Medical Progress Today

Herper argues that the furor over Avandia is only a foretaste of "open�source" drug safety, where clinical trial data is posted on the web for any would�be crusader to analyze and criticize, in short, an invitation for a lynching."

Everyone�lawyer, doctor, think�tanker�wants a piece of the drug safety debate. The catalyst now is a piece of legislation in Congress that, post�Avandia, will establish a potentially dramatic remaking of drug regulation. Before Avandia it seemed that the drug industry was going to get a bill it could live with. The FDA would get new powers and industry would make some concessions. A grand reform that would result in much tougher scrutiny for drugs would be averted.

But Henry Waxman, the Democrat who runs the House committee that oversees the FDA, will hold hearings on June 6, determined to use the Avandia flap to put the FDA and drug manufacturers on the defensive. Now big pharma needs an antianxiety pill. It would be "wholly inappropriate" for Congress to change drug safety law over Avandia, says Ronald Krall, Glaxo's chief medical officer.

One change that seems inevitable is the creation of more Steven Nissens�that is, more outside scientists looking over the FDA's shoulder. A Senate�passed bill from Senators Edward Kennedy (D�Mass.) and Michael Enzi (R�Wyo.) seeks to force manufacturers to make all study results public. Nissen was able to do his Avandia analysis because Glaxo, in order to get then New York attorney general Eliot Spitzer off its back, agreed three years ago to put drug�trial results up for public viewing. The bill would put all drug firms in this boat.

Think of this as the open�source FDA. Already outsiders have pinpointed valid safety issues, such as Vioxx. But open source can be an invitation to a lynching. AstraZeneca (nyse: AZN � news � people)'s blockbuster cholesterol pill Crestor was originally maligned over kidney worries but has since been cleared. Expect "a free�for�all" as academic researchers get more access to data from companies and from electronic health records, says FDA Deputy Commissioner Janet Woodcock. "You could imagine tort lawyers running those analyses," she says.

The problem right now is that the FDA's credibility is at low�ebb. And this is not to say that drugs are any less safe than they were even a few years ago. But what has happened is that we have moved into a 24�hour media environment where scare sells and scientific discussion is pushed to the sidelines. Also, as medical science advances and more people find themselves taking medicines for chronic ailments, consumers are paying a lot more attention to headlines touting dangerous drug risks.

This is not to say that there aren't legitimate drug safety questions at stake surrounding Vioxx or Avandia, but that, in this environment, it very hard to ask the right questions that will improve public policy.

Ross argues that the court system is the last place we should look to test claims that childhood autism is caused by vaccines containing thimerosal—a purported link that has generated a tidal wave of litigation but which has been debunked by numerous scientific studies in recent years.

Scientists years ago dismissed the alleged causal link between childhood vaccinations and autism. But a large and vocal group of advocates are nonetheless convinced there is a cause–and–effect relationship. For them and their lawyers, science is irrelevant. Their last hope for vindication: a court of law that they hope might establish—legally, not scientifically—that vaccines do indeed pose a risk of autism and other ailments.

The science demonstrating the lack of a link between children's vaccines and autism has been validated, over and over again, during the last decade. Studies confirm that autism is no more common among children who received vaccinations than among those who did not. Further, the incidence of autism has continued to rise despite elimination of mercury from vaccines.

Yet this month, despite these facts and reams of other data, the first of thousands of legal cases on this same subject began in a special "vaccine court"—actually the U.S. Court of Federal Claims. One leading advocate of a vaccine–autism link was quoted as saying these proceedings "will mark the first time ever that evidence of autistic harm [sic] from childhood vaccines is examined and cross–examined in a court of law."

Perhaps so. I find it unsettling that the safety of vaccines must be put on trial before three "special masters" in a vaccine court. What the parents of the autistic children, plaintiffs in the 4,800–plus pending cases, cannot realize (though certainly their lawyers do) is that the truth about scientific and medical facts is not, ultimately, something that can be decided either by the whims of judges or the will of the masses.

Tanner, a senior fellow at the Cato Insitute, writes that Michael Moore's soon to be released indictment of American health care, Sicko, ignores the strengths of free�market medicine while understating the problems of single�payor health care.

Eighteen of the last 25 winners of the Nobel Prize in Medicine are U.S. citizens or work here. With no price controls, free�market U.S. medicine provides the incentives that lead to innovative breakthroughs in drugs and other medical technologies. U.S. companies have developed half of all the major new medicines introduced worldwide during the past 20 years. In fact, Americans played a key role in 80 percent of the most important medical advances of the past 30 years.

Instead, Moore focuses on life expectancy, suggesting people in Canada, Britain, France and even Cuba live longer than Americans because of their health care systems. But most experts agree that life expectancies are a poor measure of health care because they are affected by too many factors�like violent crime, poverty, obesity, tobacco and drug use�unrelated to a nation's health system.

When you compare the outcome for specific diseases like cancer or heart disease, the United States clearly outperforms the rest of the world...

Moore downplays waiting lists in Canada, suggesting they are no more than inconveniences. He interviews apparently healthy Canadians who claim they have no problem getting care.

Somehow, he couldn't find any of the nearly 800,000 Canadians who are not so lucky. Nor apparently did he have time to interview Canadian Supreme Court Chief Justice Beverly McLachlin, who wrote in a 2005 decision striking down part of Canada's universal care law that many Canadians waiting for treatment suffer chronic pain and "patients die while on the waiting list."

Tierney argues that the celebration of Rachel Carson's Silent Spring skips blithely over the millions of lives lost from malaria in developing nations—which could have been saved by prudent use of pesticides like DDT. Read the whole thing.

Ms. Carson used dubious statistics and anecdotes (like the improbable story of a woman who instantly developed cancer after spraying her basement with DDT) to warn of a cancer epidemic that never came to pass. She rightly noted threats to some birds, like eagles and other raptors, but she wildly imagined a mass "biocide." She warned that one of the most common American birds, the robin, was "on the verge of extinction"—an especially odd claim given the large numbers of robins recorded in Audubon bird counts before her book.

Ms. Carson's many defenders, ecologists as well as other scientists, often excuse her errors by pointing to the primitive state of environmental and cancer research in her day. They argue that she got the big picture right: without her passion and pioneering work, people wouldn't have recognized the perils of pesticides. But those arguments are hard to square with Dr. Baldwin's review.

Dr. Baldwin led a committee at the National Academy of Sciences studying the impact of pesticides on wildlife. (Yes, scientists were worrying about pesticide dangers long before "Silent Spring.") In his review, he praised Ms. Carsons's literary skills and her desire to protect nature. But, he wrote, "Mankind has been engaged in the process of upsetting the balance of nature since the dawn of civilization."

While Ms. Carson imagined life in harmony before DDT, Dr. Baldwin saw that civilization depended on farmers and doctors fighting "an unrelenting war" against insects, parasites and disease. He complained that "Silent Spring" was not a scientific balancing of costs and benefits but rather a "prosecuting attorney's impassioned plea for action."

Ms. Carson presented DDT as a dangerous human carcinogen, but Dr. Baldwin said the question was open and noted that most scientists "feel that the danger of damage is slight." He acknowledged that pesticides were sometimes badly misused, but he also quoted an adage: "There are no harmless chemicals, only harmless use of chemicals."

Ms. Carson, though, considered new chemicals to be inherently different. "For the first time in the history of the world," she wrote, "every human being is now subjected to contact with dangerous chemicals, from the moment of conception until death."

She briefly acknowledged that nature manufactured its own carcinogens, but she said they were "few in number and they belong to that ancient array of forces to which life has been accustomed from the beginning." The new pesticides, by contrast, were "elixirs of death," dangerous even in tiny quantities because humans had evolved "no protection" against them and there was "no 'safe' dose."

She cited scary figures showing a recent rise in deaths from cancer, but she didn't consider one of the chief causes: fewer people were dying at young ages from other diseases (including the malaria that persisted in the American South until DDT). When that longevity factor as well as the impact of smoking are removed, the cancer death rate was falling in the decade before "Silent Spring," and it kept falling in the rest of the century.

Why weren't all of the new poisons killing people? An important clue emerged in the 1980s when the biochemist Bruce Ames tested thousands of chemicals and found that natural compounds were as likely to be carcinogenic as synthetic ones. Dr. Ames found that 99.99 percent of the carcinogens in our diet were natural, which doesn't mean that we are being poisoned by the natural pesticides in spinach and lettuce. We ingest most carcinogens, natural or synthetic, in such small quantities that they don't hurt us. Dosage matters, not whether a chemical is natural, just as Dr. Baldwin realized.

But scientists like him were no match for Ms. Carson's rhetoric. DDT became taboo even though there wasn't evidence that it was carcinogenic (and subsequent studies repeatedly failed to prove harm to humans)...

The human costs have been horrific in the poor countries where malaria returned after DDT spraying was abandoned. Malariologists have made a little headway recently in restoring this weapon against the disease, but they've had to fight against Ms. Carson's disciples who still divide the world into good and bad chemicals, with DDT in their fearsome "dirty dozen."

In this interview with Fred Hassan, CEO of Schering–Plough, Hassan argues that data transparency on the web is leading to an explosion of "questionable third party analysis."

Hassan, who is also president of the International Federation of Pharmaceutical Manufacturers and Associations, said the decision by companies to post their clinical trial results on the Internet increased the scope for sometimes questionable third-party analysis.

"This was always a concern, and unfortunately it's now being borne out," he said in a telephone interview. "This kind of thing could happen to many, many other drugs as well."

The world's leading pharmaceutical companies, responding to widespread demands for greater openness, recently started posting most clinical studies on a series of Web sites. Hassan said the move was good for transparency but increased the risk of potentially misleading analysis, including the pooling of results of various studies in what is known as meta analysis, which was always "very dangerous territory".

The Post argues, correctly we think, that the rush to judgment over Avandia is actually evidence that the FDA needs more resources to conduct a careful analysis of the postmarket risks and benefits of medicines.

FOR YEARS, there have been rumblings that GlaxoSmithKline's diabetes drug, Avandia, might be associated with an increased risk of heart attack or other cardiovascular events. Also for years, the drug's labels have noted the risk. Then last month, the New England Journal of Medicine published a review of the available studies on Avandia's side effects that concluded that taking the medication can significantly boost patients' chances of experiencing heart trouble.

Washington responded with a familiar fit of hypertension. In the space of a few days, congressional hearings had been scheduled, the Food and Drug Administration was under attack for being sloppy and slow, and the advocacy group Public Citizen was calling for the FDA to ban Avandia. Sen. Charles E. Grassley (R-Iowa) used the study's publication to push his proposal to reorganize the FDA's drug monitoring division. Meanwhile, Avandia users were no doubt staving off their own elevated blood pressure.

But there is good reason for the FDA to act cautiously. In an editorial after the review's publication, the Lancet, a respected British medical journal, pointed out that the two most significant studies considered did not produce many conclusions of statistical significance. The authors of the analysis admit that it suffers from significant weaknesses, among them that they did not have access to patients' medical histories. Further, the FDA has said that it has other data that contradict the analysis. A large trial is underway, the results of which will help to clarify the medication's dangers. In other words, the analysis is far from conclusive, and the FDA should not be in the business of regulating by suspicion. It always must balance potential dangers against potential usefulness of a drug.

If anything, the episode makes the case for a bill that Sens. Edward M. Kennedy (D-Mass.) and Mike Enzi (R-Wyo.) recently shepherded through the Senate. The most potent criticism of the FDA's behavior in the Avandia case is that it hasn't moved fast enough to quantify the drug's dangers. The legislation would give the FDA clear authority to order post-approval studies if the regulator got a whiff of undocumented risks. The bill would also promote the pooling of public and private data on prescription drugs so that possible side effects can be discovered earlier and appropriate studies commissioned more rapidly. The House should embrace the Senate's approach.

Offit, a vaccine inventor and chief of infectious diseases at the Children's Hospital of Philadelphia, argues that thousands of lawsuits alleging that vaccines cause autism are poised to deal a fatal blow to the vaccine industry.

No single medical advance has had a greater impact on human health than vaccines. Before vaccines, Americans could expect that every year measles would infect four million children and kill 3,000; diphtheria would kill 15,000 people, mostly teenagers; rubella (German measles) would cause 20,000 babies to be born blind, deaf, or mentally retarded; pertussis would kill 8,000 children, most of whom were less than one year old; and polio would paralyze 15,000 children and kill 1,000.

Because of vaccines all of these diseases have been completely or virtually eliminated from the United States. Smallpox�a disease estimated to have killed 500 million people�was eradicated from the face of the earth by vaccines. And we're not finished; vaccines stand as our only chance to prevent pandemic influenza, AIDS, and bioterror, and our best chance to prevent certain cancers.

Now, massive litigation could force companies to leave the vaccine business, threatening the future of one of medicine's greatest achievements. On June 11, in an unprecedented action before a federal claims court, lawyers for 4,800 autistic children will argue that vaccines caused autism. If successful, these claims could exhaust the pool of money currently set aside to compensate children who have been hurt by vaccines. Further, lawyers will likely take their claims that vaccines cause autism to civil court, where awards could be enormous.

"I don't want to see the drug companies go out of business," said David Kirby, author of the book "Evidence of Harm," speaking on Imus in the Morning in April 2005. But "we are looking at trillions and trillions of dollars of care for these people."

Predictions of massive awards, and dire warnings about the fate of vaccines, may seem over�dramatic. But vaccines were the first medical product that came close to being eliminated by lawsuits...

Certainly there is plenty of evidence to refute the notion that vaccines cause autism. Fourteen epidemiological studies have shown that the risk of autism is the same whether children received the MMR vaccine or not, and five have shown that thimerosal�containing vaccines also do not cause autism. Further, although large quantities of mercury are clearly toxic to the brain, autism isn't a consequence of mercury poisoning; large, single�source mercury exposures in Minamata Bay and Iraq have caused seizures, mental retardation, and speech delay, but not autism.

Finally, vaccine makers removed thimerosal from vaccines routinely given to young infants about six years ago; if thimerosal were a cause, the incidence of autism should have declined. Instead, the numbers have continued to increase. All of this evidence should have caused a quick dismissal of these cases. But it didn't, and now the court has turned into a circus. The federal and civil litigation will likely take years to sort out.

Autism can be a heartbreaking disorder, often draining parents emotionally and financially. Although many promising genetic, epidemiological, and biological studies have been published during the past few years, autism remains a disorder without a known cause or cure. This has been enormously frustrating for parents.

It would be nice if there were someone or something to blame. We could blame the government and use the federal vaccine compensation program to pay for care. Or we could blame vaccine makers, and get them to pay in civil court. But if vaccine makers�faced with large awards for a problem that wasn't their fault�make the same decisions they did in the early 1980s, all American children will suffer, including those with autism. Then, we'll have only ourselves to blame.

In response to the study by Dr. Nissen and his colleagues in the New England Journal of Medicine which we linked to last week) GlaxoSmithKline issued a letter in the Lancet defending the safety of Avandia based what they believe is the best available data. The Lancet has also issued its own editorial on the issue.

The Wall Street Journal reports on the growing dispute:

Ronald Krall, [GSK] chief medical officer, wrote in the letter that Glaxo did a "meta analysis" similar to the one conducted by Cleveland Clinic cardiologist Steven Nissen, whose article in the New England Journal of Medicine last week linked the drug to a potentially increased risk of heart attacks. Glaxo's own meta–analysis also found indications of increased risk, Dr. Krall wrote, but he said the number of adverse events was low.

Dr. Krall also discussed results from two large Glaxo–funded studies of the drug. Neither trial, called Dream and Adopt, was designed primarily to assess the drug's heart risks. But Glaxo's analysis of the Adopt trial showed major adverse cardiovascular events, such as heart attacks and strokes, were "rare," and heart risks were similar to those of two other diabetes drugs. The Dream trial also showed "no significant difference" in cardiovascular events between the drug and placebo, the letter said.

Meanwhile, an independent safety board recently reviewed an interim analysis of an ongoing study, Record, designed specifically to assess the drug's impact on the heart. The board determined the trial should continue, the Glaxo letter said.

In an interview, Christopher Viehbacher, Glaxo's president of U.S. pharmaceuticals, said the trial's interim results were "giving us the confidence to say that we stand behind this product." He said there is a chance the interim results will become public before the Record trial is complete, though the trade–off would be that the publicity could weaken the statistical power of the final results.

Mr. Viehbacher said it wouldn't surprise the company if the Food and Drug Administration were to call for "some labeling changes" for Avandia. One possibility would be elevating a heart–failure warning on the label to a more severe "black box" warning, he said.

Dr. Nissen criticized Glaxo's letter to the Lancet, saying the company was slicing the data differently from the Adopt and Dream results originally published. Dr. Nissen also said the company was referring to such small subsets of data in the Adopt and Dream trials, that no firm conclusion could be drawn.

"Somebody went back and looked for something that would support their contention," Dr. Nissen said. "This is not a scientifically proper way to analyze data."

It is ironic, however, for Dr. Nissen to make this charge given the admitted limitations of his own study on Avandia's safety. Experts agree that meta–analyses of aggregated clinical trial data—by GSK or Dr. Nissen—are problematic, and that the best way to adjudicate safety issues is with a prospective, randomized trial, which GSK is currently conducting.

Gawande, a guest columnist in the New York Times, continues his series on health care issues by discussing Sen. Barack Obama' latest plan. Gawande notes that while there are flaws in all existing plans—and all existing health care systems—reform is imperative.

As a surgeon, I've worked with the veterans' health system, Medicare, Medicaid and private insurance companies. I've seen health care in Canada, Britain, Switzerland and the Netherlands. And I was in the Clinton administration when our plan for universal coverage failed. So, with a new health reform debate under way, what I want to tell you in my last guest column is this:

First, there is not a place in this world that is not struggling to control health costs while providing high–quality, easily accessible care. No one—no one—has a great solution.

But second, whether as a doctor or as a citizen, I would take almost any system—from Medicare–for–all to a private insurance voucher system—over the one we now have. Job-based insurance is bleeding away the viability of American businesses—even doctors complain about the cost of insuring employees. And it has left large numbers of patients without adequate coverage when they need it. In the last two years, for example, 51 percent of Americans surveyed did not fill a prescription or visit a doctor for a known medical issue because of cost.

My worry is less about what happens if we change than what happens if we don't.

This week, Barack Obama released his health reform plan. It's a puzzle how you are supposed to regard presidential candidates' proposals. They are treated, by campaigns and media alike, as some kind of political G.P.S. device— gadgets primarily for political positioning. So this was how Mr. Obama's plan was reported: it is a lot like John Edwards's plan and the Massachusetts plan signed into law by Mitt Romney last year; and it has elements of John Kerry's proposal from four years ago. In other words—ho hum—another centrist plan. No one except policy wonks will tell the proposals apart from one another.

Well, all this may be true. And if what you care about is which candidate can one-up the others, it is rather disappointing. But if what you care about is whether, after the 2008 election, we'll be in a position to finally stop the health systems' downward spiral, the similarity of the emerging proposals is exactly what's interesting. I don't think you can call it a consensus, but there is nonetheless a road forward being paved and a growing number of people from across the political spectrum are on it—not just presidential candidates, but governors from California to Pennsylvania, unions and businesses like Safeway, ATT and Pepsi.

This is what that road looks like. It is not single–payer. It instead follows the lead of European countries ranging from the Netherlands to Switzerland to Germany that provide universal coverage (and more doctors, hospitals and access to primary care) through multiple private insurers while spending less money than we do. The proposals all define basic benefits that insurers must offer without penalty for pre—existing conditions. They cover not just expensive sickness care, but also preventive care and cost—saving programs to give patients better control of chronic illnesses like diabetes and asthma.

The European route, however, also depends on rationing care for the sickest patients, and on cost controls for new medical innovations. While we agree with Dr. Gawande's criticisms of the U.S. job–based system, we think that the consumer–driven solution—powered through a tax credit or tax voucher to level the health insurance playing field between employed and unemployed Americans—would be much preferable to government setting and picking plans for consumers.

Butler's piece makes for good reading with Dr. Gawande's op�ed, as it focuses on how we can move beyond the current employer�based health insurance system.

For most working�age families, health insurance coverage is directly connected to the workplace. But because of structural weaknesses in this traditional form of coverage, it is steadily eroding, especially for workers in the small business sector. The health insurance system needs to evolve along a different path if it is to adapt to the goals and needs of today's workforce. Unfortunately, existing laws and insurance arrangements obstruct that evolution. Three key steps are needed to achieve a gradual transformation without disrupting the successful parts of the system.

First, states should establish "insurance exchanges." Exchanges would offer an array of coverage options, and families could retain their chosen plan from workplace to workplace with the same tax benefits as those available for traditional employer�sponsored plans. Second, most employers should become facilitators, rather than sponsors, of coverage. While many large employers would continue to sponsor coverage, most employers would hand over sponsorship to an insurance exchange and focus on providing administrative support for their employees' insurance choices. Third, the federal government should reform the tax treatment of health to focus help on lower-income families.


home spotlight commentary research events news about contact links archives
Copyright Manhattan Institute for Policy Research 52 Vanderbilt Avenue New York, NY 10017 (212) 599-7000 mpt@manhattan-institute.org