Bloomberg News announced, “AstraZeneca’s Crestor slashed the risk of heart attack, stroke and death by nearly half in people with normal or low cholesterol in a study, potentially opening a way to save the lives of thousands seemingly healthy people.” MSNBC News made the same announcement and then quoted the president of the American College of Cardiology: “This takes prevention to a whole new level.” Ron Winslow of The Wall Street Journal added, “The findings could substantially broaden the market for statins, the world’s best-selling class of medicines.” Except for USA Today, which worried about the high cost to patients, health plans, and the public, most announcements read like infomercials, excited about a major new market.

In short, this “pathbreaking” study that “takes prevention to a whole new level” actually offers little benefit and offsets it with a costly side effect.

These news headlines referred to a large clinical trial published on November 20^th in the New England Journal of Medicine that purported to demonstrate the effectiveness of Crestor—even on older patients with low cholesterol who scored high on a test for CRP, or C-reactive protein. CRP levels are used as an imprecise indicator of heart disease, though the molecule is “a nonspecific marker for low-grade inflammation,” according to Dr. Bernadine Healy, an adviser to U.S. News and World Report.

Almost no one learned that the “slashed nearly in half” reduction in cardiovascular trauma was tiny, from 1.36 percent to 0.77 percent, a difference of just 0.59 percent.

And almost none of the stories reported that the people taking Crestor had a comparable increased risk (0.60 percent) of getting diabetes. Those that did said the increase was “small,” but then so was the reduction in cardiovascular events. Suppose newscasters announced, “Major study finds patients taking Crestor for systemic inflammation experience less than 1 percent reduction in cardiovascular events and an equal increase in diabetes”? In short, this “pathbreaking” study that “takes prevention to a whole new level” actually offers little benefit and offsets it with a costly side effect.

American medicine is rife with such commercial bandwagon tests, procedures, and drugs. An effective policy solution would involve the creation of a comparative effectiveness institute that offered independent evaluations and subjected treatments to head-to-head trials in order to make recommendations about which ones are actually worth the money. President-elect Barack Obama’s health care platform calls for such an entity, and in August, Senate Finance Committee Chair Max Baucus (D-MT) and Senate Budget Committee Chair Kent Conrad (D-ND) introduced the “Comparative Effectiveness Research Act,” legislation that would create a nonprofit institute.

The closer you look, the less beneficial this breakthrough looks. For example, the investigators had screened out 80 percent of their sample so that the trial included only patients with a high CRP but without 13 other prevalent health risks. Those 13 risks include a history of cardiovascular disease, diabetes, arthritis, high blood pressure, cancer, hypothyroidism, or substance abuse. Also excluded were people taking hormone replacement therapy or lipid-lowering therapy.

Put another way, the vast majority of older women and men with low cholesterol and high CRP were excluded because they had conditions that might weaken the results. The trial aimed to select just those people who were most likely to produce a dramatic result but establish the basis for everyone to take the test to see if they have high CRP. If they do, they probably have other risks or behaviors like those people screened out of the trial, so taking Crestor (the most expensive statin) might or might not increase their risk for diabetes and reduce their risk for cardiovascular trauma.

Only a few news stories noted vaguely that Crestor itself has serious side effects. Reports to the FDA of kidney problems from patients taking Crestor exceeded reports for all other statins combined and led The Health Research Group in Washington, D.C. to recommend it be taken off the market. Crestor also lowers levels of CoQ10, a compound that helps generate energy and maintain muscle (including the heart muscle). Fatigue and weakness can result.

Moreover, the trial was stopped with 3.1 years remaining, and it is during this later period of testing when adverse side effects are most likely to surface. Running trials long enough to record benefits but too short to record adverse effects is a common practice in company-sponsored trials. It is one reason why adverse side effects are now epidemic, the 4^th leading cause of death, according to the Food and Drug Administration. As Professor Mark Hlatky at Stanford Medical School wrote in a cautious editorial, “Long-term safety is clearly important in considering committing low-risk subjects without clinical disease to 20 years or more of drug treatment.”

Currently, new drugs “just have to be better than nothing.”

The results of this market-driven trial were reported to the press in a way to get the public as well as the medical profession mobilized to generate large new revenues, thus making the media an agent of commercial interests. No mention was made of the fact that doctors are already prescribing statins to millions of patients to lower their cholesterol when in fact doing so does not reduce cardiovascular risk for those who have no other specific risk. The over-prescription of statins is costing everyone billions. Instead, the news emphasized how statins would now benefit millions more with low cholesterol.

The additional cost to the nation’s insurers, employers, and taxpayers of prescribing Crestor to patients with CRP is estimated to be $9.0-9.7 billion. The reduction of an already small risk would cost about $557,000 per life saved, according to James Stein at the University of Wisconsin School of Medicine and Public Health. That does not include the $80 for the patented CRP test that a much larger population would first have to take, nor the costs of treating new cases of diabetes and other side effects. Yet official guidelines for doctors appear likely to change and recommend the CRP test, whose patent is held by the principal investigator of the trial and his employer, Brigham and Women’s Hospital in Boston.

The main beneficiaries will be the patent-holders and AstraZeneca, the sponsor of the trial. Industry-sponsored trials are nearly 4 times more likely to produce results favorable to the sponsor’s product than independently funded trials, and this one is no exception.

In order to avert future misleading claims about new drugs and to help lower the costs of health care, the country needs an organization like the Comparative Effectiveness Research Institute proposed by Senators Baucus and Conrad. Their bill, S.3408, cosponsored with Senators Jeff Bingaman (D-NM) and Sheldon Whitehouse (D-RI), aims to control costs by improving the effectiveness of treatments used. It would have independent funding to assess the additional clinical benefit of new tests and interventions against their costs in order to get good value for our money.

Currently, new drugs “just have to be better than nothing,” according to Dr. David Barbe, chair of the American Medical Association Council on Medical Service. As Gail Shearer, the director of Consumer Reports’ Best Buy Drugs website and service said, “People are ready to talk about value.” The CRP-Crestor trial and bandwagon illustrates why an institute like this is a vital part of any health care reform under the new administration.

Donald W. Light is a professor of comparative health care at the University of Medicine & Dentistry of New Jersey and a senior fellow at the Center for Bioethics, University of Pennsylvania. His forthcoming book, The Risks of Prescription Drugs, will appear in bookstores this winter.

Basic Books

Change for America: A Progressive Blueprint for the 44th President

Change for America is a joint project between CAP’s sister organization, the Center for American Progress Action Fund, and the New Democracy Project, and offers recommendations for the next president and administration on priorities for a broad swath of executive branch departments and offices. Cox spent nearly a decade at FDA and the Department of Health and Human Services, and is now senior vice president at the Consumer Healthcare Products Association. Her recommendations focus on restoring the reputation of this embattled office, which has lost more than 1,000 scientists over the past few years in the face of insufficient funding and a mushrooming workload. Here’s a look at some of the key guidance she offers:

Increase Funding and Recruit and Retain a Workforce That Can Keep Pace With New Technological Demands

“Less than 4 percent of [the FDA's] workforce is under 30 years of age, and 44 percent are over 50,” she explains. “Almost 50 percent of its managers and supervisors are eligible for retirement in the next five years.”

Protect the Food Supply

The agency released a comprehensive Food Protection Plan in November 2007, but in the intervening year, the Bush administration declined to request funding for implementation. Cox recommends that the president-elect and his transition team work with Congress to appropriate the necessary funding and give FDA the necessary authority to implement the plan. Moreover, FDA should implement science-based controls for food safety monitoring and require that manufacturers can regularly assure the FDA that they are producing safe products. Food safety is important to avert contamination like the salmonella outbreak of this year, and the potential for a bioterrorism attack on the food supply is all the more reason to act.

Improve Drug Safety

The new administration must, within its first year in office, make sure that the FDA implements plans to conduct more thorough postmarket monitoring to ensure that drugs are still safe after they’ve gone on sale to the public.

Reduce Risk From Abroad

“A recent GAO report showed that 80 percent of all drugs sold in the United States are made, in whole or in part, overseas,” Cox writes, and FDA needs to make sure that those pharmaceuticals and other products are safe before they enter the United States. “The new administration will need to develop and implement a comprehensive risk-based approach to overseeing foreign inspections.”

Long-Term

Beyond the first year in office, Cox argues that FDA must set up protocols to ensure the safety of products made from cloned or genetically engineered animals (an issue Rick Weiss has covered here and here). As well, the agency must adapt to assure the safe and environmentally-friendly use of nanotechnology (see Weiss’s coverage here and here) and monitor the judicious application of genomic research for personalized medicine (Weiss, again).

Finally, FDA has an important role to play in addressing the deceleration of drug development through its Critical Path Initiative, which is designed “to help modernize the drug-development system by creating a process to identify new critical therapies, to prioritize innovation, to work with the nongovernmental scientific community, and to streamline processes,” but requires administration support to move forward with a more detailed plan.

For full listing of chapters in the book, including several that are available for download now, in advance of the January 5 release, visit the CAPAF project page.

According to their annual reports, Merck’s net profits have been steadily declining since 2002, and Pfizer experienced a sharp 29 percent drop in net profit in 2007. Eli Lilly, however, has enjoyed a steady increase in net profit since 2004.

Interestingly, Pfizer’s pharmaceutical revenues have actually increased by 11 percent since 2003—the drop in profit has been due to a 28 percent increase in costs. Merck’s situation is similar: since 2002, revenues have increased by about 11 percent, but costs have skyrocketed 32 percent.

Part of the problem may be that the number of new drugs approved by the Food and Drug Administration for Merck and Pfizer has dropped dramatically in recent years. The Wall Street Journal cited increased concern for consumer safety as a reason the FDA is approving fewer and fewer drugs each year.

So is this why these once cut-throat competitors are now joining forces? Perhaps, but don’t forget that all things considered, the pharmaceutical industry is not exactly suffering. Merril Goozner reported in January 2008 that the sector had the highest profit margin, 20 percent, of various other profitable industries, including gas and oil, during the first nine months of 2007. Perhaps the formation of a joint company is the start of a new era for pharmaceutical companies, but either way, we can be sure that drug companies will continue to prosper for many years to come.

This U.S. policy development is of special concern to Russians, as an increasing number of U.S. pharmaceutical companies conduct their drug trials in Russia, which currently lacks extensive regulations. Merrill Goozner is currently reporting on that country’s health care system, which he explains has the potential to become “ground zero” in the discussion over the FDA’s withdrawal from the Declaration.

Russian health care and longevity has fallen dramatically since the end of communism, and in some areas is just now starting to recover. In some of the most rural parts of Siberia, the first health clinics are just now being built. Even with the recent improvements, the lack of regulations regarding pharmaceutical companies conducting trials concerns Sergey V. Smirnov, the Russian director of the nongovernmental organization, Community of People Living with HIV. Goozner spoke with Smirnov for Scientific American about his activism on the regulation of pharmaceutical trials:

Two years ago, Smirnov joined an informal working group of scientists and bioethicists in drafting legislation designed to beef up clinical trial patient protections. Among backers: representatives of the Russian government’s Bioethics Commission, the Russian Academy of Sciences, and the local UNESCO office.

The legislative draft would give the government power to require greater disclosure of sponsors of and participants in clinical trials. It also provides a framework for protecting the patient privacy and safety in the trials, including requiring that they give their (noncoerced) consent to participate.

Smirnov hopes that the bill will be voted on sometime this year, remedying the current lack of effective regulations for clinical trials.

The decision by the FDA to withdraw from the Declaration of Helsinki has evoked much criticism, both at home and abroad. In recent years, the FDA has noticed that even with the Declaration in effect, many international drug trials run by American pharmaceutical companies are not reported until after they are conducted, and as such, the FDA cannot regulate them. The new guidelines may be an attempt to reassert control over these pharmaceutical companies, rather than rely on international law. By relaxing the rules, the FDA may either encourage more international drug trials—and therefore increase the number of drug trials that go unreported and unregulated—or it may find that companies are more likely to adhere to the slightly lower testing standards.

• 20 percent of respondents report using medications to increase memory retention, concentration or focus.
• 60 percent of those who admitted non-medical use of cognitive-enhancing drugs used Ritalin.
• 44 percent of the admitting respondents used Provigil, known generically as modafinil.
• 15 percent admitted use beta-blockers.
• 9 out 10 respondents said they used the drugs to improve concentration and attention.

Science Progress advisory board member Martha Farah expressed concern about the ethical use of brain-enhancing drugs during a Seed Magazine-sponsored briefing on the Hill last month:

If higher productivity can come in a harmless pill, Farah wondered if workers might find themselves saying one day, “I want this job, but I don’t want to have to take a drug to get it.”

If Wired’s coverage is any indication, her concerns may already be manifest in some workplaces. In a recent edition of the magazine’s Mr. Know-It-All column, a reader asks the following question:

One of my coworkers, a rising star at the firm, is using unprescribed modafinil to work crazy hours. Our boss has started getting on my case for not being as productive. Should I tell him about my coworker’s pharmaceutical enhancement? Or should I start taking modafinil, too?

The question of what sort of social or governmental rules will govern such ethical choices about brain enhancement remains unanswered, but it’s obvious that deliberations have already begun.

According to the panelists, off-label can increase the risk of joint pain, carpal tunnel syndrome, and even cancer. Specifics about HGH’s athletic benefits are still unknown because little clinical data exists on the subject and the few related case studies involve athletes using HGH in conjunction with steroids, making it difficult to link performance enhancement to HGH alone. Committee Chairman Henry Waxman (D-CA) cited a 2007 Stanford study which concluded that “HGH could not be recommended as an anti-aging therapy.” Yet the market for HGH anti-aging therapies continues to grow, raking in two billion dollars in sales last year. Panelists also pointed out the lack of physician supervision for off-label users means they may not know the correct doses, leading to the risk of acromegaly–a serious condition resulting from too much HGH in the body.

Tackling the problem of HGH abuse is difficult in a sports culture fixated on shortcuts and competitive advantages. And reports of use among professional baseball players only compounds the struggle to end steroid use among young athletes. Dr. Alan Rogol, of the University of Virginia and Indiana University School of Medicine, emphasized the importance of raising public awareness about the abuse of performance-enhancing drugs with the results of a startling survey indicating that 3 out of 5 kids in grades 8 through 12 who were using steroids were willing to continue use even if they knew the drugs could shorten their lives.

In light of such statistics, HGH is a public health priority. Panelists suggested developing drug tests that can detect HGH use among professional athletes and further restricting access to the hormone. Today, the the Committee held a second round of testimony on illegal steroid use in Major League baseball.

Exactly what should the public make of genetic tests indicating a predisposition to depression? How can we ensure that medical information about depression does not lead to employer discrimination? Experts tackled these and other issues at a Monday symposium, “DNA and Depression: Tests, Trust, and Treatment,” part of a Johns Hopkins University series of Genetic Perspective on Policy Seminars hosted by the University’s Genetics and Public Policy Center.

Dr. Francis McMahon of the NIMH discussed the research that his team carried out on the genes that predispose patients to having suicidal thoughts while taking Selective Seratonin Reuptake Inhibitors such as Prozac. This research came in the wake of FDA research indicating that SSRIs can can cause a rise in suicidal thinking and behavior in adolescents; the Agency subsequently mandated “black-box” warnings on the medications. Dr. McMahon also noted that these types of drug side effects can be minimized as personalized medicine, which is based on a patient’s personal genome information, becomes standard practice. In the near future, doctors may be able to recommend preventative treatments based not just on family history, but on indicators found in a patient’s own genome.

“Everyone has predicted that the complete genome will be part of your medical record in five years or so,” McMahon said. However, as private companies offer to decode and interpret the genomes of consumers, doctors will no longer be the sole gatekeepers of genetic information. “We don’t have a monopoly on the information anymore,” McMahon affirmed.

While genome sequencing is not currently a part of regular mental health diagnoses, Kim Bechthold, CEO of Neuromark, which develops diagnostic tools to help doctors determine if SSRIs pose a risk for their patients based on their genomes, explained that surveys show that “patients and consumers trust genetic tests,” which means that “we have a very exciting and very challenging task” in trying to accurately convey genetic information to doctors and patients. She explained that the public trusts genetic diagnosis more than they trust diagnoses based on lifestyle, environmental factors, and socioeconomic status.

Bechthold also stressed the need to protect patient privacy with regard to genetic information and added that Congress must pass the Genetic Information Nondiscrimination Act in order to prevent employer discrimination against employees at risk for ailments—mental health or otherwise. “Without GINA…preventative medicine is simply not going to get off the ground,” she said.

The University of Virginia is home to a Johnson & Johnson-funded study on Topamax’s ability to treat alcoholism. The Health Blog describes claims from the Public Citizen’s Health Research Group, which says that the University of Virginia, where the study took place with funding from J&J, put out a press packet that encouraged doctors to prescribe the medication off-label. Doctors can prescribe drugs off-label for uses not formally approved by the Food and Drug Administration, but drug makers cannot advertise or promote these alternative uses. The Health Blog also notes that the scientist who led the study at UVA, Bankole Johnson, chairman of UVA’s Department of Psychiatric Medicine, has financial ties to J&J.

In their main article on the study (subscription), The Wall Street Journal relays Dr. Johnson’s comments about how the current drugs used to treat alcoholism are only prescribed after a person stops drinking or goes through detox. According to Johnson, a drug like Topamax is a welcome development because it can be introduced while a person is still drinking.

The Wall Street Journal also reports that a spokeswoman for Ortho-McNeil Neurologics, the J&J subsidiary that produces Topamax, says they have no intention of submitting the drug for FDA approval as a treatment for alcoholism. And in an article by MedPage Today, they quote a UVA spokeswoman:

“We are not suggesting a go-ahead for doctors, but we are stating a fact,” said a spokesperson. “Doctors who are interested are allowed to prescribe it. No off-label use is being proposed, advocated, or promoted.”

Looking a bit deeper into the specifics of the scientific methodology, Mark Willenbring, doctor at the National Institute on Alcohol Abuse and Alcoholism, commented in an editorial in The Journal of the American Medical Association that accompanied Johnson & Johnson’s paper on Topamax that alcoholic subjects who volunteer for a study such as this one are self-selecting, whereas many alcoholics who undergo specialty treatment are coerced by judges or employers. This self-selecting group mostly closely resembles patients likely to be seen in primary care where pharmacotherapy would be most appropriate.

The New Scientist goes into some detail about how much the patients actually improved and how the drug works by blocking the brain-chemical (or neurotransmitter) dopamine; the piece is more optimistic than The Wall Street Journal.

A letter to Food and Drug Administration Director Andrew von Eschenbach from Sidney Wolfe, MD of the Public Citizen’s Health Research Group, emphasizes the current FDA warnings that caution against taking the drug with alcohol and calls attention to the statistically significant increase in side effects mentioned in the study such as dizziness and trouble concentrating.

Although the results of the study look promising, the side effects seem substantial and even the authors admit that there was no follow-up to determine whether the patients relapsed.

The findings aren’t necessarily hype, but Public Citizen is right to call attention to the fact that FDA approval is more than red tape. Large studies must be done on diverse populations in order to ensure safety and effectiveness and assess the overall risk-benefit relationship. That’s why Topamax remains off-label for alcoholism treatment and should remain so until the FDA approves it. Although it may be worth asking whether news coverage of the study and controversy itself may spur more patients or doctors to consider off-label use.