Early Stage Clinical

For The Times They Are a-Changin’: Recognizing the Importance of Early Data in Making Drug Development Decisions

Time was when data and reports from early phase clinical research were the last to be considered in decision-making for drug development and registration. Once a compound showed activity and continued to be promising in Phase III, the early data were prepared to be integrated with the more important Phase II-III efficacy data and added to the integrated safety database for regulatory submission. Including these early data in the submission was often their only importance.

However, to quote a song writer of the 60’s, “The Times They Are a-Changing” Recognizing the importance of early data in making drug development decisions, the FDA initiated the Critical Path Initiative (CPI). Among other accomplishments, the CPI has improved preclinical approaches with surrogate biomarkers and new assays, and streamlined clinical trials by using more modern scientific techniques and by employing enhanced bioinformatics and in silico techniques. 1 Clinical trial simulation – using in silico modeling – can predict efficient designs for development programs that reduce the number of trials and patients, improve decisions on dosing, and increase informativeness. 2 Known as Clinical Pharmacometrics or Model Based Drug Development, these approaches also have taken on a more important role in End-of-Phase 2 A (EOP2A) meetings. 3, 4, 5

Clinical Pharmacometrics has been a tool used within the FDA for many years. In a review of its own drug approval process, the FDA has shown that modeling and simulation of pharmacokinetic (PK) and pharmacodynamic (PD) parameters by its own staff proved instrumental in 65% of its final drug approvals, and in 55% of its final labeling decisions. While these processes are especially important in early drug development, the FDA recommends the use of modeling and simulation throughout all phases of drug development. 6 Among the 2020 goals of the FDA Pharmacometrics group are to: 1) have 100% of early/late phase protocols designed through modeling and simulation techniques; and 2) have sponsors use “learn and apply” cycles as the Clinical Pharmacometrics iterative approach allows them to learn and exploit definitive information about the properties of a potential new drug or biologic. 7

Modeling and simulation are often overlooked or not recognized as being useful. In particular, many smaller and mid-sized pharmaceutical companies do not take advantage of such techniques in their early trials. Compared with standard empiric drug development approaches, Model Based Drug Development accelerates the drug development process, increases the probability of success, allows termination of patient trials early for efficacy, safety or futility, and leads to more ethical treatment of subjects or patients through improvements in decision-making, protocol design, dosing recommendations, 8,9 biologic sample collection and sample size estimation.


QPS, LLC Brock G. Guernsey, Pharm.D.; Vice President & Head of Early Clinical

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