Shionogi Inc

Safwan Kezbor

Clinical Development Authority

A great deal of discussion has evolved in the last few years to come up with out-of-the-box creative notions to accelerate the drug development process and shorten the time to deliver innovative, life-saving therapies to patients. There is no doubt that the COVID-19 pandemic has fueled this dialogue in the light of the unprecedented development timelines observed in COVID-19 therapies which challenged both the pharmaceutical industry and the regulatory agencies to apply these accelerated timelines to other therapeutic areas programs. Many great proposals and lessons-learned topics were emphasized, with many already implemented. For most of the fellows engaged in these discussions, the topics were mainly focused on the later stages in drug development which include global multi-centre studies by nature with intensive discussion on boosting enrollment, enhancing study participants' experience and engagement, and delivering numerous effective and convenient options through decentralized clinical trials and other strategies. Understating the fact that late-stage drug development contributes only to a limited part of the entire clinical program strategy will underscore the need for equivalent thoughtful discussion around accelerating the decisionmaking process in earlier phases of drug development.

The decision to move the clinical program to global phase 3 clinical study is often not an easy one given the noteworthy investment and commitment required at that stage and often requires good deliberation inside the organization by careful review of the data and the evidence generated at the early stages of the clinical trials. Applying the concepts of quality of design and systematic critical thinking during the early stages of clinical development and First-In-Human (FIH) studies can deliver the accurate and adequate data-driven information needed to accelerate this decision and gain momentum in the global clinical program as a result. The thinking around FIH study design has moved away from the traditional design targeting winning a fast proof of the drug safety and tolerability as primary objective to more dynamic thinking of the secondary objectives desired to gain additional information beyond the safety and the pharmacokinetics (PK) data to enable better and fasterinformed decision in the further steps. Several sub-studies found their way to be implemented as essential parts in the FIH study design to accelerate the clinical program by leveraging the phase 1 unit settings which offer a better-controlled environment that allows collecting and investigating tests that might not be feasible or accessible in later stages of outpatients clinical studies settings. Food-effect studies are easily added to a healthy volunteer group during the conduct of the FIH study to inform the decision about the future usability and market use of the drug in realworld settings. Drug-drug interaction studies during FIH study offers accelerated access to data that can significantly influence the decisions for further studies. The FIH study settings in the phase I unit provide an excellent opportunity to implement continuous ECG recording to obtain QTc critical data that can offer a significant advantage through derisking the clinical program and open up a potential pathway for regulatory waivers for a separate Thorough QT study with tremendous benefits for the program timelines and resources. Based on the safety and PK data obtained in earlier SAD cohorts, an accelerated dose escalation process can allow MAD cohorts to be initiated before the completion of all SAD cohorts which can shorten the time to get access to the entire unblinded study data without compromising the safety of the participants. Data from patients’ cohorts in the FIH studies can add great insight into the pharmacokinetics and pharmacodynamics and speed up the decision for any required dose adjustment or additional safety monitoring assessments. Sensible and well thought out studying of specific biomarkers related to the drug MoA pathway in the patients’ groups in the FIH can inform the design, schedule of events and duration of required testing in later phases.

Planning for diversity in clinical trials is essential. This planning should typically start in the early phases of clinical development. Although the sample size is naturally small at this stage, diverse data can shed light on any significant outliers such as significant differences in biomarkers response and PK variabilities between sex, race or comorbidities. This can boost the thinking of the study design and the target population in later phases of clinical development. The recent FDA guidance for diversity highlighted the need for adequate planning for diversity at early stages in clinical development. Getting early diverse data can significantly boost clinical development milestones.

Careful considerations of this accelerated design and strategies in the FIH study can enable early insight into how the drug can progress in later stages, how the target product profile can be modified as a result of these findings, and what value the new investigational drug can deliver in the competitive market, how the drug differentiates from its class therapeutics, and what impact the drug can have on the patient’s life in real-world settings. These elements can certainly increase the value of the new investigational drug at very early stages and shorten the timeline to deliver the drug to patients.