Wednesday, December 31, 2008

The World is Complicated, but Working on the Averages May Kill You

Article source: "The Evidence Gap; Patient’s DNA May Be Signal to Tailor Medication," ANDREW POLLACK, The New York Times, December 29, 2008.

This article points to the potential advantages of personalized medicine, noting that "most drugs, whatever the disease, work for only about half the people who take them. Not only is much of the nation’s approximately $300 billion annual drug spending wasted, but countless patients are being exposed unnecessarily to side effects." Genetic testing, when it is cheap enough, may allow doctors to choose drugs that are more likely to be effective.

Currently, drugs are tested on large groups of people whose genetic makeup is unknown. If the drug works on a large portion of them without causing too many or too serious side effects, it is approved for general use. There are really no ways to follow up on the millions of users to determine the characteristics of those in whom the drugs work, those in which the drug doesm't work, and those that the drug actually harms.

This could all change. Of course such a change will require funding to improve the technology. It will also require government to regulate and maintain records. Indeed, the drug companies may not be too happy about a system that reduces the sale of their products to only those they will actually help, although other companies will probably love the new market for DNA testing devices.

A couple of examples from the article:

  • The colon cancer drugs Erbitux and Vectibix, for instance, do not work for the 40 percent of patients whose tumors have a particular genetic mutation. The Food and Drug Administration held a meeting this month to discuss whether patients should be tested to narrow use of the drugs, which cost $8,000 to $10,000 a month.
  • A cautionary case is Herceptin, a Genentech breast cancer drug that is considered the archetype of personalized medicine because it works only for women whose tumors have a particular genetic characteristic. But now, 10 years after Herceptin reached the market, scientists are finding that the various tests — some approved by the F.D.A., some not — can be inaccurate.
  • In 2003, more than 25 years after tamoxifen was introduced, researchers led by Dr. David A. Flockhart at Indiana University School of Medicine figured out that the body coverts tamoxifen into another substance called endoxifen. It is endoxifen that actually exerts the cancer-fighting effect. The conversion is done by an enzyme in the body called CYP2D6, or 2D6 for short. But variations in people’s 2D6 genes mean the enzymes have different levels of activity. Up to 7 percent of people, depending on their ethnic group, have an inactive enzyme, Dr. Flockhart said, while another 20 to 40 percent have an only modestly active enzyme.
  • Tamoxifen, now a generic drug, costs as little as $500 for the typical five-year treatment. But most patients in the United States are currently treated with a newer, much more expensive class of drugs, called aromatase inhibitors, that cost about $18,000 over five years. Those drugs — made by AstraZeneca, Novartis and Pfizer — performed better than tamoxifen in clinical trials before the role of 2D6 was generally understood.
  • Last year, for instance, European regulators said Amgen’s colon cancer drug Vectibix did not provide enough benefit to patients to be approved. So Amgen reanalyzed the data from its clinical trial. After the results showed Vectibix worked better in patients whose tumors did not have a mutation in a gene called KRAS, the drug was approved for those patients only.
  • The labels of about 200 drugs now contain some information relating genes to drug response, said Lawrence J. Lesko, the F.D.A.’s head of clinical pharmacology. But in many cases, he said, doctors are not told specifically enough what to do with the test results, such as how much to change the dose.
Comment: I want to point out the nature of our current knowledge on the efficacy of pharmaceuticals. In theory it might be possible to predict with great accuracy which drug would be effective for a specific patient with a specific disease. However, in practice doctors can not do that. They can only say that this drug will help such and such a percent of patients with your diagnosis. It now can cost as much as half a billion dollars to test a drug before it is released, but that test provides only this probabilistic result, often providing little information. Yet drug testing may be the best use of scientific evidence in product testin. Of course, pharmaceuticals are special in that they are potentially life saving and potentially life threatening. JAD

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