Clinical trial design and Clinical Trials Unit Nina L. Jebsen, MD, PhD Centre for Cancer Biomarkers, University of Bergen Centre for Bone- and Soft Tissue Tumours, Haukeland University Hospital Outline • Why clinical studies? • Preconditions • Principles • Types of clinical trials • Different phases in clinical trials • Design of clinical trials – Basket design – Enrichment design – Umbrella design – Marker-based strategy design – Adaptive design • Clinical Trials Unit • CTU, Haukeland University Hospital Why clinical studies? • Control/optimize an experimental process to – reduce errors/bias = internal validity/credibility – reduce variability = external validity/reproducibility – QA data collection settings = model validity/design • Understand the biological chain of events that lead to disease progression and response to intervention • Simplify and validate statistical data analysis • Generate evidence for effect of a specific treatment . in a specific population • Results extrapolated for standard clinical use . • Necessary (Phase III) for drug approval • Take into account ethical issues Preconditions • Access to patients (be realistic) • Approvals by legal authorities • Accept from local hospital department • Adequate resources/financial support • Infrastructure • Necessary equipment • Experienced personnel • Well-functioning routines • Study-team with mutual understanding of all implications Study population vs clinical practice • Age – study patients often younger • Performance status – study patients better performance status • Comorbidity – exclusion criteria in trials • Lower disease stage – higher tumour load in real life • Symptom independency in trials in advanced cancer – when to treat a patient with no symptoms? Clinical trial design - Principles • Sponsor: clinical investigator, research institution, pharmaceutical company? • Optimal design (model validity) • Clear study objectives and study hypothesis - PROTOCOL! • Trial of drug, medical device or medical procedure? • Patient population or healthy volunteers? • Indications for use of drug/device/procedure • Clinical endpoints (symptoms? survival? radiological response? biomarkers?) • Control group? Placebo? • Major goals: safety and efficacy Types of clinical trials • Observational studies – observe subjects and measure outcomes • Prevention trials – preventions therapies, vaccines, diagnostics, surgical techniques – large numbers and long-term follow-up • Screening trials – to detect presence or not of disease • Interventional studies – objects are exposed to medical drug/device/procedure – evaluation/comparison of outcomes Clinical studies – different phases Several years Months Phase IV Phase III Weeks Phase II “Real life” Therapeutic Post-marketing confirming Long-term effects Years Phase I Therapeutic Comparative Rare AEs explorative Efficacy Optimal use Safety Safety Human Efficacy pharmacological Interactions Pre-clinical Dose Safety In vitro & Side-effects in vivo experimental studies Model-based designs in clinical trials • Basket design • Enrichment design • Umbrella design • Marker-based strategy design • Adaptive design Biomarkers Definition: characteristics that are objectively measured and evaluated as an indicator of normal biological process, pathogenic processes or pharmacological responses to a therapeutic intervention 1. Screening (diagnostic – pathological process) 2. Prognostic (disease outcome) 3. Predictive (treatment response) • Clinical (age, tumour size…) • Physiological (BP, CRP, Hgb…) • Morphological (imaging, histology…) • Molecular biological (proteins aberrations, mutations…) Biomarkers tell us who we should not treat Basket design • Multiple diagnosis (typically rare tumour types ) • Collective screening procedure • Allocation to cohorts based on diagnose and/or biomarkers • Explorative, early phases – biomarker independent • Biomarker dependent – late phase • Randomization? • All patients are given same treatment (or vs. standard) Basket design Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 New treatment Randomize New drug Standard Enrichment design • Identify patients positive for a specific biomarker and use this for eligibility • Randomize to test group and control group • Target subgroup of patients → higher efficacy • Patients unlikely to respond are not exposed to toxic drug • Prerequisites: – understanding the mechanism of action of the drug – late phase trials Enrichment design New Biomarker treatment Randomize positive Standard Test for biomarker treatment Biomarker Off study negative Umbrella design • Specific diagnosis (single tumour type) • Multiple cohorts/sub-studies depending on biomarker – different status and/or different markers • Connected through initial screening procedure • Randomization within sub-cohorts – active drug or control • Explorative, different phases Umbrella design Test for biomarkers Positive marker Positive marker Positive marker 1 2 3 Sub study 1 Sub study 2 Sub study 3 Randomization Randomization Randomization New New New Standard treatment Standard treatment Standard treatment 1 2 3 Marker-based strategy design • Patients are tested for biomarkers • Randomly assigned to either have 1. treatment defined by their biomarker status 2. treatment by a non-marker-based method, such as physician choice Marker-based strategy design Negative Standard Marker Test for Positive Experimental based biomarker marker 1 drug 1 Positive Experimental marker 2 drug 2 Randomize Standard Non-marker Physicians Experimental based choice drug 1 Experimental drug 2 Adaptive design • Several stages • Flexible approach which allows for modification during recruitment phase based on treatment outcomes • Adapted second phase according to different scenarios • Bayesian decision rules: real time data → – interim analyses – optimization of trial parameters – “learning-as-you-go” • Aims: – improve efficacy/reduce use of resources – increase likelihood of success Adaptive design First phase Second phase Marker Marker independent independent response recruitment Marker Marker Study Biomarker dependent dependent Treatment response recruitment Marker independent Stop trial non-response Clinical Trials Unit • Facilitate clinical studies – Design/Phase (more or less specialised at diff. units) – Conduct (local investigators or commercial companies) – Legislations (approvals) – Coordination (multiple departments or centres) – Recruitment (clinicians or directly by patients) – Investigation (intervention) – Reporting (i.e. CRFs and AEs) – Analyses (results and outcomes) • Quality assurance – Good Clinical Practice • Education Study personnel Contract/Economy Monitor Mercantile Bioengineer Investigator Patients Pharmacist Study nurse Co-investigator Study personnel Contract/Economy Monitor Mercantile Bioengineer Study nurse Patients Pharmacist Investigator Co-investigator Clinical Trials Unit - HUS • Experienced study nurses involved in – recruitment/patient information – blood/tissue sampling and processing – drug administration – data collection (CRFs) – safety reporting (AEs) • Clinical trials of different phases and diagnoses – many associated investigators • General Biobank – longitudinal sampling blood (incl. plasma for liquid biopsy) – tissue (fresh, frozen, fixed) • Investigator initiated biomarker studies Clinical Trials Unit, HUS Activity adults per 3.2017 Clinical wards Recruiting trials: 19 32 active Haemato-oncology Active, not recruiting: 13 Surgery and ICU Non-recruiting/non-active: 5 Intervention centres Closed: 3 Radiology Pending: 4 Pathology • 1/3 academic Clinical trials unit Department of • Oncology/haemato-oncology adults Research research and • Phase I: 3 laboratories • Phase II: 10 development • Phase III: 14 • Phase IV: 2 Activity children per 12.2016 Industry initiated: 17 24 active Investigator initiated: 9 Clinical oncology Clinical trials unit • Phase I: 2 Oncology research groups Radiation therapy children • GynaecologicalPhase II: 2 cancer • Phase III: 13 Hyperthermia Dep. of paediatrics research unit Nuclear medicine.