Holes in U.S. Drug Safety Net

Consumer Reports: Drug Approval, Follow-Up 'Flawed'

http://www.webmd.com  

Once touted as the world’s most rigorous drug regulator, the FDA is now being scrutinized by congressional committees and the Government Accountability Office for possible regulatory lapses.   
The agency’s transformation started in the 1980s, when AIDS and cancer activists pushed for quicker access to potentially life-prolonging drugs for severely ill patients. But that acceleration was subsequently applied to all medicines, including those for problems that aren’t life-threatening as well as for “me too” drugs, which offer little or no advantage over existing medicines whose risks are well known.

In 1992 Congress passed the Prescription Drug User Fee Act (PDUFA), which forced a sea change at the FDA. The law imposed tight deadlines for drug evaluation and required companies to pay fees earmarked for hiring more reviewers. In fiscal year 2004 the FDA collected some $250 million from drug companies, almost half of its drug-review budget. That year, the agency boasted in a report to the president and Congress that “drug-approval time has been cut almost in half” since the advent of PDUFA.

Current deadlines require that reviews be completed within 10 months for standard drugs, compared with an average of more than 20 months before PDUFA; priority drugs, including at least two high-risk medicines on our list, Celebrex and Zelnorm, are assessed in 6 months. The FDA maintains that it hasn’t lowered its standards. But even with the extra reviewers, meeting the deadlines can be difficult.  “With the clock ticking, you did the best you could,” says Elizabeth Barbehenn, Ph.D., a drug reviewer at the FDA’s Office of New Drugs for 13 years before leaving in 1998 for the nonprofit Public Citizen Health Research Group. “It was extraordinarily frustrating.”  Close to 20 percent of FDA reviewers say they “have felt pressured to approve or recommend approval” of a drug despite “reservations about its safety, efficacy, or quality,” according to a 2003 survey of some 400 agency reviewers by the Department of Health and Human Services’ inspector general. Fewer than one-fourth of the 400 indicated that the “work environment” allowed “expression of differing scientific opinions.” The accompanying report concluded: “Workload pressures increasingly challenge” the effectiveness of the review process.

Cruzan, the FDA spokeswoman, said the agency has recently taken several steps to improve communication on scientific disagreements within the agency. For example, investigators as well as drug sponsors can now contact an “ombudsman for dispute resolution on procedural issues regarding reviews,” she said.  But the data with which FDA reviewers work aren’t always the best. Federal law allows drug makers to submit as few as one clinical trial plus confirmatory evidence. Typically companies need show only that their product works better than a placebo, rather than an established drug, to achieve an effect that may have little relevance for patient outcomes, according to an opinion piece in the September 8, 2005, issue of The New England Journal of Medicine. Such a “minimal standard” would be “unacceptable anywhere else in research,” the piece said.

Some of the studies, involving drugs that will be taken for decades, last as little as a few months, said Marcia Angell, M.D., former editor-in-chief of The New England Journal of Medicine, by e-mail. She added that drug companies typically recruit patients who are younger and healthier than those who would ultimately use the drug. Such patients “are less likely to experience side effects,” Angell said.

POWERLESS AFTER APPROVAL

While longer, more realistic studies and tighter scrutiny should theoretically detect more risks before approval, some hazards will unavoidably emerge only after drugs are used by a larger group of consumers. Monitoring such “postmarketing” drug reactions is therefore critical.

But the FDA lacks the legal authority to force companies to do the necessary research. In a report in the Federal Register in February 2005, the agency noted that companies had committed to conducting 1,191 postmarketing studies of approved drugs. But 68 percent were still “pending” as of late September 2004, meaning they hadn’t been started.

Many of those studies were pending for good reasons, Goldhammer says, notably difficulty lining up research sites and recruiting patients. But Randy Juhl, Ph.D., a former dean of the School of Pharmacy at the University of Pittsburgh and a former FDA advisory panel member, says the drug companies’ failure to meet post-marketing study commitments shows that they “do not take these responsibilities seriously.” The FDA should ask Congress “for additional enforcement power,” possibly an “umpteen-million-dollar fine per day” to get the studies done, he says.

An injection of resources may be equally important: The FDA’s Office of Drug Safety, which monitors adverse reactions to a medication after approval, is one-tenth the size of the agency’s Office of New Drugs, which handles the original approval process. And the new-drug office, not the safety office, has the final say about post-approval safety concerns.

That’s a bad setup, says Eric J. Topol, M.D., chairman of the department of cardiovascular medicine at the Cleveland Clinic and a former FDA advisory panel member. New-drug officials who approve the medication in the first place are, in effect, “champions of the drug,” he said. “They cannot be objective” if safety issues arise after it’s marketed, he added.

Cruzan, the FDA spokeswoman, said by e-mail that the agency has asked the National Academy of Science’s Institute of Medicine to study “the effectiveness of the nation’s drug-safety system,” emphasizing the post-market phase. The report may suggest structural changes at the FDA’s Center for Drug Evaluation and Research, the agency said in a statement released in November 2004. But the results are not expected until the summer of 2006. As we went to press, the FDA proposed modestly reorganizing its drug-safety office, but few details were available.

David Graham, M.D., associate director for science and medicine at the FDA’s Office of Drug Safety, testified before a Senate committee in November 2004 that officials in the new-drug office had made clear that his department should not offer recommendations that contradict their department. He said, too, that senior management in his own office pressured him to change his conclusion that high doses of the pain reliever Vioxx increased the risk of heart attack.

The FDA immediately issued a denial, stating that Graham’s testimony “does not reflect the views of the agency.” Drug-safety scientists have “independent authority,” and “when drug safety issues are identified, they must be factored into the risk-benefit equation,” the statement said.

weakness about warnings

The FDA cannot force companies to add newly emergent risks to drug labels. “I think it’s unconscionable,” says Arthur Levin, M.P.H., director of the Center for Medical Consumers in New York City, a nonprofit advocacy organization. “We want the FDA to get stricter about this stuff, but we don’t give them the means to enforce their decisions.”

Six of the 12 high-risk drug types we identified had no black-box warning, the strongest kind, when we went to press, though in most of those cases the FDA should request that warning, says Marvin Lipman, M.D., chief medical advisor for Consumers Union, the publisher of Consumer Reports. In February 2005 an FDA advisory committee recommended severe warnings about the two eczema drugs we cited, Elidel and Protopic, because of a possible increased risk of cancer. The agency issued a public-health advisory a few weeks later and requested black-box warnings, but as of October 2005, neither drug manufacturer had made the change. Representatives of both companies say their research shows no need for the severe warning, though they were still discussing it with the FDA as we went to press.

For complete Ratings and recommendations on appliances, cars & trucks, electronic gear, and much more, subscribe today and have access to all of ConsumerReports.org.

INDUSTRY Bull Shit

Alan Goldhammer, Ph.D., associate vice president for regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA), the industry’s leading trade group, says that companies are not “automatically looking for patients who are going to be the best responder” and that studies are conducted “after discussions” with the FDA.     {Notice that he admits to this practice of searching for those who will show less side effects.  And what does discussion with the industry friendly FDA make their various violations of scientific objectiveness permissible?  The fundamental problem lies with our two party system that receives 10s of millions of dollars from the drug companies.  They have consistently appointed industry executives to the top post in the FDA, and he has selected similarly minded people to run the FDA various departments--jk}

There are dozens in related articles our healthfully.org site verifying the abuse of the medical profession by the for profits pharmaceutical system.  It isn’t how good things are, but rather how much better they ought to be.  In fact they aren’t that good.  The United States has the most expensive medical system in the world, yet rates only 37 as far as services. 

“A survey by the World Health Organization in 2000 placed America first in terms of total spending on health (at $3,700 per year), but only thirty-seventh in terms of service.”

John Micklethwait & Adrian Wooldridge, The Right Nation , 2004, p. 305

Similar report in Webmd based on Consumer Report article.

Holes in U.S. Drug Safety Net

Consumer Reports: Drug Approval, Follow-Up 'Flawed'

http://www.webmd.com  

Dec. 5, 2005 - Millions of Americans unknowingly risk rare but serious drug side effects, Consumer Reports says.

In its January 2006 issue, the independent consumer magazine points to a dozen common prescription drugs linked to serious risks -- including death. These risks, the article says, were "undetected or underestimated when the FDA approved them for use." The issue isn't these 12 drugs. For people who need them, their benefits outweigh their risks. What's flawed is the U.S. drug safety system, says Marvin M. Lipman, MD, chief medical advisor for Consumers Union and emeritus professor of medicine at New York Medical College, Valhalla. "This is a report that criticizes not only the preapproval process, but also the postapproval surveillance system," Lipman tells WebMD.

System Geared for Approval

Once upon a time, the FDA was very slow to approve new drugs. That changed in the early '90s, when Congress passed the Prescription Drug User Fee Act (PDUFA). The law gave the FDA deadlines for making approval decisions. In return, it charged drug companies fees used to hire new drug reviewers.

The Consumer Reports article quotes a former FDA reviewer as saying that the tight deadlines were frustrating. Indeed, a 2003 HHS survey found that 20% of FDA reviewers said they felt pressured to recommend approval despite reservations. "The relationship of the FDA to the pharmaceutical industry has to be examined very closely," Lipman says. "Under the PDUFA law, a lot of money is paid by the drug companies to have their drugs reviewed. There is something inherently bad about that. It doesn't smell right."  {This is like having all the judges salaries being paid for by large corporations, and then having the chief judges at all levels be former CEO’s—jk}

Drug Industry Reaction {Their mouthpiece deny there is a problem—jk}

Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA), says PDUFA fees improve drug safety. "PDUFA has raised hundreds of millions of dollars for FDA in a time when Congress has approved only stagnant funding, even though regulators' duties have expanded dramatically," Trewhitt tells WebMD. "PDUFA money is also being used to increase staffing in the Office of Drug Safety at FDA. It's recently allowed FDA to double the number of safety officers from 100 to 206 officers."  And Trewhitt notes that fewer than 3% of drugs are withdrawn from the market due to safety concerns -- a rate that hasn't changed since PDUFA took effect. Laurence B. Gardner, MD, chairman of the department of medicine at the University of Miami Miller School of Medicine, agrees with most of the points made by the Consumer Reports article. But he says the FDA's preapproval process isn't the problem. {The very program of funding was drawn up by the Pharmaceutical industry and approved by Congress in 1990--jk}

"Consumer Reports implies that people at the FDA rush approvals through and don't look at safety data," Gardner tells WebMD. "But we are still the safest country in the world when it comes to drug approval. That being said, there are a lot of issues with our health care system. And current regulations don't protect the consumer."  (This is incorrect, for England, Finland, and others have a better record—jk)

Consumer Reports: Drug Approval, Follow-Up 'Flawed'

When the FDA approves a drug, it sometimes ask {not require} the manufacturer to conduct further safety studies. Consumer Reports notes that in February 2005, companies agreed to 1,191 such studies. Yet as of September 2005, more than two-thirds of the studies were still "pending."   The most important drug-safety experiment comes in the years following drug approval. The subjects of this study: consumers who take the drug.  Preapproval studies enroll no more than a few thousand people -- usually healthier people than many of those who will take the drug after approval. And the studies usually last only a few months. Rare side effects, problems for people with multiple conditions taking multiple other drugs, and long-term side effects can only be seen in the years following approval. And that, Lipman says, is where the U.S. system breaks down. Doctors are supposed to report any side effects that happen. But because there is no reliable system -- and, Gardner says, because these reports aren't easy to file -- only a small fraction of side effects actually get reported. Compounding this problem, Lipman says, is direct-to-consumer advertising. Ads heavily promote new drugs. Yet there's a drug risk associated with every drug benefit. And the Consumer Reports article states the ads stress benefits but don't adequately identify risks.  "It is impossible to monitor all the ads that are out there," Lipman says. "And more ludicrous, the ad goes into the media, and it takes FDA  three to six months to catch up with the ad. By that time, the damage is done. You need an approval system before, not after the ads hit the media. They should submit copy for vetting by the FDA, and the FDA needs resources for this. They don't have the personnel or the money."  {The industry spends twice as much on advertising as it does research—jk}

The Consumer Reports article notes that PhRMA in August 2005 announced guiding principles for direct-to-consumer ads, including a wait before advertising new drugs. As of November, the article reports, most of PhRMA's 33 members had signed on.

Independent Drug Safety Board Needed?

Currently, the FDA's drug-safety office is one of 12 subgroups reporting to the director of the FDA's Center for Drug Evaluation. It's been lacking a permanent chief for some time.  Lipman says there should be a drug safety office -- with regulatory teeth -- outside the FDA. "What is really needed, in our opinion, is an independent office of drug safety: nonbiased safety experts not part of either the pharmaceutical industry or the FDA," he says. "The same people can't be responsible for drug approval and drug safety. It just makes it that much harder for a drug to be withdrawn by the people who approved it."

Gardner {industry mouthpiece} isn't so sure. He thinks that a drug safety office would be no better than the expert advisory panels that currently advise the FDA. Instead of a new layer of bureaucracy, he would like to see more power given to these panels of experts. PhRMA's Trewhitt doesn't see the need for any of this. "Simply put, the FDA still has the world's best drug safety record," he says.  {Bull shit, and the issue isn’t how many died or were improperly treated, but how to lower the deaths and mistreatments even further.-jk}

Institute of Medicine to the Rescue

Lipman, Gardner, and Trewhitt {the industry mouthpieces} all praise one thing about the FDA. The agency already has asked for help. Last year, it turned to the independent Institute of Medicine (IOM) for advice. An IOM committee has since been holding hearings. Its recommendations are expected in July 2006.  "The FDA has asked the IOM to thoroughly investigate the drug safety system," Trewhitt says. "It would behoove us to wait to see the results."  Lipman says it's already time for Congress to act.  "We are getting to where this is a problem for our government," he says. "There have to be some bills written that would address some of these problems and that would create a better workforce for the FDA, and that would give them more monetary resources so they don't have to rely on pharmaceutical company fees to process new drugs. Basically the buck passes back to our Congress."

Gardner says the problem goes far beyond the FDA. The real issue, he says, is health care in America. "Our health care system is in real trouble," Gardner says. "This is an example of a real problem where we don't have the politics yet to create a solution."  

Those 12 Drugs

The Consumer Reports article lists 12 drugs as examples of safety-system failures. "These drugs are just examples," Lipman says. "There are bound to be others. Even a perfect safety system could never detect every problem of every drug."

The drugs are:

• Celebrex
• Estrogen, either alone (Premarin and others) or with progestin (Prempro and others)
• Accutane
• Ovide
• Depo-Provera
• Lariam
• Crestor
• Serevent
• Meridia
• SSRI antidepressants and other antidepressants
• Zelnorm
• Topical immunosuppressants such as Elidel and Protopic

Do not stop taking these drugs if you're using them, Consumer Reports warns. The drugs are helpful for people for whom the benefits outweigh the risks.  "These are important drugs. They are very useful drugs," Lipman says. "But in many cases they are not the only drug for the condition. And the patient should know that by taking one of these drugs there is a certain inherent risk, and the patient should be aware of this risk." Lipman advises patients using these drugs to talk with their doctors about whether there is another drug that can be used with less risk. And all patients taking any drug should be aware of possible side effects and should tell their doctors about any ill effects -- even those not listed on the label.

SOURCES: Consumer Reports, January 2006; pp 34-39. WebMD Feature: "How Safe Are America's Medicines?" FDA web site. IOM web site. PhRMA web site. Marvin M. Lipman, MD, chief medical advisor, Consumers Union; emeritus professor of medicine, New York Medical College, Valhalla. Jeff Trewhitt, spokesman, Pharmaceutical Research and Manufacturers of America (PhRMA). Laurence B. Gardner, MD, vice dean, medical school, and chairman, department of medicine, University of Miami Miller School of Medicine.