Clinical Trials I - University of Bremen - 2024/2025 PDF

Faculty 03 Mathematics and Computer Science Clinical Trials I Introduction Dr. Max Westphal Winter Semester 2024/2025  Clinical Trials I Dr. Max Westphal Winter Semester...

Faculty 03 Mathematics and Computer Science Clinical Trials I Introduction Dr. Max Westphal Winter Semester 2024/2025  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Contents of the course 2/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Contents of the course Introduction Study types Randomized controlled trials Methods of randomization Hypotheses and endpoints Adjustment for covariates and stratification Principles of sample size calculation Responsible persons and their roles Responsibilities of Biometricians 3/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Clinical trials and their history 4/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Definition of a clinical trial Clinical trials are prospectively planned research studies that investigate interven- tions and evaluate their effects on human (patients or probands) health out- comes in a controlled setting. Important criteria are: Prospectively planned Intervention Health outcomes In humans (not in animals or in vitro) Controlled setting (explanation later during the course) 5/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Prospectively planned studies Study is planned in advance Patients are recruited, treated and observed during the course of the study Hence, data is captured "prospectively" (in contrast to retrospective studies) Nature and frequency of the treatment and observations are specified in advance as precise as possible 6/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Medical intervention Possible medical interventions: drugs, surgery, radiation, chiro-, physio-, or other therapies... not only therapies, but also preventions (e.g. vaccines), diagnostic methods Medical measures that are performed for study purposes and not in the scope of standard of care Studies to assess routine measures are called observational studies (or epidemiological studies) 7/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Goals of clinical studies The goal of a clinical trial is to gain evidence for the efficacy and safety of a medical intervention for all subjects with a given medical indication Extrapolate from a (limited) sample to a defined population (range of indications) Consequence: Great importance of biostatistics (biometry) 8/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 History of clinical trials Early ideas and studies: Book of Daniel (Bible, 800 BC, written 164 BC): 10 people with vegetarian diet vs. unknown number in control group Paré 1537 wound management with boiling oil or a new mixture, unplanned "experiment" Beginnings in the 18th century: Study of Lind (1747) to counter scurvy on a ship (HMS Salisbury). Oranges and citrus fruits most helpful 9/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 History of clinical trials - Lind’s experiment “I took twelve patients in the scurvy on board of the Salisbury at sea. The cases were as similar as I could have them... they lay together in one place... and had one diet common to them all.” “Two of these were ordered a quart of cider a day. Two others took twenty-five gutts of elixir vitriol... Two others took two spoonfuls of vinegar... Two were put under a course of seawater... Two others had each two oranges and one lemon given them each day... Two others took... an electuary....” 10/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 History of clinical trials - Lind’s experiment “The most sudden and visible good effects were perceived from the use of oranges and lemons....” As a consequence, the British navy introduced a citrus diet in 1795 11/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 History of clinical trials Few studies in the 19th century: French physiologist Claude Bernards’s (1813-1878) book “Introduction to the study of experimental medicine” P.C.A. Lius (1837). “The applicability of statistics to the practice of medicine.” London Medical Gazette 20: 488-91. Breakthrough in 20th century: Studies with random allocation and blinding Ethics: Declaration of Helsinki (Nuremberg Code) German Medicines Act (1961, 1976, 1986,...) Since 1996/1998 international quality standards, e.g. Guidelines of the “International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)”. 12/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Particularities of clinical research 13/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Particularities of clinical research Research in humans (patients resp. probands) Very high ethical requirements Highly regulated research European regulations and directives Local legislation High quality requirements GCP (Good Clinical Practice, ICH Guideline E6) SOPs (Standard Operating Procedures) 14/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Intersection of disciplines Besides medicine and biometry, numerous other disciplines play a role: Law (regulation), Ethics / Philosophy (ethics, human rights), Economics (health care system, revenue), Psychology (recruitment, information and consent, acceptance), Cultural studies (patient information). 15/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Biometry and ethics Ethical responsibility in: Study planning and study design, Sample size calculation, Correct biometric analysis, Correct interpretation of results 16/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Drug development - from formula to pill 17/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Drug development new drug in-vitro experiment clinical trial animal testing mass deployment 18/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Effect and efficacy (Pharmacological) Effects: change of vital parameters, laboratory parameters, micobiological findings etc., e.g.: reduction in blood pressure, reduction in blood glucose, inhibition of bacteria growth, platelet aggregation (Aspirin). The pharmacological effect describes (in a neutral way), how the substance under investigation affects the body function 19/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Effect and efficacy (Therapeutic) Efficacy: Cure or relevant improvement of the course of disease, chance of survival, long-term effects etc., e.g.: less migraine attacs, avoidance of myocardial infarction, avoidance of diabetic long-term damage, cure of pneumonia, survival time No therapeutic efficacy without pharmacological effect! Pharmacological effect without therapeutic efficacy is possible and can be observed in praxis 20/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Definitions Effect: Pharmacological effect Efficacy: Performance of an intervention under ideal and con- trolled circumstances Effectiveness: Performance of an intervention under real world con- ditions Efficiency: Benefit of a therapy also under cost-benefit aspects 21/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Benefit and efficiency Besides efficacy, the tolerability/safety is a decisive factor for the use of therapies The therapeutic benefit results from the trade-off between efficacy and safety For the actual use the efficiency and costs are relevant e.g. IQWiG - Institut für Qualität und Wirtschaftlichkeit (founded in 2004) 22/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 AMNOG (2011) AMNOG: Arzneimittelmarktneuordnungsgesetz High increases in spending in the public health system Particularly high increase in high-cost special preparations Need for reorganization, pharmaceutical companies are obligated to make a statement of the risk-benefit-assessment when applying for Regulatory Approval Without the proof of an additional benefit, the refund is limited to the price of comparable drugs 23/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 “Funnel” of drug development Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 5 Pre-clinical development (12.4) 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 24/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Pre-clinical trials Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 5 Pre-clinical development (12.4) 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 25/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Aims of pre-clinical development Physiological mechanism Pharmacological effect Pharmacological effects in animals Adverse effects Pharmacological interactions Pharmacokinetics in animals (ADME - absorption, distribution, metabolism, excretion) Toxicology (toxicity, geno-toxicity, carcinogenicity, reproductive and developmental toxicity) Mechanical description of the mechanism of action 26/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Advantages and disadvantages of pre-clinical devel- opment Advantages: Large production of knowledge Reliable results (controlled setting) Precise description of the mechanism of action (in animals) and (in part) also of the efficacy (in animals) Disadvantages: No established findings for the effect (let alone the efficacy) in humans Only hints for clinical application 27/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Pre-clinical Trials Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 Development plan for 5 Pre-clinical development (12.4) clinical Phases I to III and Pharmacovigilance 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 28/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 The phases of Clinical Development in de- tail 29/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase 0 Clinical Trials In some instances so called Phase 0 clinical trials are conducted Single sub-therapeutic doses (“microdosing study”) No therapeutic intent, no intent to examine tolerability Aims at gaining information on pharmacokinetics Small number of subjects (< 20) 30/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase I Clinical Trials Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 5 Pre-clinical development (12.4) 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 31/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Aims of Phase I Clinical Trials “First-in-human study” Investigating safety in healthy, mostly young and male volunteer subjects When the therapy is toxic (e.g. chemotherapy), trials are conducted in patients Proof of safety Careful and step-by-step approaching of the toxic range Determination of a safe starting dose Determination of the maximally tolerated dose (MTD = highest dose without limiting side effects/toxicities) Sometimes also first investigation of dose-response relationship (no efficacy) 32/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase Ia vs. Phase Ib Phase Ia Phase Ib Small groups of subjects (20-80) Small groups of subjects (20-80) Single ascending dose (SAD) Multiple ascending doses (MAD) Safety and tolerability Investigate PK/PD Subsequent dose escalation Safety and tolerability Investigate pharmacokinetics (PK) Subsequent dose escalation and pharmacodynamics (PD) 33/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 DLT and MTD DLT MTD One or more non-acceptable Usually defined as a dose with a reversible side effects certain rate of DLTs observed Pre-defined Or as the highest dose without a certain rate of DLTs observed Definitions of DLTs vary between studies and indications 34/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Standard design in Phase I (3+3 design) Enter 3 patients at given dose 0/3 subjects with DLT 1/3 subjects with DLT ≥ 2/3 subjects with DLT Enter 3 more subjects STOP Escalate to next dose level at current dose level MTD = previous dose level 1/6 subjects with DLT ≥ 2/6 subjects with DLT 35/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase II Clinical Trials Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 5 Pre-clinical development (12.4) 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 36/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Aims of Phase II Clinical Trials “Proof of Concept” Often: first use in patients Therapeutic effect in the indication Tolerability in patients Estimation of therapeutic window (min. efficacy, max. efficacy or MTD) PK in patients Dose finding for phase III Gather information for planning of phase III 37/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Procedure in Phase II Narrow range of indication (e.g. specific stage of disease) Often restriction to “uncomplicated cases” Small collectives of approx. 50-300 subjects Dosage below MTD Investigation of tolerability by description of adverse events (AEs) and change in laboratory values or other physiological parameters Focus is more on effect than efficacy Definition of desired or expected effects (primary endpoint). 38/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Criticism of Phase II Clinical Trials Collective is too narrow (also in comparison to the subsequent phase III trials) Collective is too small to make precise statements Focus is too much on effect rather than efficacy Primary criteria differ: Phase II rather surrogate parameters, e.g. laboratory values Phase III rather clinically relevant parameters, e.g. healing, survival 39/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase IIa vs. Phase IIb Phase IIa Phase IIb First trial in patients with several Near final dose doses Exploring effect and efficacy in Focus on dose finding and patients dose-response relationship 40/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase III Clinical Trials Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 5 Pre-clinical development (12.4) 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 41/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Aims of Phase III Clinical Trials Clinical Efficacy Determination of efficacy and tolerability/safety in controlled clinical setting Clinically relevant endpoints Investigation in “standard patients” Comparison to standard of care (SOC) or placebo Usually: 2 pivotal phase III trials needed for Regulatory Approval 42/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Procedure in Phase III Collectives larger than in Phase II (1000-3000) Comparison to control group Randomization Investigation of efficacy with respect to superiority over placebo, or superiority over SOC, or non-inferiority to SOC Investigation of safety (AEs, laboratory findings,...) 43/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase IIIa vs. Phase IIIb Phase IIIa Phase IIIb Prior to applying for approval After applying for approval but before launch Support initial claims of efficacy and safety “Label expansion” trials Obtain additional safety data Support marketing claims 44/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Phase IV Clinical Trials Years 0 1 2 Synthesis and testing (5.000 - 10.000 compounds) 3 4 5 Pre-clinical development (12.4) 6 Clinical Phase I (8.6) 7 8 Clinical Phase II (4.6) 9 10 Clinical Phase 11 III (1.6) 12 Application for regulatory approval (1.1 compounds) 13 On average approved after 13.5 years (1 compound) 14 Clin. Phase 15 IV 16 (1) 17 45/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Aims in Phase IV Clinical Trials Detection of rare, unknown AEs More precise determination of rates of known adverse reaction (and side effects) “Post Marketing Surveillance” Analysis of effects of medication in an unselected collective in practice Investigation of long term effects and efficacy 46/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Procedure in Phase IV Often no control group Cover whole range of indication Avoid “laboratory setting” Fast, cost-effective and simple implementation Often only observational studies Large collectives (several thousand patients) 47/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Revocation or withdrawal of marketing authoriza- tion: Adverse Reactions (Selection) Time point Indication Substance(s) Adverse Reaction 12/1997 Antidiabetic Troglitazon Liver toxicity 11/1998 Parkinson drug Tolcapon Hepatitis 11/1998 Calcium antagonist Mibefradil severe cardiac arrhythmia 01/1999 Antipsychotic Sertindol (deadly) QT prolongation 04/1999 Antibiotic Trovafloxazin acute liver cell failure............ 01/2016 Medication for migrane Dihydroergotamin Fibrosis and ergotism 05/2016 Antibiotic Fusafungin severe hypersensitivity reaction............ 04/2018 Analgesic Flupirtin serious liver damage............ 01/2020 Atkin Keratosis Ingenolmebutat increased risk of skin cancer 48/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Formal requirements for clinical trials Study protocol Statistical analysis plan (SAP) Lots of appendices (Helsinki-Declaration, SAE-Form etc.) CRF (Case Report Form) Patient information, Informed consent form Patient insurance policy and conditions Report in a specific format (GCP/ICH) Documentation and archiving of all documents (10 years) 49/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Questions? 50/51  Clinical Trials I Dr. Max Westphal Winter Semester 2024/2025 Literature S.J. Pocock: “Clinical Trials - A Practial Approach” John Wiley & Sons Chichester, 1983 D. Meinert: “Clinical Trials” Oxford University Press New York, 1986, (revised ed. 1991) L.M. Friedmann, C.D. Furberg, D.L. DeMets: “Fundementals of Clinical Trials” 3rd ed. Springer New York, 1998 M. Schumacher, G. Schulgen: “Methodik Klinischer Studien” Springer Berlin, 2002 D. Machin, S. Day, S. Green, B. Everitt, S. George: “Textbook of Clinical Trials” John Wiley & Sons Chichester, 2004 Texts und figures party originate from talks of Prof. Mühlbauer and Dr. Hilf, Quintiles of the advanced trainings course for investigators of the KKSB 51/51