Unsafe at Any Dose?

My apologies to Ralph Nader for knocking off the famous title of his book on car safety, but I wanted something bold to catch your eye even if I transformed an uncompromising assertion into a tentative question. Drug safety is a topic of overriding importance and something that all healthcare providers must consider in their work. Ever since Hippocrates said to “do no harm,” safety has been up front in physicians’ minds.

In the yin–yang of medical treatment, safety is on the opposite side of efficacy. Just as advances in the treatment and prevention of musculoskeletal disease should excite us, their potential for harm should frighten us. We should worry that danger lurks and that agents that produce startling results in diseases like rheumatoid arthritis will exact a price in toxicity. That price may not be here today, but it could be here tomorrow.

Are we watching closely to ensure that the benefits of the drugs we prescribe outweigh the risks?

Ralph Nader is a smart, clever man, and he made product safety a national focus. He could act as a scold and an outsider, but he has a prophet’s charisma. He does not smile much nor crack jokes but, then again, prophets are not famous for their easy way or sense of humor. Whatever he lacks in charm, Nader gets the job done.

The poster child for Nader was the Corvair, a popular Chevrolet that had a profitable run in the 1960s. The Corvair had a rear engine and a complicated suspension that required different inflation pressures for the front and rear tires. Unless the tires were filled with air just right, the Corvair was subject to “tuck under,” whatever that is. (Sorry, Wikipedia failed me on this one.)

The need to keep more than a 10-psi difference in the front and rear tires was hidden in the owner’s manual and the “tucking under” effect caused accidents. In addition to sounding the alarm on the Corvair, Nader unmasked other car problems such as chrome dashboards whose glare in the sun blinded drivers and engines that spewed noxious fumes. The outcome of Nader’s exposés was to increase safety regulations from Congress and spur industry to build safety into their vehicles.

Safety a Challenge for Drugs, Too

My title is obviously exaggerated (this is a magazine after all), and cars are not drugs. Furthermore, unlike new car models, new drugs undergo long and elaborate testing in animals as well as people. Monitoring by the Food and Drug Administration (FDA) is rigorous and should root out the bad apples that develop in industry’s orchards. Even if phase 3 testing looks good, postmarketing surveillance programs can keep a bright light shining on the thousands of products that comprise today’s medicine chest.

Given the attention to drug safety that is the FDA’s mission, many physicians (as well as consumers) behave as if drugs are safe. Certainly, the use of pharmaceuticals is booming and it is not unusual for patients today to be on 20 or 30 different prescription drugs. Who can imagine what happens in a body bombarded simultaneously by so many different molecules?

While the belief in the safety of drugs is high, in medicine, as in everything else in life, there is no free lunch. No drug is totally safe, and safety concerns—real or theoretical—must be balanced against efficacy. The risk–benefit equation must therefore tilt solidly in the direction of benefit. As responsible providers, we have to ask whether that is always the case.

Nader on Drug Safety

By chance, I actually discussed drug safety with Ralph Nader one day while waiting in Washington Reagan Airport. In the large expanse of the terminal’s main hall, I saw Nader sitting in front of a bookshop, ready to sell autographed copies of his newest work, The Good Fight. He was by himself, looking serious and intense, and I had an hour to kill.

After some hesitation about engaging such a legendary figure, I went up to Nader and told him how much I admired his work. This being early 2008, I asked him whether he was going to run again for president. He said that he was still thinking about the future and then he asked me what I did. I told him that I was a doctor. His face immediately lit up and he expounded passionately about the necessity for healthcare reform, including the need for a single-payer system.

We then moved on to drug safety. Not surprisingly, given Nader’s history of taking on the big boys in industry, he was dismissive of the current system, including the conflicts of interest, the cozy relationships of industry with academia, and the fact that industry picks up some of the tab at the FDA via the Prescription Drug User Fee Act (PDUFA) program. In response to his critique, I told Nader about evidence-based medicine and the many efforts to prevent unsafe drugs from coming to market and to remove those that failed to live up to their promise.

If nothing else, Nader is smart and informed and—looking straight at me with fiery eyes—he quickly demolished my arguments. Because the airport was quiet and no one else came up to meet Nader, we talked for about 15 minutes. I bought a copy of the book, asking Nader to inscribe it to my wife and me, which he did, adding “For Justice.” I thanked him and then I hurried off to catch my flight.

Are We Using Drugs Safely Enough?

My conversation with Nader was very disturbing and his assessment of the FDA and the medical profession shook my confidence. I could not help but remember our own Corvairs, which were enthusiastically prescribed until safety concerns blew them up. In rheumatology alone, we have had Duract, Suprol, Xomax, Oraflex, Selecryn, Vioxx, and Bextra removed from the market and, unless you treat racehorses, I wouldn’t write a prescription for phenylbutazone if I were you.

On the plane home, I began to think of whether I was still prescribing Corvairs to my patients and how many of the drugs I prescribe actually have risks that outweigh their benefits.

In a future column, I will provide my own perspective on using drugs more safely. I will also discuss the Peltzman Effect, a concept that arose in the aftermath of Nader’s scrutiny of the auto industry, and how it influences medical practice.

Dr. Pisetsky is physician editor of The Rheumatologist and professor of medicine and immunology at Duke University Medical Center in Durham, N.C.