For the Sake of Public Safety FDA & NIH Must Be Detatched from Drug Industry

Tue, 21 Dec 2004

Daily front page reports about lethal drug effects leave no doubt that we are in the midst of a major health safety and credibility crisis, largely due to a drug development and approval process that has been tainted by industry’s marketing priorities and business ethic which is governed by: profits urber alles!

The Wall Street Journal is taking a poll on its website, posing the question: How much do you trust the FDA to ensure drugs are safe? To cast your vote go to: http://discussions.wsj.com/n/mb/message.asp?webtag=wsjvoices&nav=messages&msg=3368

In recent years, FDA’s drug safety and efficacy standards have sunk back to pre-1962 Keefauver-Harris amendments to the 1938 Food, Drugs and Cosmetics Act which were passed in the wake of the thalidomide crisis. That catastrophe was averted in the US, thanks to Dr. Frances O. Kelsey’s diligent, comprehensive review of the scientific data, which went far beyond FDA safety standards then and now.

The 1962 legislation requires manufacturers to prove a product’s safety and effectiveness for its intended use, prior to gaining FDA approval. However, following the Prescription Drug User Fee Act (1992), industry money and industry influence was brought to bear into the review process, and the FDA shifted the emphasis from safety requirements to rapid approval of new drugs. The legislation was an accommodation to industry’s marketing priority of getting drugs approved and marketed rapidly. Additionally, the FDA Modernization Act (1997) lifted restrictions on direct to consumer drug advertising. The consequences of these two ill-advised legislative amendments can be measured in preventable human casualties.

The daily revelations about previously undisclosed fatal drug side effects are linked to widely advertised, and therefore, widely prescribed blockbuster profitable drugs – including SSRI antidepressants, COX2 pain killers, antipsychotics, and many more. We learned that Merck withdrew their painkiller, Vioxx, after public disclosure that a study found that it increased the risk of heart attack and stroke by more than 100%. Yet, Pfizer is hanging tough even as a study showed that patients given high doses of Celebrex had a 240% increase in heart problems, including death.

Industry’s control of how the trials are conducted and what is reported to the public has put the public health at increased risk of harm inasmuch as the true risks have not been disclosed either to the public or to physicians. Through its lavish advertising campaigns, the drug industry has encouraged the use of expensive new drugs whose lethal risks remain in company vaults. Dr. David Graham’s courageous public alert warning in testimony before the Senate Finance Committee: “I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx,” has been more than validated by a spate of recent revelations about widely marketed drugs whose hazardous effects have not been previously disclosed: The makers of Celebrex, Bextra, Aleve (naproxen), Strattera (widely promoted for the treatment of children loosely diagnosed with ADHD) have announced hazardous side effects.

In today’s NY Times, we learn that there were 70 heart attacks and strokes in the trial comparing Aleve (naproxen) against Celebrex in Alzheimer patients. But as recently as Dec. 10, a safety committee of the University of Washington decided that though "the safety data for some time has been giving a weak signal of possible increased risk of cardiovascular and cerebrovascular problems with naproxen,” the results were not worrisome enough to stop the trial." Not worrisome to the researchers and the university safety committee? The Times further reports that only when the widely publicized Celebrex trial findings that the drug could more than triple the risk of heart disease did Dr. Breiten’s committee decide to end the study and issue their warnings about Aleve. What, if any, are the standards for worry about lethal drug effects? Many doctors agree that "the one drug that is known to protect the heart is aspirin ­ All other painkillers are now under suspicion."

Ironically, the very FDA officials who publicly improperly criticized Dr. Graham for testifying about drug safety issues, are now defending the agency by acknowledging that widely used drugs are fraught with risks: FDA’s Acting Director of center for drug evaluation and research, Dr. Steven Galson, responding to the latest revelations about Aleve, is quoted in The NY Times: “This illustrates the fundamental dynamic that all drugs have risks. All should be taken carefully.” And Dr. Sandra Kweder, deputy director of F.D.A.’s office of new drugs, acknowledges: “We know that there are other phenomena that occur across these class of drugs, including gasrointestinal bleeding.” Heart problems, she acknowledged, “may be another class phenomenon.”

Why are drugs that trigger life-threatening effects–including gastrointestinal bleeding and heart attacks, liver damage and suicide–allowed to be widely advertised to consumers, encouraging them to believe the drugs are safe when the FDA knows they are not?

Below is an OP-ED in today’s NYT by Merrill Gozner providing a good overview of the problems and the decisions that must be made if safety in medicine matters, and if public trust in medicine is to be restored. Halfway measures will not do – industry’s ubiquitous influence on medicine has undremined the creidbility of scientific reports and the integrity of scientists on the take.

See: series of reports in The Wall Street Journal:

Celebrex Drama May Finally Prompt Changes at the FDA By ANNA WILDE MATHEWS and BARBARA MARTINEZ

December 20, 2004; Page B1 http://online.wsj.com/article/0,,SB110350181185804363,00.html;

As Safety Issues Hit Celebrex, Pfizer Decides to Hang Tough by Scott Hensley and Ron Winslow, Dec 20 A-1;

Ills of Drug Stocks May Prove Difficult to Cure By GREGORY ZUCKERMAN and SCOTT HENSLEY December 21, 2004; Page C1;

Patients Weigh Pain vs. Risk by Heather Won Tesoriero, Dec. 21, 2004 D-1;

Making Sense of Side Effects by Andrea Petersen, Dec 21 D-1;

Lilly Warns Drug For Hyperactivity May Harm Liver by Leila Aboud, Dec 20, B-4.

Contact: Vera Hassner Sharav
212-595-8974

http://www.nytimes.com/2004/12/21/business/21fda.html?oref=login&pagewanted=print&position=
December 21, 2004
A 4th Painkiller Is Tied to Increased Heart Risk
By GARDINER HARRIS

A new study has found that Aleve, a popular over-the-counter painkiller made by Bayer, could increase heart problems, and federal officials are warning patients not to exceed the recommended dose of two 200-milligram pills a day or continue therapy for more than 10 days without consulting a physician.

It was the fourth big-selling pain medicine in recent months to be suspected of hurting the heart, and federal drug officials said that similar drugs, like Advil, might also increase heart risks.

The study, sponsored by the National Institutes of Health, was intended to measure whether Aleve and Celebrex, made by Pfizer, might prevent Alzheimer’s disease. Nearly 2,500 patients were given one of the two drugs or a placebo and were followed for three years. Those taking Aleve had a 50 percent greater rate of heart problems – including heart attacks and stroke – than those given a placebo. The Celebrex patients saw no increase in heart events.

The latest findings follow an announcement Friday that a different national study found that those given high doses of Celebrex had a 240 percent increase in heart problems, including death. Merck executives withdrew their painkiller Vioxx after a study found that it increased the risk of heart attack and stroke by more than 100 percent. Also, Pfizer announced recently that a study of Bextra found that it increased the risk of heart attacks in those who have had cardiac surgery.

“This illustrates the fundamental dynamic that all drugs have risks,” said Dr. Steven Galson, acting director of the Food and Drug Administration’s center for drug evaluation and research. “All should be taken carefully.”

Federal drug officials said that the entire class of painkillers known as nonsteroidal anti-inflammatories – drugs that include Celebrex, Advil and Mobic – could cause worrisome effects on the heart. Sales of Celebrex, along with other anti-inflammatories like Advil and Mobic, are expected to fall as a result.

“We know that there are other phenomena that occur across these class of drugs, including gastrointestinal bleeding,” said Dr. Sandra Kweder, deputy director of the F.D.A.’s office of new drugs. Heart problems “may be another class phenomenon.”

Dr. Kweder said that the agency was studying the results of this latest study and “will be assessing what regulatory actions are appropriate over the next day or two.” Researchers stopped the study, but patients will be monitored.

Patients taking a prescription form of Aleve known as Naprosyn or naproxen should also consult their physicians, Dr. Galson said.

At the very least, the latest results could prove beneficial to Pfizer, which has been arguing that last week’s finding about Celebrex should be placed in the context that similar pills may be just as hurtful to the heart and that other studies of Celebrex have shown no such worries. Indeed, if there is one message from these studies it is that nothing is certain in this science.

“This is a very confusing situation,” Dr. Kweder said. “Every doctor and patient is going to have to have a conversation about their unique risks.”

The results surprised many because other studies suggested that naproxen may actually protect the heart. Some said the latest results suggested that many pain pills were far too popular in the United States.

“I’ve been saying for a long time that over-the-counter Nsaid’s are extraordinarily dangerous,” said Dr. Mark Fendrick, professor of internal medicine at the University of Michigan. Nsaid refers to nonsteroidal anti-inflammatories, which include Aleve, Advil and Mobic.

Many critics of the drug industry say that the industry has used widespread advertising to sell medicines to more patients than need them. Drug makers make more than half of their sales and the majority of their profits in the United States and drug side effects are one of the leading causes of deaths in this country, critics say.

The one drug that is known to protect the heart is aspirin, Dr. Fendrick said. All other painkillers are now under suspicion, he said.

But Dr. Garret FitzGerald, chairman of the University of Pennsylvania’s pharmacology department and the first to speculate that drugs like Celebrex and Vioxx could be uniquely hurtful to the heart, said he simply did not believe the announcement.

The heart problems found in the study have not been examined by a panel of heart experts or statisticians, Dr. FitzGerald noted. Such a vetting could change the results substantially, he said.

“It’s much too early from the information provided to know if this is a meaningful result or not,” he said.

Indeed, those making the announcement yesterday cautioned that the results were preliminary. Researchers decided to stop the trial because news of problems with Celebrex had led many of the patients to threaten to drop out. Researchers had long known that those given naproxen in the study had a somewhat increased risk of heart problems, but that increased risk is not what led them to stop the study, said Dr. John Breiten of the University of Washington.

“The safety data for some time has been giving a weak signal of possible increased risk of cardiovascular and cerebrovascular problems with naproxen,” Dr. Breiten said.

A safety committee overseeing the trial met as recently as Dec. 10 and decided that the results were not worrisome enough to stop the trial, Dr. Breiten said. Only when last week’s widely publicized test of Celebrex found that that drug could more than triple the risk of heart disease did the researchers decide to end the study and issue their warnings about Aleve, even though Dr. Breiten said that the increase in heart risks may not prove to be statistically significant with further analysis.

A Bayer spokesman had no comment.

Dr. Breiten said 70 people experienced heart attacks or strokes, but he would not give numbers for each drug group, saying those numbers would probably change with further vetting.

Dr. Elias A. Zerhouni, director of the National Institutes of Health, said that making a decision to suspend a trial is far different and far easier than making regulatory decisions about those drugs. In the case of the Alzheimer’s trial, patients were taking the medicines simply in hopes of preventing a disease, not because the medicines were providing a needed benefit.

It is very different advising patients who need such medicines to solve their pain, Dr. Zerhouni said.

http://www.nytimes.com/2004/12/21/opinion/21goozner.html?oref=login&pagewanted=print&position=
December 21, 2004
OP-ED CONTRIBUTOR
Overdosed and Oversold
By MERRILL GOOZNER

IN the early 1960’s, Congressional hearings on skyrocketing drug prices went nowhere. But the political logjam was broken when a eagle-eyed doctor at the Food and Drug Administration averted a potential disaster by advising the agency not to let thalidomide into the United States market.

While the final legislation back then had little to do with prices or safety, the new law ushered in efficacy testing and led to the withdrawal of hundreds of drugs of no medical benefit from the market.

Once again, an agency badly in need of reform faces growing popular outrage over drug safety. The F.D.A.’s failure to spot the warning signs that popular painkillers like Pfizer’s Celebrex or Merck’s Vioxx increased the risk of heart attacks, or its failure to warn doctors and parents about the risk of suicide among children taking antidepressants, has resulted in bipartisan anger on Capitol Hill. Prominent voices have joined the call for an independent drug safety board.

But reform at the F.D.A. needs to go much further if it is to once again become the gold standard of medical oversight not just for consumers but for providers and insurers. Only an updated regulatory system can provide them with the information they need to come up with the right answers.

People confront dizzying choices in health care every day: are brand-name drugs better than generic versions? What are the real costs and benefits of a medical intervention? How serious are the side effects of a drug and how do its benefits compare to, say, losing 30 pounds or going for 10 sessions of therapy? Does an expensive new imaging system or test really provide doctors with critical information?

To make rational choices, doctors and consumers need the F.D.A. and other agencies to be independent arbiters of not just the safety and efficacy of new drugs and devices, but of their relative medical usefulness and economic viability. Moreover, the medical oversight system needs a new ethic – one that scrupulously adheres to a standard that says its studies and decisions have been made entirely free of commercial bias and conflicts of interest.

Sadly, that is very far from the situation today. Drug and device companies sponsor most clinical trials; F.D.A. advisory panels are larded with scientists tied to private companies; corporate user fees help finance the F.D.A. that is conducting reviews; doctors get most of their medical information either from sales representatives of drug companies or corporate-sponsored continuing medical education; and the companies are given primary responsibility for post-marketing safety surveillance of their own products.

To break these ties, there needs to be an independent arm of F.D.A. that contracts with independent clinicians and scientists for the final testing of all new drugs and medical devices. After a company submits its drug application based on safety and early efficacy trials, this arm would design the protocols to learn not just if the new drug is effective versus a placebo, but how it compares to other therapies and how it can be most effectively used. At the same time, the F.D.A. agency would need an adequately financed post-marketing system that would follow through on a drug’s safety, using information and financing independent of the drug manufacturers. It should also reimpose the pre-1997 restrictions on direct advertising to consumers, one of the elements that led to vast popularity of Celebrex and Vioxx among arthritis patients.

Congress should also set up an independent agency for conducting comparative trials for thousands of existing therapies. This new center, perhaps housed at the National Institutes of Health, would also evaluate the cost-effectiveness of new technologies and finance the work of scientists who want to test older, off-patent medicines for new uses. And it could oversee the creation and updating of clinical practice guidelines free from commercial sponsorship so that hospitals and doctors can base their decisions on objective evidence.

This new center could also be the data bank for registration of all clinical trials, whether conducted by the public or private sector. This should include the trials’ initial goals, the final results and reasons for stopping the trial if that occurred.

The medical profession also has to play a role. It should adopt strict ethics rules that limit the access of drug representatives to doctors’ offices, and ban the growing practice by medical institutions of accepting donations from drug makers for continuing-education courses.

Unless the entire oversight system is overhauled, there will be many more fiascos in which risks or long-term side effects are played down or ignored, as they were with Celebrex and Vioxx. Not until the system of medical approval and information is returned to objective hands will doctors and consumers be able to make the wisest and most cost-effective medical choices.

Merrill Goozner, director of the Integrity in Science project at the Center for Science in the Public Interest, is the author of “The $800 Million Pill: The Truth Behind the Cost of New Drugs.”

Copyright 2004 The New York Times Company

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