Medical Progress Today
  Volume 2, Number 7
  February 18, 2005


In the Spotlight

The New Frontier for Drug Safety
Personalized Medicine


Gualberto Ruaño, M.D., Ph.D., Robert Goldberg, Ph.D., Center for Medical Progress, 2-17-05

It is now clear that the needs of the pharmaceutical industry, the FDA, and the public at large for improved drug safety can be addressed with personalized medicine in ways that the current "one size fits all" model could not even begin to reach.

Continue reading . . .


Featured News:
FDA Establishes Board to Review Approved Drugs - Steps on Safety Monitoring Follow Concerns Over Vioxx; Critics Question Autonomy
Wall Street Journal, 2-16-05
Featured Commentary:
Medicating the FDA
Henry Miller, M.S., M.D., Washington Times, 2-17-05
Featured Research:
Detection of Bladder Cancer Using a Point-of-Care Proteomic Assay
H. Barton Grossman, MD, The Journal of the American Medical Association , 2-16-05

News

FDA Establishes Board to Review Approved Drugs - Steps on Safety Monitoring Follow Concerns Over Vioxx; Critics Question Autonomy
Wall Street Journal, 2-16-05

The FDA has said that it intends to create a new Drug Safety Oversight Board “to review safety issues that arise in drugs already approved by the agency.”

“The board, expected to consist of FDA and other government officials, will be charged with making recommendations to the agency if it thinks action is needed, but will lack the authority to pull drugs or change labeling. It also is to recommend when the agency should alert consumers about potentially problematic drugs at an early stage, through a new Web site.”

Anything short of an independent drug safety agency will undoubtedly fail to satisfy some agency critics. Still, the real question isn’t the autonomy of the oversight board, but the quality of the information that the FDA collects - or doesn’t collect. This is a critical problem because, as Scott Gottlieb has argued, the FDA is still a veritable dinosaur when it comes to utilizing information technology.

While the jury is still out on the effectiveness of the FDA’s proposed safety board, it isn’t too early to start improving the agency’s datamining technology and creating a more effective adverse event reporting system. That structure will ultimately determine the success or failure of the FDA’s drug safety efforts, no matter what name we call it.

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What Makes a Drug Too Risky? There's No Easy Answer
Wall Street Journal, 2-16-05

Pharmaceuticals can pose serious risks for a very small numbers of patients - perhaps just a handful of patients out of thousands or even millions. Does that make them unsafe?

Unlike pharmaceuticals, we have safety rules for cars, alcohol and many other consumer products that don’t necessitate product withdrawals every time there is an unfortunate accident. However, when it comes to drug safety, scientists often lack the ability to do anything other than identify a potential risk (for instance, heart attacks), let alone identify the precise cause of it. For instance, even when a given drug is only dangerous for very small numbers of people “medical science can’t definitively rule anybody in or out of danger.”

“At the same time, there are risks for not being treated. Many experts credit a rise in use of Paxil, Prozac and other antidepressants known as SSRIs for a 25% reduction in teenage suicides in the past 10 years…Failure in school and criminal behavior are among possible outcomes for kids whose attention disorders go untreated while switching pain relievers can also mean trading a risk of heart problems for one of gastro-intestinal troubles that can be just as serious.”

However, doctors and patients can navigate this tangled web of costs and benefits if they have access to the right information. Increasingly, personalized medicine will allow patients and doctors to chose therapies from exercise to drug therapy with confidence that they really work based on reliable DNA tests - as opposed to trusting the conclusions of a randomized and highly artificial clinical trial.

Safety is, in the final analysis, defined in a personal context, patient by patient. Anything short of that is just a lucky guess.

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Bush to Retain FDA's Acting Chief - Veteran Administrator Would Be Unlikely to Seek Broad Changes at Agency
Wall Street Journal, 2-15-05

It depends on what you mean by “broad changes.” President Bush has nominated Lester Crawford, the Acting FDA Commissioner, to formally head the Food and Drug Administration at what may be its most troubled era in decades.

Recent drug safety scares have left the agency virtually under siege, accused of becoming too deferential to the pharmaceutical industry and insufficiently concerned about patient safety.

But the chief problems facing the FDA are more scientific than they are regulatory. Controversies from antidepressants, to Vioxx, to Adderall all underscore how little the agency knows about the science underlying adverse events and how to prevent them.

As Gualberto Ruaño and Robert Goldberg argue in this week’s Spotlight, the future of drug safety lies in personalized medicine - developing targeted treatments that are tested and designed for specific subgroups of patients and have significantly increased safety and efficacy profiles.

The FDA can help accelerate the adoption of personalized medicine by embracing new science based regulations that expedite approval for drugs developed using cutting edge genetic science.

Under the current paradigm, the FDA is dependent on large scale clinical trials that might not detect adverse events until tens of thousands or even millions of patients are treated in the real world - years after a drug is first tested and approved.

New pharmacogenomics tests can allow us to spot potential adverse effects early in the drug development process, long before a single patient ever receives the drug. Moving that knowledge from the laboratory to the beside is the challenge facing the industry and the FDA now, and hopefully Commissioner Crawford will help the agency meet that challenge.

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Middle-Class Families Strain Public Health-Insurance Plans
Wall Street Journal, 2-15-05

“More and more middle-class American workers are choosing to enroll their children in taxpayer-funded health insurance programs instead of the more expensive plans offered by their employers. It’s a trend that will cost publicly funded state and federal programs billions of dollars and could eventually force even consumers of private health insurance to pay higher premiums.”

This is a classic government squeeze play. As the government enlarges enrollment in public programs to higher and higher income brackets, its own costs inevitably rise. The government then squeezes health care providers by lowering reimbursement rates and throwing up burdensome regulations that drive up costs even further. Since government costs are capped, private providers pass their losses onto consumers outside of government programs in the form of higher health care costs and insurance premiums.

And then, as insurance becomes ever less affordable for employers and individuals, the government sweeps more and more people into its “safety-net” - an odd definition for a program that tends to hurt everyone who’s not in it.

Manhattan Institute Senior Fellow David Gratzer observed that "with Medicaid enrollment swelling [including the State Children’s Health Insurance Program or SCHIP], some academics have argued that the program is successful - after all, look at all the new recipients. But the reality is that governors across America have loosened eligibility requirements. In Vermont today, for instance, a family earning $51,000 is still entitled to some Medicaid benefits. Indeed, it seems that Medicaid crowds out private insurance, leaving taxpayers on the hook."

Taxpayers are actually on the hook twice: once for their taxes and again for their health insurance premiums. Getting consumers off the hook by introducing market forces into Medicaid would not only lower program costs, it would ensure better health care for low-income Americans.

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States' Bid for Cheaper Medicine Sputters - Official Web Sites for Buying Drugs From Canada Are Slow to Take Off With Consumers
Wall Street Journal, 2-14-05

“With great fanfare, at least nine states over the past year launched Web sites to help their residents buy inexpensive prescription drugs from Canada. But so far, the sites aren’t doing much business.”

One reason for the sputtering programs, as Sally Pipes suggested last week, is that access to affordable prescription drugs is just not a large enough problem to warrant national angst. Low income seniors and other Americans on tight budgets have many options for decreasing their prescription drug costs, meaning that state programs are likely to receive a tepid response from consumers.

“In Illinois, Gov. Rod Blagojevich predicted a ‘prairie fire’ of popular support when he defied the Food and Drug Administration in October and unveiled a Web site designed to help 18 million people in Illinois and Wisconsin buy low-price drugs from Canada and Ireland. Since then, the site…has processed only 3,200 prescriptions.”

In short, the “prairie fire” many anticipated has turned out to be a tempest in a teapot.

The real driving force behind these Web sites is the perception that prescription drugs (even when affordable) are just too expensive. Critics who accuse the drug companies of profiteering want the U.S. government to adopt Canada’s price control policies - if they have to import or implement those policies one state Web site at a time.

Since that’s the real agenda, we should have a national debate on price controls and skip the faux excitement over Web sites that Americans aren’t much interested in anyway.

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Rare Strain of HIV Resists Drugs, Builds Rapidly Into AIDS
Wall Street Journal, 2-14-05

A new strain of the AIDS virus may have been discovered in an individual case in New York City (there may be other cases in California as well). The strain appears to be “highly drug resistant” and “[progresses] rapidly to [full blown] AIDS”, a process that normally takes years.

While the aggressiveness of this particular strain may be due to the genetic or physiological profile of the infected patient (who is also a drug addict), scientists have known for years that the AIDS virus mutates quickly and that drug resistant strains of the virus are becoming increasingly common.

Alarmingly, this patient’s HIV virus “didn’t respond to three of four classes of antiretroviral medications most commonly prescribed. He is now receiving a fourth ‘cocktail’ in hopes his rare HIV strain will respond.”

The potential discovery of an HIV “super virus” also comes at a time when AIDS drugs are under enormous pricing pressure in the developed and developing worlds. While it makes sense for developing nations to have access to the least expensive and most effective generic or branded drugs possible, the public should keep in mind that the next generation of AIDS medicines for drug resistant virus strains won’t come from generic companies.

They’ll come from pharmaceutical companies that are devoted to new, and expensive, innovative research. And that research is funded by the profits they make on their drugs primarily in the U.S. and Europe. Without those profits, there will be less AIDS research, fewer new AIDS drugs - and less hope for patients who contract drug resistant viruses.

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Why U.S., Canada Differ on Safety Of Attention-Deficit Drug
Wall Street Journal, 2-11-05

The problem with drug safety monitoring is that safety is an inherently slippery concept. A “safe” drug for a cancer patient may be poison to everyone else. Many patients with irritable bowel syndrome (IBS) demanded that GlaxoSmithKline and the FDA return Lotronex to the market after it was withdrawn due to a very rare but potentially fatal side effect in a small number of patients. For those patients, a small risk of catastrophic side effects was more than outweighed by the relief afforded by the drug.

Consider also the recent decision by Canadian regulators to remove the attention deficit drug Adderall XR from the Canadian market because of 20 reports of sudden deaths in patients taking the drug since its debut in 1994. (To date, over 38 million prescriptions have been written for Adderall in the U.S. and Canada.) The FDA, on the other hand, has decided to leave the drug on the market.

The FDA defended its decision not to remove the drug, saying that “although its database did have a dozen reports of sudden deaths in the U.S. of children and teens taking the drug, those cases may largely be explained by factors other than the medication. The 12 cases occurred between 1999 and 2003, when 30 million prescriptions were written in the U.S.”

Which agency made the right call? It is difficult to say because no one has been able to identify a causal link between the drug and adolescent deaths. Indeed, there may not be a link at all. Oftentimes, pharmaceutical regulators are at the mercy of statistical analysis that may only identify a very small anomaly without being able to explain it. Said one researcher commenting on the FDA position, “it is essentially invalid to make comparisons between drugs based on spontaneous reports…There’s no right or wrong because there’s no science.”

And more science is what we badly need. The FDA and industry need to work together throughout the entire life of a drug to identify genomic or physiologic biomarkers that clinicians can easily use to screen out patients at high risk for serious adverse events. Under the current system, a handful of tragic incidents can lead to the FDA depriving millions of patients access to critical medicines - which just compounds the tragedy.

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Commentary

Medicating the FDA
Henry Miller, M.S., M.D., Washington Times, 2-17-05

Miller takes stock of the U.S. drug development and FDA approval process, and notes that more needs to be done to identify adverse drug events (ADEs) and improve patient safety - provided we don’t keep valuable medicines away from patients and doctors.

“The efficient detection of ADEs is essential, and the United States needs improved pharamcovigilance…This should be done not by creating a new, independent agency, but by fixing the FDA. However, it is questionable if the newly announced FDA Drug Safety Oversight Board…is the answer.”

Miller concludes that “we need better data rather than more bureaucrats”, and that, ultimately, “public health is more imperiled by lack of drugs in the development pipeline..than by side effects from approved drugs…we must make sure that the cure [for drug safety] isn’t worse than the disease.”

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Biology's New Forbidden Fruit
Oliver Morton, The New York Times, 2-11-05

The ongoing revolution in the biological sciences is astounding, and will lead to many advances in human health and well-being. In can also, in the wrong hands, lead to massive suffering and death. As it becomes easier to modify biological organisms to produce medicines, that same knowledge can be used to manufacture drug resistant strains of deadly diseases ranging from smallpox to anthrax.

While encouraging the government to pursue biodefense research and prudent regulation of dangerous technologies, Morton also calls for the public to widen its discussion over the potential misuse of biotechnology and how it can be checked.

“The best basis for oversight is a concerned citizenry that wants to keep up with what is possible and discuss what is desirable. But to spur such debates in the wider public, biologists themselves will have to become more willing to think and talk about the ever more powerful technologies that they increasingly take for granted in the lab.

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Brouhaha
Grace-Marie Turner, Galen Institute, 2-11-05

Turner takes issue with last week’s story in the Washington Post claiming that the “new Medicare prescription drug benefit will cost more than $1.2 trillion in the coming decade” (or triple the original cost). She believes the reporters used shoddy math and failed to subtract “$468 billion in new federal revenues anticipated from beneficiary premiums, state payments, and Medicaid savings.”

The real net cost of the benefit is $724 billion - with the actual year-to-year costs unchanged from original estimates. Turner is concerned that the new numbers will drive a push for drug price controls, despite unshakable evidence that “price controls haven’t worked because central planners never get the prices right.”

“The only way to continually find the best and lowest prices is through competitive negotiation, which is exactly what is going on with the Medicare discount cards right now.”

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Misdiagnosing the diseases of the poor
Barun Mitra, International Policy Network, 2-9-05

As India embraces patents on pharmaceutical products under the auspices of the World Trade Organization, anti-patent (and anti-capitalist) ideologues there and abroad are casting the move as a plot by multinational corporations to deny poor patients in the developing world access to critical generic medicines.

Mitra replies that this view is wrongheaded—and just plain wrong. “The present debate over the Indian patent law, despite the passion, is underscored by the desire to score political points…India has been a proving ground for those who oppose patents on pharmaceutical products. We scrapped all product patents in 1972. As a result, India is now home to over 20,000 pharmaceutical companies producing copies of drugs developed - and patented - elsewhere. However, access to medicines remains poor - suggesting that patents are not the key determinant of access that their opponents claim.” [emphasis added]

He goes on to note that although India produces many of the world’s generic AIDS drugs, less than 1% of Indian AIDS patients are treated with those drugs. “The real reason for the lack of access to medicines and other forms of healthcare is the prevailing stranglehold of government regulation of the health sector. The public sector healthcare provision [in India] is a sick joke, characterized by shortages of hospitals, beds, equipments, medicines, and manpower. Claims of medical negligence and malpractice are frequent. Hospitals in India are often dangerous places. In spite of the risk of infection with HIV, the government of India recently admitted that 69% of injections administered in public hospitals could be unsafe.”

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Research

Detection of Bladder Cancer Using a Point-of-Care Proteomic Assay
H. Barton Grossman, MD, The Journal of the American Medical Association, 2-16-05

Pharmacogenomics and other “omics” sciences promise to move disease treatment and prevention from a medical art into a true science by identifying the underlying biological basis of human pathologies at the genetic and molecular levels.

This study recounts the success of a proteomic test used for the diagnosis of bladder cancer. Currently, “no single procedure detects all malignancies”, and although “urine test are frequently part of an evaluation” they have also “been either nonspecific for cancer or required specialized analysis at a laboratory.” The proteomic test used in this study measures the nuclear matrix protein NMP22 in voided urine.

“Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ.”

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Assessing Consumer Gains from a Drug Price Control Policy in the U.S.
Rexford Santerre, John Vernon, NBER Working Paper, 2-15-05

“This paper uses national data for the period 1960 to 2000 to estimate an aggregate private consumer demand for pharmaceuticals in the U.S. The estimated demand curve is then used to simulate the value of consumer surplus gains from a drug price control regime that holds drug price increases to the same rate of growth as the general consumer price level over the time period from 1981 to 2000. Based upon a 7 percent real interest rate, we find that the future value of consumer surplus gains from this hypothetical policy would have been $319 billion at the end of 2000. According to a recent study, that same drug price control regime would have led to 198 fewer new drugs being brought to the U.S. market over this period. Therefore, we approximate that the average social opportunity cost per drug developed during this period to be approximately $1.6 billion. Recent research on the value of pharmaceuticals suggests that the social benefits of a new drug may be far greater than this estimated social opportunity cost.”

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Medical Progress Today is published by the Center for Medical Progress at the Manhattan Institute for Policy Research.

For more information about Medical Progress Today, please contact the managing editor, Paul Howard, at phoward@manhattan-institute.org, or via telephone at 212.599.7000, x319.

Press inquiries regarding Medical Progress Today can be directed to Lindsay Young, executive director, communications at communications@manhattan-institute.org, or via telephone at 212.599.7000, x315.

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SPOTLIGHT

The New Frontier for Drug Safety

NEWS

FDA Establishes Board to Review Approved Drugs - Steps on Safety Monitoring Follow Concerns Over Vioxx; Critics Question Autonomy
What Makes a Drug Too Risky? There's No Easy Answer
Bush to Retain FDA's Acting Chief - Veteran Administrator Would Be Unlikely to Seek Broad Changes at Agency
Middle-Class Families Strain Public Health-Insurance Plans
States' Bid for Cheaper Medicine Sputters - Official Web Sites for Buying Drugs From Canada Are Slow to Take Off With Consumers
Rare Strain of HIV Resists Drugs, Builds Rapidly Into AIDS
Why U.S., Canada Differ on Safety Of Attention-Deficit Drug

COMMENTARY

Medicating the FDA
Biology's New Forbidden Fruit
Brouhaha
Misdiagnosing the diseases of the poor

RESEARCH

Detection of Bladder Cancer Using a Point-of-Care Proteomic Assay
Assessing Consumer Gains from a Drug Price Control Policy in the U.S.
Center for Medical Progress 
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