优化早期临床试验 降低风险并提升决策效能

Optimizing Early-PhaseClinical Trials to Minimize Risk ELIZABETH ALLEN, PhD, Vice President, Early Phase Development Centre of Excellence, Scientific Strategy, IQVIARAYMOND COOK, MD, Vice President, Medical Strategy for Early Phase Development, IQVIADAPHNE C. TSITOURA, MD, PhD, Vice President, Therapeutic Strategy, IQVIA Table of contents Introduction: The increasing importance of early-phase trialsin a changing environment Pillars of success 4Pillar one: Innovative trial design frameworks4Adaptive and hybrid trial designs4Basket trials5Master protocols6Bayesian analytics7Pillar two: Selecting CRO partners that align scientific expertise Global strategiesPillar three: Integrated deliveryCase Study: Early-phase study in sickle cell diseaseFuture horizons: Early stage and beyondAbout the authors Timing of emerging data has also become a critical issue,as rising development costs increasingly tighten decisionwindows and demand earlier and clearer decision-readysignals around dose, exposure, biological activity, andearly efficacy. These signals must be clear, credible, and Introduction:The increasing importance For more than half a century, clinical trials have adopteda model wherein phase I and II trials examine the safety,pharmacokinetics, dose range, optimal dosing, and earlyefficacy of a new molecule in small groups of healthyvolunteers and patients. These phases have traditionallyoperated consecutively, with phase II studies beginningafter the results of phase I have been reported andstatistically analyzed. Today, this paradigm is changing To meet the development of recent scientific advances,the regulatory environment has also shifted. Emergingtherapeutic innovations including novel modalities,precision dosing paradigms, and hybrid trial designsnecessitate a substantially higher level of operationaland scientific sophistication compared with traditionalhealthy volunteer studies. Consequently, real-time data At the same time, the operational environment is alsochanging in ways that directly affect early-phase feasibilityand risk. Regional variability in ethics and regulatorypractices and differing expectations for data governance,as well as volatile geopolitical factors, may influence Pillars of success PILLAR ONE: INNOVATIVE TRIAL DESIGN FRAMEWORKS Adaptive and hybrid trial designs Adaptive and hybrid trial designs are flexible early-phase strategies that focus not on completing predefined steps,but on delivering insights that accelerate the program forward, or, in some cases, stop it early. As such, they are Combined hybrid andadaptive designs Adaptive designs Hybrid designs Figure 2. Adaptive and hybrid trial designs. Adaptive designs are particularly useful in first-in-human(FIH) and later early development studies, because theypermit sponsors, clinical research organizations (CROs),and investigators access to real-time emerging clinicaldata during the course of a study, allowing them tomake any necessary changes if required: for example,dose adjustments can be made as real-time safetyand pharmacokinetic/pharmacodynamic (PK/PD) data Hybrid trial designs integrating both healthyvolunteers and patient cohorts within a single protocolenable earlier characterization of a candidate’spharmacodynamic and disease-modifying effects “In an adaptive-design study, size ofstudy cohorts can be re-estimated,ineffective study arms dropped, When integrated with adaptive design elements,basket trials demonstrate enhanced analytical andoperational efficiency, enabling dynamic modificationof cohort expansion, patient stratification, anddecision thresholds based on emerging interim data.Incorporation of adaptive elements in basket designs Basket trials Basket trials represent an advanced early-phaseclinical development strategy in which a sharedinvestigational hypothesis typically defined by acommon molecular target or mechanism of actionis evaluated across multiple biomarker-selected ormolecularly defined patient populations within a Figure 3. Basket trials. The incorporation of these advanced designframeworks introduces additional complexity.Specifically, the increased sophistication of protocol The implementation of these advanced trial designsis also associated with increased regulatory scrutiny.While regulatory authorities have demonstratedgrowing receptivity to innovative methodologies, they Equally important is the alignment of the trial designwith the scientific and clinical requirements of theinvestigational molecule. The selected design shouldbe purpose-built to address the key pharmacologic, design assumptions, methodological rigor, and These adaptive design features have the capacity togenerate high-quality, rapid, and integrative PK/PD,biomarker, and safety data. However, their successfulimplementation is contingent upon robust and well- When appropriately designed and executed, adaptive,hybrid, and basket trial methodologies enable theefficient generation of early clinical sign