The mantra that is repeated over and over about the FDA drug approval process is “for a drug to win approval it must prove to be both safe and efficacious by rigorous clinical testing.” To a large extent that mantra rings true on the efficacy side of the equation, but with regard to safety, FDA-mandated clinical testing regimes oftentimes fall short.Human complexity and why it is an issue for drug safety
I blame neither the pharmaceutical industry, nor the FDA for the vast majority of these safety shortcomings. No drug development company can afford to conduct a clinical trail large enough to elucidate the entire side effect profile of a drug. Why is that? The answer lies in how complex real-world patient populations are versus how non-complex clinical trial patient populations are.
Think about 10 of your friends – do they all react the same way to coffee, alcohol, nicotine, etc.?, of course not. That same complexity holds true for how individuals react to FDA approved drugs.Who is selected for a clinical trial, and do they represent all potential patients?
Potential clinical trial participants are subjected to rigorous inclusion and exclusion criteria. Subjects that pass these selection processes and are ultimately enrolled in the trial, therefore, end up being a relatively homogenous group. These selection steps are vital for determining a compound’s efficacy and are usually necessary for both financial and logistic reasons. The downside of such methods, however, is that this homogeneous group of subjects may react in similar ways to a test drug, and therefore, the clinical trail process does not uncover many of the side effects that occur once the drug is introduced to real-word, heterogeneous, patient populations.
A member of the FDA’s Office of Drug Safety summed up this exact issue by stating: 1) “the complete adverse event profile of a drug is not known at the time of approval because of the small sample size, short duration, and limited generalizability of pre-approval clinical trials” and, 2) “since most trials exclude the elderly, children, pregnant women, patients with multiple diseases, and those on medications suspected of interaction with the study drug, the studies’ participants may not be representative of the real world where the drug is eventually used.”
Indeed, many serious side effects have only been elucidated after FDA approval (severe cardiac complications from the weight management drug Meridia, a fatal muscle-wasting syndrome from the cholesterol management drug Baycol, and increased heart attack and stroke rates in patients taking Vioxx prescribed for osteoarthritis and joint pain.4
In sum, the clinical trail process is, by necessity, conducted in homogeneous and limited patient populations and therefore cannot be expected to uncover rare, or even properly evaluate common, side effects associated with a test medication. Accordingly, a drug’s true side effect profile is almost never properly illuminated until after FDA approval.
That is why we love what we do here at AdverseEvents, Inc.
We are trying to bring healthcare providers, insurers, and you, actionable insights regarding links between side effects and approved drugs - in the real-world populations of patients using these medications everyday.
To learn more about the FAERS, see our comprehensive guide to the FDA Adverse Event Reporting System.
Keith Hoffman, PhD
Vice President, Scientific Affairs