainly doesn't come from me." Headline news A sticking point for the media mania around Nissen has been his apparent eagerness to make headlines. That was also the charge levied by California Republican Rep Darrell Issa during the congressional hearing, where he accused Nissen of caring more for making a "public splash" in the media than informing the FDA directly of his concerns about rosiglitazone. Even earlier, a Bloomberg news report posted online when his meta-analysis was first published notes that Nissen "put the Cleveland Clinic's in-house television studio to good use this week, appearing on a dozen broadcasts across the world." Nissen agrees that his paper "had more than the usual amount of media attention," but, he insists, "We published this because of the science. It was certainly not about politics, it's certainly not about media. . . . Ninety-nine percent of the coverage of the rosiglitazone story has been very good and very responsible. It's a very tiny group that's making an effort here to make this about the messenger, not the message." Nontraditional media have their say The bulk of that negative press has come from independent bloggers and other nontraditional media, many with major conflicts of their own. One of the more novel was a video podcast on the popular video-sharing website, YouTube, that opens with the question, "What do you think about a doctor … who compares a diabetes drug to 9/11?" a reference to a comment Nissen made during an interview that aired on ABC's Nightline website. The one and a half minute video features Dr Michael Weber (SUNY, Brooklyn, NY) expressing his misgivings about how Nissen described rosiglitazone's risks in the media. But the YouTube video was funded by the Center for Medicine in the Public Interest (CMPI), a "research" organization funded by the pharmaceutical industry, and Weber's own ties to industry have been scrutinized in the past. Contacted by heartwire, Weber said he did not even know what YouTube was. He stated that he is a member of an external, unpaid advisory group of directors for the CMPI and that the CMPI approached him to do "a video," not the other way around. He also emphasized that his comments were not about the scientific validity of the study, but about how they were disseminated. "As far as I'm concerned, the full story about Avandia still isn't known, and the concerns that were raised by Dr Nissen may be something we need to find out about," Weber said. "I'm not criticizing or disputing the scientific data, and in fact the whole reason I agreed to be videoed was because I did get very upset when I saw that Steve had said that the Avandia situation was worse than what happened on 9/11. I found that to be the sort of hyperbole that is really unacceptable in discussing these sorts of issues, and as a New Yorker, the statement was particularly unacceptable." But Weber rejected any suggestions that he himself was conflicted in this particular circumstance. "I do consult for industry, and I have done research projects and been a part of research activities that have been funded by industry, and I've always fully disclosed or acknowledged those. In this case, there is really not an industry connection, because I have not in any way defended Avandia or defended the way the company that manufactures Avandia has managed the situation." Nissen says he hasn't seen the video and doesn't want to. "What can I say? We publish scientific work, we did this analysis not to address the YouTube audience but because we believe that providers and patients have a right to know that there are significant safety issues with rosiglitazone," he told heartwire. "If it in fact stimulates people to create YouTube videos, I can't do anything about that, but that's not the audience." Blogs and missed potential Other blogs, associated with online editions of newspapers and magazines, have also debated Nissen's role. Ivan Oransky, blogger for The Scientist online, pointed out that Nissen has twice in the past year been wrong about drugs that he thought "held promise": torcetrapib (Pfizer), and now rimonabant (Sanofi-Aventis), the latter unanimously panned by the FDA's advisory panel last week. Oransky's observations were subsequently picked up in the WSJ health blog by veteran reporter Scott Hensley, who observed that Nissen, "a frequent and outspoken critic of the drug industry," has an "imperfect crystal ball." Oransky, quoted by Hensley, writes: "I think it's worth noting the record of someone whose pronouncements on drugs are so often held up by drug industry critics and that make media headlines." This is not like handicapping horse races; it's about doing good scientific studies and reporting the results in a faithful and accurate fashion. Nissen calls this a "straw-man" argument. "I'm always enthusiastic about drugs that we're studying, but when results come in, we tell it the way it is," he told heartwire. "I don't predict the success of drugs, I study the effects of drugs. . . . I have no vested interest, personally, one way or another in whether a drug works or not. It's my job to report scientific results in a neutral fashion, and I never predicted that torcetrapib would be successful. I thought it had great potential, and that was a potential that didn't pan out." In the case of rimonabant, investigators, including Nissen, did not have data on psychiatric side effects of the drug. "I'm glad that those data were reviewed; I hope that it can be overcome, because I do think [rimonabant] has potential. But this is not like handicapping horse races; it's about doing good scientific studies and reporting the results in a faithful and accurate fashion." Biting the hand that leads For health reporters, Nissen is a rare gem in the parched, baked earth that is the medical/pharmaceutical beat. In a sphere where wooden interviews, cautious opinions, and technical jargon are the norm, Nissen speaks his mind and is deliciously quotable. At the major cardiology meetings when he's spoken at a press conference, Nissen will glide through the pressroom like he's hosting a garden party, offering opinions, warmly greeting reporters by name. Asked whether the proximity he's always enjoyed, even nurtured, with the press has come back to bite him, Nissen cordially steers the conversation back to where he insists it should remain. "The last thing in the world I want is for this to be about me. It has to be about the science. If there are criticisms of the manuscript, let them be directed at the science, not at the messenger." Yet even as the hue and cry dies down, many journalists following the rosiglitazone saga are left wondering if Nissen—always so frank with and accessible to the media—may, this time, have gotten more attention than he wanted. Which just goes to prove the adage: Be careful what you wish for, you just might get it.

Voltando ao caso Avandia: impacto para a empresa

Abaixo, notícia publicada no Valor Econômico de ontem, 24/10/2007 sobre os lucros da Glaxo Smith Kline.

Um detalhe: traduzir The New England Journal of Medicine para Jornal de Medicina de Nova Inglaterra é excesso de licença poética! The Lancet será O Bisturi? Cuidado, O Bisturi já existe há quase cem anos. Ele é o jornal do Centro Acadêmico "Oswaldo Cruz" da FMUSP.

GlaxoSmithKline registra queda de 7% em seu lucro líquido no terceiro trimestre SÃO PAULO - A farmacêutica GlaxoSmithKline (GSK) anunciou hoje uma queda de 7% em seu lucro líquido no terceiro trimestre, para 1,88 bilhão de libras, contra 2,02 bilhões de libras no mesmo intervalo do ano passado. As vendas recuaram 3% no período, para 5,48 bilhões de libras. Os motivos para as quedas no lucro e nas vendas foram a forte redução no comércio da droga anti-diabetes Avandia e a competição com medicamentos genéricos no mercado dos EUA. Além do resultado, a empresa também anunciou um programa de reestruturação para cortar 1,5 bilhão em custos no intuito de tentar compensar os problemas com genéricos e com o Avandia no ano que vem. A GlaxoSmithKline se mantém no caminho para alcançar suas metas para o ano, apesar desses desafios significativos, disse o executivo-chefe da empresa, Jean-Pierre Garnier, que deve se aposentar em 2008. As vendas da família Avandia caíram 38%, para 225 milhões de libras entre julho e setembro. Apenas nos EUA, elas recuaram 48%, para 130 milhões de libras. Nesse país, a queda foi causada pela preocupação dos usuários quanto à sua segurança, questionada por um artigo publicado em maio no Jornal de Medicina de Nova Inglaterra.

Avandia: agora osteoporose

Quando uma empresa força demais a indicação de um medicamento, ocorre uma reação inversa, que muitas vezes é desproporcional ao potencial dano do medicamento. Um exemplo é o relatado abaixo pela Associated Press e, repetido em todos os jornais do planeta. Apesar, da empresa reconhecer a possibilidade de aumento de fraturas, o objeto de discussão - osteoporose - não é objeto de preocupação em termos clínicos. Primeiro, os dados foram obtidos em animais. Segundo, o risco cardíaco é mais importante do que o aumento de risco de osteoporose. Por último, notem que o pesquisador que identificou o mecanismo em ratos de forma súbita já indica ações médicas a longo prazo.

Popular Diabetes Drug May Increase Osteoporosis Associated PressDecember 2, 2007 1:29 p.m. WASHINGTON -- The popular diabetes drug marketed as Avandia may increase bone thinning, a discovery that could help explain why diabetics can have an increased risk of fractures. New research raises the possibility that long-term treatment with rosiglitazone, as Avandia is also called, could lead to osteoporosis. The diabetes drug is used to improved response to insulin. While bones seem solid, they constantly are being broken down and rebuilt by the body. Researchers found that in mice, the drug increased the activity of the cells that degrade bones, according to a report in this week's online issue of Nature Medicine. Avandia recently was labeled with warnings about the risk of heart failure in some patients. GlaxoSmithKline, which markets the drug, already has acknowledged that a study found a higher risk of fractures among women who take the drug. But this report is the first to attempt to explain the link between the drug and fractures. The finding "has led to a better understanding of the challenges associated with long-term treatment of patients with Type II diabetes," said Ronald M. Evans of the Salk Institute for Biological Studies in La Jolla, Calif., lead author of the report. "It also provides a basis for the development of a "next generation" of drug that can specifically dial out this side effect and a new insight into a previously unrecognized aspect of bone physiology that has important medical consequences," he said in an interview via e-mail. Nearly 21 million people in the United States have diabetes. Rosiglitazone is widely used in people with Type II, or adult onset diabetes, the most common form of the disease. Evans said the discovery was fortuitous. Researchers were looking at different aspects of the diabetic mice and did not realize they would be able to change the bone-removing activity. The assumption had been that more brittle bones in diabetics were the result of a reduced bone-building activity, not increased bone removal. "Considering the widespread use of these drugs and the known action in people it is surprising that such a key observation had been missed," he said. "The long-term use of rosiglitazone should be cautious in patients with higher risk of fractures such as older women," he added. Using it in combination with anti-osteoporosis drugs could be beneficial, he said. The research was funded by the Howard Hughes Medical Institute and the National Institutes of Health.

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.