L11 Clinical Trials PDF

L11 Clinical Trials Clinical Trials Dr. Anthony Kong Clinical Reader, KCL Consultant clinical oncologist, Guy’s Cancer centre  Clinical trials are studies conducted with patients Gener...

L11 Clinical Trials Clinical Trials Dr. Anthony Kong Clinical Reader, KCL Consultant clinical oncologist, Guy’s Cancer centre  Clinical trials are studies conducted with patients Generally designed to confirm the safety and effectiveness of a new promising treatment Also evaluate and optimize different therapeutic approaches including surgery, radiation therapy and combinations of approved drugs + other targets e.g. QoL, better diagnostic tests You can evaluate multiple factors in a clinical trial. 2  Built following unethical medical practices in world war two. 3  Priority = no harm done to the patient. See appendix at the bottom. Later phases = confirmation trial for approval of drugs in humans. 4  The sample size for each trial varies depending on the endpoints used, expected efficacy compared to standard etc Sample size determined by primary endpoint. 5  Primary endpoint must be predefined, and this forms the basis of the hypothesis of the trial. Tends to be a null hypothesis. Secondary endpoint do not contribute to calculating sample size. Phase 0 for research purposes rather than for clinical benefit. 6  Finds the highest dose that can be given without any assessed toxicity/side effects. End point = maximum tolerated dose and recommend 3+3 = give 3 patients 3 increasing doses. When 2/3 patients have adverse effects, the MTD is the level before. 7  Phase 2 tends to look at efficacy. End point tends to be tumour response. 8  Single arm = non comparative response rate Randomised = compare experimental vs standard treatment. Phase III = complementary study, compare to standard of care or placebo. Controlled randomized = very expensive, phase 2 must have shown promising efficacy. 9  Unknown factors have a reduced influence in randomized controlled trials as there tends to end up being a random distribution of age, sex and races. 10  Crossover sometimes needs to be done ethically e.g. cancer Problem with crossover so that the effects of the treatment can be diluted. Regulatory approval based on survival approval, therefore crossover may cause something to not be approved. Prevents bias from being introduced. Placebo can make a difference so it is important that no one knows what the drug is. 11  May not be used due to cost or complexity. Manufacturing placebo is costly as it has to be EXACTLY the same as the other treatment. Stratification can try and introduce balance. 12  13  Overall survival (OS) is a direct and true clinical efficacy measure and has been the gold standard endpoint for randomized phase 3 trial (other endpoints such as PFS and DFS are indirect surrogate measures) Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology In the UK, a clinically and statistically significant improvement in overall survival compared to existing therapy is often required for approval of a new drug use in the NHS Drugs have already been approved and licensed. Phase 4 allows for a more accurate view over how the drug affects the general population e.g. multiple medical conditions or other medications. 14  Can give patients full dose before surgery etc. May only give one or two dose to see effects before surgery. Compare biopsy before and after surgery when the drug has had an effect. 15  Quality of life used as an endpoint Often secondary measure 16  The quality-adjusted life year (QALY) Measures how well treatments lengthen and/or improve patients' lives The metric has served as a fundamental component of cost-effectiveness analyses in many countries including NICE It is a measure of the state of health of a person or group in which the benefits, in terms of length of life, are adjusted to reflect the quality of life One quality-adjusted life year (QALY) is equal to 1 year of life in perfect health Demonstration of quality-adjusted life years QALYs are calculated by estimating the years of life (QALYs) for two individuals. Individual A (who did remaining for a patient following a particular not receive an intervention) has fewer QALYs than treatment or intervention and weighting each year with a quality-of-life score (on a 0 to 1 scale) individual B (who received an intervention). The letters A and B designate the boundary lines, with It is often measured in terms of the person’s ability the QALY for A being only the blue area, the QALY to carry out the activities of daily life, and freedom for B being the blue area plus the additional tan from pain and mental disturbance area. NB It is possible to experience an QALY scores range from 1 (perfect health) to 0 improvement in health-related quality of life with (dead) age, for example through healthier life choices. 1 = perfect health 0 = terrible health QALY = 1 extra year with perfect health, does the person live longer WITH a good quality of life? Measures length of life and deterioration of health. Systematic reviews combine evidence from many different trials. 17  Aggregate studies together. Must be very careful to avoid bias 18  Example Meta analysis better shows the effect size of the treatment. Is there a test to see who responds to which drug? 19  Does a proven biomarker for one cancer show an effect in other cancer types? Look for mutation and see if they respond to drug. 20  One tumour types and multiple interventions. 21  Good Clinical Practice A brief introduction to GCP guidelines University of Warwick, available freely and downloaded online 22  GCP Principles 1. Ethical conduct Conduct trials according to the ethical principles originating from the Declaration of Helsinki 2. Risks & benefits Assess risks & benefits; trial should only start & continue if anticipated benefits justify the risk GCP Principles 3. Participant safety Ensure participant rights & safety prevail #1 priority 4. Adequate background information Must have adequate justification (inc. clinical & non-clinical information on an IMP, where applicable) to support the proposed trial 23  GCP Principles 5. Protocol Clear, detailed protocol defining scientifically sound trial (and peer reviewed) 6. Follow the protocol Trial must be conducted to approved protocol Have a system to deal with and review/monitor non- compliances GCP Principles 7. Responsibility for medical care The person responsible for medical care of participants must be appropriately qualified. At a recruiting site, this will be the PI 8. Training, education, experience Everyone involved in a trial must be suitably educated, trained & experienced to perform their delegated task(s) 24  GCP Principles 9. Informed consent Freely given informed consent must be obtained from each participant Provisions in the Mental Capacity Act 2005 allow for enrolment of participants in emergency situations 10. Trial documentation Record, handle & store information in a way that allows for accurate reporting, interpretation & verification GCP Principles 11. Data protection/security Identifiable data must be collected, stored and handled in accordance with the 2018 Data Protection Act (including GDPR) 12. IMPs & GMP IMPs should be manufactured, stored & handled in accordance with Good Manufacturing Practice and used in accordance with approved protocol 25  GCP Principles 13. Importance of Quality Assurance Systems with procedures that assure the quality of every aspect of the trial should be implemented 22 26