Show 1443: Rethinking Medications: Uncovering the Truth About Common Drugs

Americans take a lot of medications. Luckily, the Food and Drug Administration only approves those that are safe and effective. However, the agency’s definition of “safe” includes medicines that can harm or kill some people, and the definition of “effective” covers some drugs that only work a little better than placebo. Has the FDA changed its standards? Maybe we should be rethinking medications.

Rethinking Medications:

If you watch television or streaming video, you probably see a lot of commercials for prescription pharmaceuticals. Decades ago, prescription drugs weren’t advertised on television, and the prices for prescriptions were much lower. How has the pharmaceutical industry changed? On this episode, we talk with an expert observer of the industry and its regulation. Dr. Jerry Avorn is one of the country’s most respected pharmacoepidemiologists. He describes how the business of making and selling medicines has evolved.

What Is the Role of Orphan Drugs?

The Orphan Drug Act was passed in 1983. Its goal was to offer incentives to drug companies to develop medicines for rare diseases.  The FDA encouraged Congress in this, viewing these as “significant drugs of limited commercial value.” The idea was to make sure that even though only a few hundred Americans might have leprosy, for example, that drugs would still be developed to treat their condition.

Tax breaks, patent extensions and market exclusivity made the proposition more appealing. In fact, one of the reasons Americans spend twice as much on drugs per capita as citizens of Canada, Australia or other countries is the cost of orphan drugs. Although these compounds were seen as having “limited commercial value,” the industry has figured out how to charge exceedingly high prices for anything considered an orphan drug.

How Effective Is Your Medicine?

When it comes to evaluating effectiveness, pharmaceutical firms have a powerful tool. Dr. Avorn considers it one of the best inventions of all time, although it is a concept rather than a thing. RCT stands for Randomized Controlled Trial, which in turn is shorthand for randomized placebo-controlled double-blind (or in the UK, double-dummy) clinical study.

The idea is to take a group of people who are alike in some important ways, so that they are equally likely to develop some type of health problem. Divide them up using a random number generator or some other similar impersonal technique. Those on one side of the divide get the medicine, while those on the other side get an indistinguishable placebo. Neither the participants nor the investigators know who is in which group. At some pre-specified time, the researchers will check to make sure there have not been too many adverse reactions. They may also check that the intervention appears to be doing something. When the trial is over, the methods and results should be described in a publication so that doctors will know if they should incorporate the treatment into their practice.

We love RCTs when the outcome is avoiding some serious problem such as a stroke or a cancer diagnosis. For us, biomarkers are less compelling, even though they have become far more common. What is a biomarker? It is easy to measure, like blood sugar or blood pressure. The biomarker is a stand-in or surrogate for a condition like diabetes or heart disease because they are often correlated. It is important to remember, though, that the biomarker is not the disease.

Comparing Absolute and Relative Risk While Rethinking Medications:

Once the company has completed its RCT, more than likely it will want to publicize the results to promote the drug. How it describes effectiveness can change the way people think about the medicine. One of our favorite examples comes from a print advertisement for Lipitor. It boasted that Lipitor (atorvastatin) lowered the risk of a heart attack (myocardial infarction) by 36 percent. That sounds great, doesn’t it? There was an asterisk next to that number, and in small print lower on the page was an explanation.

During a five-year trial, out of 100 people on Lipitor, two had heart attacks. Out of 100 people on placebo for that trial, three had heart attacks. So you can see the absolute difference between Lipitor and placebo was just one heart attack per hundred (the absolute risk reduction). That probably would not have sold many pills. But stated as a relative risk reduction of 1 fewer heart attack compared to the baseline of 3 (1/3), using larger numbers because there were thousands of people in the study, you get 36 percent.

What Do We Know About Safety?

When patients see multiple health care providers who don’t talk with each other often, it may be difficult to detect serious safety problems. That was the case with the anti-inflammatory drug Vioxx. Early warning signs of cardiovascular problems resulting from this pain-reliever were overlooked for years. Researchers detected trouble as early as 2001, but the drug company resisted removing the drug until 2004. As a result, millions of people were needlessly exposed to danger and too many died. The silver lining to this cloud is stepped-up surveillance for side effects.

Rethinking Medications with Respect to Side Effects:

Some years ago, Dr. Avorn and his colleagues conducted a brilliant study (Drug Safety, 2009). They compared the side effect profiles from RCTs of different antidepressants. Mind you, they were not looking at the side effects of the drugs. They examined the side effects of the placebos in studies of tricyclic antidepressants and compared them to side effects of placebos in studies of SSRI antidepressants. All the participants had depression, so there should have been no differences due to the underlying condition. Yet the placebos had vastly different side effect profiles, mirroring the divergent side effects of the active agents.

This striking difference might be due to changes in the way researchers elicited symptoms. Or it might be due to the nocebo effect, in which a person who expects to feel nauseated becomes queasy. Nocebo is like an inverse of the placebo effect. Either way, it suggests that when side effects of the placebo are similar to those of the investigational drug, we shouldn’t assume that the drug has no side effects.

How Can You Protect Yourself?

In rethinking medications, it is important to make sure that you really need all the drugs you are taking. Dr. Avorn strongly recommends a brown bag review periodically, in which the patient brings in everything he or she is taking, including OTC meds and dietary supplements. The health care provider reviews them, looking for duplication or incompatibilities. If they find problems, it’s time for a conversation about alternatives or deprescribing. Some medicines cannot be stopped suddenly, so the prescriber should provide detailed instructions about tapering and should monitor progress as the patient reduces the dose.

This Week’s Guest:

Jerry Avorn, MD, is a professor of medicine at Harvard Medical School and a senior internist in the Mass General Brigham health-care system. He built a leading research center at Harvard to study medication use, outcomes, costs, and policies and developed the educational outreach approach known as “academic detailing,” providing evidence-based information about medications to prescribers. One of the nation’s most highly cited researchers, Dr. Avorn is the author of Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs, and he has written or cowritten over six hundred papers in the medical literature as well as opinion pieces in TheNew York Times, The Washington Post, JAMA, and The New England Journal of Medicine. Dr. Avorn’s new book is Rethinking Medications: Truth, Power, and the Drugs You Take.

His website is www.RethinkMeds.info