Katherine Eban

“As Graedon scrutinized the FDA’s standards for bioequivalence and the data that companies had to submit, he found that generics were much less equivalent than commonly assumed. The FDA’s statistical formula that defined bioequivalence as a range—a generic drug’s concentration in the blood could not fall below 80 percent or rise above 125 percent of the brand name’s concentration, using a 90 percent confidence interval—still allowed for a potential outside range of 45 percent among generics labeled as being the same. Patients getting switched from one generic to another might be on the low end one day, the high end the next. The FDA allowed drug companies to use different additional ingredients, known as excipients, that could be of lower quality. Those differences could affect a drug’s bioavailability, the amount of drug potentially absorbed into the bloodstream. But there was another problem that really drew Graedon’s attention. Generic drug companies submitted the results of patients’ blood tests in the form of bioequivalence curves. The graphs consisted of a vertical axis called Cmax, which mapped the maximum concentration of drug in the blood, and a horizontal axis called Tmax, the time to maximum concentration. The resulting curve looked like an upside-down U. The FDA was using the highest point on that curve, peak drug concentration, to assess the rate of absorption into the blood. But peak drug concentration, the point at which the blood had absorbed the largest amount of drug, was a single number at one point in time. The FDA was using that point as a stand-in for “rate of absorption.” So long as the generic hit a similar peak of drug concentration in the blood as the brand name, it could be deemed bioequivalent, even if the two curves reflecting the time to that peak looked totally different. Two different curves indicated two entirely different experiences in the body, Graedon realized. The measurement of time to maximum concentration, the horizontal axis, was crucial for time-release drugs, which had not been widely available when the FDA first created its bioequivalence standard in 1992. That standard had not been meaningfully updated since then. “The time to Tmax can vary all over the place and they don’t give a damn,” Graedon emailed a reporter. That “seems pretty bizarre to us.” Though the FDA asserted that it wouldn’t approve generics with “clinically significant” differences in release rates, the agency didn’t disclose data filed by the companies, so it was impossible to know how dramatic the differences were.”
― Katherine Eban, Bottle of Lies: The Inside Story of the Generic Drug Boom