Food and Drug Warning
by Donald Devine

For all of its zaniness, Lewis Carroll’s Alice in Wonderland is chock full of wisdom. “One day, Alice came to a fork in the road and saw a Cheshire cat in a tree. ‘Which road do I take?’ she asked. ‘Where do you want to go?’ was his response. I don't know, Alice answered. Then, said the cat, it doesn't matter.” It is often difficult to know where one should go.

The Food and Drug Administration has just proudly announced a revolutionary new warning label for the immensely popular anti-clotting blood thinner warfarin--cautioning that a lower dose “should be considered for patients with certain genetic variations.”

Larry Lesko, director of FDA’s clinical pharmacology office, presented gene warnings as a ground-breaking way to escape the agency’s traditional generalist and reactive mode and begin tailoring government warnings directly to individual genetics. Until now genetic warnings have only been posted for a few limited-audience drugs, so warfarin is the first mass test. Research has been approved to extend the model to other popular drugs such as Prozac, metformin and albuterol. “If the potential wasn’t huge, we wouldn’t be doing it,” the director boasted announcing the FDA’s more active role promulgated this August.

Notice, however, that he says “potential.” Professor Ann Wittkowsky of the University of Washington told the Wall Street Journal’s Anna Wilde Matthews before the FDA’s warfarin decision: “It would be irresponsible and potentially harmful to suggest that testing be used or even mentioned on the label. It is fascinating science but it is not yet ready for prime time.”

The problem is that only certain variants of the genes CYP2C9 and VKORC1 seem to affect safe dosage and the FDA is not sure how much lower the dosage should be. Not only are genetic tests in their infancy and not conclusive, they cost from $300 to $500. There is concern from critics that patients will avoid the inconclusive tests because of the cost and time and then come back and sue the doctors and/or drug companies. So will doctors prescribe it? What could replace it? Warfarin was used as a low cost generic 30 million times last year.

Drugs are complicated things. Warfarin started as a rat poison. A military recruit tried to commit suicide with it but his use of a low dose that prevented blood coagulation led scientists to realize it could be useful as a human drug. When President Dwight Eisenhower was given permission to use it after his heart attack in 1955, warfarin became the most popular anti-clotting agent in history. Yet, too small or too large a dose can cause too much clotting or too much bleeding.

Doctors try to balance a person’s size and age and test blood pressure frequently (often daily at the beginning) to get the dosage right. It is an art not a science. Warfarin is the second most likely drug to send a patient to an emergency room, after insulin. Yet, many more patients would suffer and even die without warfarin--and insulin—so physicians do not let the perfect be the enemy of the good and keep adjusting dosage.

The 2002 study of CYP2C9 complicated an already complex dosage problem when it found that this gene affects how people process warfarin and some variants of it appear to retain warfarin in the body and increase bleeding. The 2005 study of VKORC1 found that it too seemed to affect how much of the drug should be prescribed. But the findings are ambiguous. The two genes—or “variants” of them--“appear” to make a difference. How much and how? No one knows. As Dr. Wittkowshy put it, gene research is not yet ready for such sophisticated dosage decision-making for individuals. There is a computer estimate of dosages when the genetic factors are evident but it is only one guess and is not accepted as authoritative.

Most important, it takes 10 days for the test and only two labs even do the studies, although others will join now that the government has acted. During those 10 days the expectation is that the older seat-of-the-pants method will be used. Or will doctors try to avoid lawsuits and wait to be certain, with increased risk from delayed treatment? Even then, nothing is certain since once the genes are found for an individual, it is still hit-and-miss on dosage.

So there are dangers any way one proceeds. It was a rat poison after all.

Gene therapy is complex too. Arthur Nienhuis, the president of the American Society of Gene Therapy says, “Gene therapy holds a great deal of potential” [there is that word again] but, after more than a decade of failure, a dozen children are now living normal lives after receiving gene injections. On the other hand, he admits there have been a handful of cases where gene therapy in volunteers caused leukemia. This past July, a 36 year old generally healthy Illinois woman with rheumatoid arthritis received a gene injection in her right knee to relieve local pain and died from an otherwise mild fungus and virus that became virulent and ravaged her organs and blood throughout her body. “It’s a major mystery,” concluded Kyle Hogarth, who heads the University of Chicago Medical Center, the hospital where she expired.

But the FDA is covered. The bureaucrats can say they gave the warning and it is up to the physicians, drug companies and medical professionals to deal with it. If they are sued because of the warning, that is their problem. It is perfect bureaucratize. The FDA warning is not in the key “black box” section at the top but in a less visible “Precautions” section below. The FDA even told the media to notice that the government did not directly recommend that doctors actually conduct the tests. Whatever this new policy actually is, it is not any more proactive than the old seat-of-the-pants process. The only absolute is that the government is safe whatever happens.

How about a new warning label? “The FDA exists because private underwriters could not guarantee perfect safety and the government promised it could. But perfect safety is a myth and the old market saying ‘let the buyer beware’ must still be the guide.” One can sue private underwriters but one cannot force government responsibility. China tries. Zheng Xiaoyu, the head of its FDA, was executed in July after he allowed tainted lead paint, juice additives, toothpaste and pet food to enter the marketplace. While a bullet to the back of the head does promote some kind of responsibility, it will not work either. Maybe government bureaucracy is not the solution.

Donald Devine, the editor of Conservative Battleline Online, was the director of the U.S. Office of Personnel Management from 1981 to 1985 and is the director of the Federalist Leadership Center at Bellevue University.