Session 4: Randomized Concentration-Controlled Trials
Organizer: Russell Reeve (Quintiles)
Chair:
Seth Berry (Quintiles) “Pharmacokinetic/pharmacodynamic modeling and simulation in the design and analysis of RCCTs”
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling is needed to design and understand the properties of a randomized concentration-controlled trial (RCCT). We will cover the exposure-response causal chain principles underlying these designs; will explore how PK variability in concentration-time profiles impacts dose-response analyses; and will discuss how implementing RCCTs can help control for the variability in PK, improving the signal while reducing noise in the PD properties of the biological system, and consequently enhancing the trial design.
Russell Reeve (Quintiles) “Efficiency of randomized concentration-controlled trials relative to randomized dose-controlled trials, and application to personalized dosing trials”
The literature on randomized concentration-controlled trials (RCCTs) is surveyed, comparing this trial design to the more traditional randomized dose-controlled trial (RDCT). It is shown that RCCTs require smaller sample sizes than RDCTs for the same power, and that they elicit more informative information on the exposure-response relationship. RCCTs are similar in spirit to personalized titration designs, and the relationship is explored, where it is shown that personalized titration designs have similar power, even in the face of categorical responses, such as a rheumatoid arthritis trial using the binary ACR20 as the primary endpoint.
Michael Hale (Baxter) “Practical Reasons Your Randomized Concentration Controlled Trial Might Flop”
The Randomized Concentration Controlled Trial (RCCT) is based on the idea that the clinical response to a dose of drug is mediated through exposure, and so randomizing people to different exposure targets should reduce “experimental noise”, compared with randomizing to different doses. Implementing an RCCT can be very challenging, however, and few have actually been performed. This talk will consider some of the practical hurdles which must be overcome, based on the speaker’s experience in designing and implementing a well-known RCCT for mycophenolate mofetil in renal transplantation.
