CDER’s Temple Covers ‘Individualization’ in Drug Development
CDER deputy center director for clinical science Robert Temple says the agency and drug industry are in the third age of drug development — the age of individualization. Speaking last month at a precision dosing workshop at the agency’s Silver Spring, MD headquarters, Temple noted that the previous ages covered drug safety (1938 to 1962), and drug effectiveness (post-1962).
Unlike the previous two ages that were brought on by drug disasters and subsequent legislation, Temple said the individualization age was not guided by either and is now in full swing. “Better dose response is part of this, but we have been moving swiftly toward closer attention to individual differences,” he said. “For a long time, we have been particularly worried about how to choose the dose for individuals. We are very interested in population subsets, especially demographic analyses and excretion subsets.” He said drug reviewers are also interested in pharmacokinetics (PK) and pharmacodynamics (PD) or pathophysiologic factors that affect outcomes and interactions, and genomic factors and other “enrichments” that affect outcomes.
Temple told the workshop that there has been growing recognition that individuals can have significant metabolic differences. He joined CDER in 1972 as a medical officer in the Division of Metabolic and Endocrine Drug Products. “When I started here, we didn't know that people had different metabolic differences,” he said. “There were some old cases, such as pseudocholinesterase differences, and differences in the degree of acetylation, but we began to look at what stimulated a lot of this, like 2D6 and 2C19 poor metabolizers and the growing recognition that other drugs being taken can have profound effects on PK of another drug.”
Temple said that evaluating metabolism and drug interactions got a huge boost from a disastrous interaction related to terfenadine, an antihistamine causing torsades de pointes when metabolism was blocked by 3A4 inhibitors. “It has now become routine to examine metabolism and DDI’s, as well as the effects of age and gender on PK, to do population PK, and to examine effects of renal and hepatic impairment on PK,” he said. “So we always know this stuff at the time of drug approval, which was a huge change.”
Pharmacodynamic differences were difficult to document in the past, Temple told the workshop, mainly because almost all clinical trials looked at group and not individual data, and there was little ability to look at individual dose response data unless the trials were cross-over or forced titration, which are both unusual designs. “Genomics and proteomics change all this, providing an easy measure that can predict major differences in PD, and we’re just at the beginning of far more targeted therapy than we’ve ever imagined,” he said. “But there are some differences between people that we don’t understand the basis, so it is hard to detect those.”
Overall, Temple boiled down drug development as doing this: “In general, we study a broad population, drawing overall conclusions from that population, then examine the subgroups (age, gender, race, renal function, and ‘other’). A model for presentation of subgroup data is the forest plot, which can look at many variables, but so far this has been used only for outcome studies and despite some urging by me, it hasn’t been done for symptomatic treatments and I want to see those in every label for age, gender and race, at least. What we now put in labeling under age, gender and race is minimal. We don’t show the numbers and it would be useful if we did.”
Additionally, Temple’s presentation covered the history of demographic and subset analyses. A Web case replay of the presentation can be found here (begins at 24:30 on the replay). His slides can be found here. For information on the full precision dosing workshop, click here.