“Why do approved drugs turn out to be dangerous?”
The real question is, risky for whom and when?
Drug development: a long and winding road
The Food and Drug Administration (FDA) tightly regulates everything that happens to a drug from its initial discovery throughout its life on the market. What the FDA cannot regulate as tightly (though health plans certainly try) is the drug’s actual uses, and in whom.
After the drug is tested in the lab, and usually in animals, preliminary trials in healthy human volunteers come next. If all goes well, early trials in patients with the condition in question are performed next. Usually, these will not involve too many patients, and they may involve a variety of doses or dosing schedules.
After the most promising amount(s), timing and frequency of dosing is identified, it is time for “Phase III trials,” of which at least two are usually needed for FDA approval, and there are similar systems in other countries.
Regulatory agencies like the FDA must approve prescription drugs before they can be marketed. To label the drug for use in a particular population, like people at a certain stage of disease, the manufacturer must test safety and efficacy (how well it works) in that exact population.
Most of the time, the manufacturer has to test the drug using the same measures of success that other drugs approved for its target population used in their trials, though it may work differently and show less of an effect on those measures than on other measures used by physicians.
So new drugs are often tested using old measures, because anything else is time-consuming and expensive to justify.
And the broader the patient population in the clinical trials, the more likely the new drug will fail.
Neither the FDA nor the manufacturer wants to label a drug as safe and effective for everyone. All prescription drugs carry risks for some patients.
However, the “gap” between the “real world” drug effects and the early data reflects all the patients that were excluded from trials. It might have been because they had conditions or took drugs that violated the trial’s “exclusion criteria,” (factors that make patients ineligible for the trial) or didn’t have exactly the same condition that others in the trial did.
Once the drug is marketed, any patient that the physician thinks will benefit from it, which is a much larger group than the population that qualified for the clinical trials, will be able to try it assuming it is reimbursable/otherwise affordable for her. Of course, that’s a big “if” since the more expensive the drug, the more likely its use is restricted by payers.
Still, generally speaking, almost every drug has different kinds of patients that use it after launch, than it did in the trials to get it there.
Trials vs. real life: mind the gap
Besides FDA rules about eligible populations and endpoints, other factors that account for the “gap” include:
- Clinical trials are often shorter or longer than real life use
- Patients in trials are given considerable information and support that they may not receive in “normal life.”
- To volunteer and then remain enrolled in a clinical trial, which often entails hours of travel, visits and tests, implies motivation that typical patients may not have, to improve their health in other ways, like quitting smoking or walking more.
- Patients in trials also often have to agree that, depending on the luck of the draw, they might only be receiving a placebo (no therapy at all), or have to continue a therapy they aren’t doing that well with. If they decide to pass on this gamble, we don’t see them in the trial, but they show up for the “real world.”
So it’s not surprising that after the drug is approved, “unforeseen risks” may seemingly arise. Actually, however, these are not “new” risks. It’s the patients who have changed. It’s like getting to the checkout counter and finding out someone switched your grocery cart. So, when the “real world” has shown that having a drug on the market is a bad idea, it has been withdrawn (sometimes, arguably, prematurely).
There are also often unforeseen drug benefits, when many patients not eligible for the trials show improvement in their conditions when they take the drug. Sadly, though, if the drug is pricey and the trial was not designed to show these unexpected benefits, payers may resist reimbursement for the drug in that population. That may hold true even if alternatives are more expensive, and so manufacturers may launch additional clinical studies to justify these expanded uses.
