Tmax Quotes

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.

To successfully launch a product, generic drug companies must tread in reverse through this obstacle course. Once a generic company zeroes in on a molecule, and its scientists figure out how it operates in the body, its lawyers get to work to establish how well protected it is legally. The next step takes place in the laboratory: developing the active pharmaceutical ingredient by synthesizing it into ingredient form. That alone can take several years of trial and error. Once successful, the finished generic has to take the same form as the brand, whether that be pill, capsule, tablet, or injection. Formulating it requires additional ingredients known as excipients, which can be different, but might also be litigated. Then comes testing. In the lab, the in-vitro tests replicate conditions in the body. During dissolution tests, for example, the drug will be put in beakers whose contents mimic stomach conditions, to see how the drugs break down. But some of the most important tests are in-vivo—when the drug is tested on people. Brand-name companies must test new drugs on thousands of patients to prove that they are safe and effective. Generic companies have to prove only that their drug performs similarly in the body to the brand-name drug. To do this, they must test it on a few dozen healthy volunteers and map the concentration of the drug in their blood. The results yield a graph that contains the all-important bioequivalence curve. The horizontal line reflects the time to maximum concentration (Tmax) of drug in the blood. The vertical line reflects the peak concentration (Cmax) of drug in the blood. Between these two axes lies the area under the curve (AUC). The test results must fall in that area to be deemed bioequivalent. Every batch of drugs has variation. Even brand-name drugs made in the same laboratory under the exact same conditions will have some batch-to-batch differences. So, in 1992, the FDA created a complex 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. But the formula also required companies to impose a 90 percent confidence interval on their testing, to ensure that less than 20 percent of samples would fall outside the designated range and far more would land within a closer range to the innovator product.