MD214 U1L3 22 Clinical Trials and SRs PDF

MD214 Unit 1 Lecture 3: Clinical Trials Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; University of Galway University ofGalway.ie MD214 Unit 1 Lectures 1. Introduction to drugs. Drug...

MD214 Unit 1 Lecture 3: Clinical Trials Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; University of Galway University ofGalway.ie MD214 Unit 1 Lectures 1. Introduction to drugs. Drug targets and receptor families 2. Agonists and antagonists. Dose and concentration responses 3. Mechanisms and dose responses of selected drugs. Clinical trials, systematic reviews and meta analysis 4. Adverse drug reactions and poisoning Unit 1, Week 1: Drug Action What are drugs? Sources Classification What are drugs targets? Proteins Others What is the nature of drug interactions? Agonists Antagonists How are drug effects measured? Receptor occupancy Names Receptors Ion channels Enzymes Transporters Full Partial Inverse Biased Competitive Noncompetitive Kd and Bmax Potency Dose response EC50 and Emax Efficacy Unit 1, Part 2: Drug Action and clinical effects Clinical Evaluation Specific drug examples Therapeutic effects Mechanism of action Harmful effects Dose response Clinical Trials Systematic reviews ADRs Phase IV Phases 1-III Meta analyses Poisoning Types Treatment Overview – today’s lecture and online mini-lecture At the end of these lectures you will be able: • To understand where to find more information about drugs • To appreciate the processes involved in the clinical evaluation of drugs including clinical trials, systematic reviews and meta-analysis • To identify the mechanism of action of a number of drugs that appeared in our survey • To appreciate the application of dose response relationships for a selection of these drugs University ofGalway.ie Prescribing Guidelines and formularies 2018 ESC/ESH Guidelines for the management of arterial hypertension University ofGalway.ie sPC (Summary of Product Characteristics) Clinical Trials University ofGalway.ie University ofGalway.ie Overview At the end of this section you will be able to: • Identify the various stages of clinical trials and their purpose • Be aware of the planning, design and conduction of clinical trials University ofGalway.ie The Clinical Trial • A specialised bioassay designed to measure therapeutic efficacy and detect adverse effects • Prior to the 1960s, no objective testing was required Rationale of Clinical trials Planned experiment involving patients to elucidate most appropriate treatment of future patients with a given medical condition (limited sample, inferences on general population). Phase I Trials: Clinical Pharmacology and Toxicity: 20-80 subjects Phase II Trials: Efficacy and safety testing in a small number of patients (100-300). “Screening” process: 2 years. Phase III Trials: Full-scale Evaluation of Treatment. Large-scale efficacy and safety testing in substantial numbers of patients (1000-3000): 3 years. Phase IV Trials: Post-marketing Surveillance for drugs administered over long periods of time: several years. University ofGalway.ie Phases of Clinical Development Clinical General Phase Aim Subjects/ Design Data Collected No. of subjects Time required Ia Exploratory, safety, tolerability Healthy subjects; ↑ single dose; placebo, random, double-blind Adverse events; PK parameters 20-100 6 months Ib Exploratory, safety, tolerability Healthy subjects; ↑ repeat dose; placebo, random, double-blind Adverse events; PK parameters 20-100 6 months IIa Exploratory, safety & efficacy Patients; clinical dose; placebo, random, double-blind Adverse events; PK parameters; efficacy ‘proof-of-concept’ 50-200 6 months – 2 years IIb Confirmatory; dose selection Patients; selected dose levels; placebo, random, double-blind Statistical analysis of dose response; confirmation of dose 200-500 2-3 years III Confirmatory; efficacy & safety Patients in target indications; selected dose level; placebo, random, double-blind Statistical measurements demonstrating safety & efficacy 300-3000+ 1-4 years IV Obligatory post marketing surveillance Treated patients Adverse events 10 000+ 2-4 years + University ofGalway.ie Scientific Method Issues Size: The trial must recruit enough patients to obtain a reasonably precise estimate of response on each treatment. Avoidance of bias: The selection, ancillary care and evaluation of patients should not differ between treatments, so that the treatment comparison is not affected by factors unrelated to the treatments themselves. University ofGalway.ie Scientific method of clinical trials • • • • • Define the purpose of the trial: state the specific hypotheses Design the trial: a written protocol Conduct the trial: good organization Analyse the data: descriptive statistics Draw conclusions: publish results University ofGalway.ie Organization and planning • Which patients are eligible: representative, source, criteria of eligibility, exclusions. • Which treatments are to be evaluated: drug formulation, route, amount, frequency, duration, side effects, dose modification and withdrawals, patient compliance, ancillary treatment and patient care. • How each patient’s response is to be assessed: baseline assessment before treatment starts, criteria of patient response, side effects, other aspects of patient monitoring. University ofGalway.ie PICO Population Intervention Control/Comparison Outcome University ofGalway.ie Characteristics of a Phase 3 trial • • • • • • Randomization to groups Placebo controlled Compared against current best treatment Most funded by pharmaceutical industry Well-defined protocol Results submitted to Regulatory Authorities Protocol features • Background & general aims, specific objectives. • Patient selection criteria, treatment schedules, methods of patient evaluation. • Trial design, registration and randomization of patients, patient consent. • Required size of study, monitoring of trial progress, forms and data handling. • Protocol deviations, plans for statistical analysis, administrative responsibilities. Sources of Funding Pharmaceutical companies: responsible for organizing the great majority of clinical trials. National Health Organizations: MRC (UK), NIH (USA): Only justified for trials of major treatment issues. Locally based trials: No external backing. The best of such studies can provide important source of new therapeutic ideas, but many are poorly organized University ofGalway.ie Regulatory Authorities • Two important stages: Investigational New Drug (IND) for first in human studies. New drug Application (NDA) for launching on to the market • Food and Drug Administration (FDA): founded in 1930, USA • European National authorities: In Ireland, the Health Products Regulatory Authority (HPRA) • European Union: European Medicines Evaluation Agency (EMEA). Mutual recognition • Japan: usually insist on some clinical trials in Japan itself. • World Harmonization University ofGalway.ie Randomized controlled trials • Problems with uncontrolled trials: no direct comparison with a similar group of patients on more standard therapy. • Problems with historical trials: potential incompatibility with patient selection and patient environment. • Problems with concurrent non-randomized controls: Systematic assignment and judgement assignment. • Feasibility and ethics of randomization? An essential tool for testing the efficacy of therapeutic innovations. University ofGalway.ie Blinding and Placebos Justification for placebo controls: to make patient attitudes to the trial as similar as possible in treatment and control groups. Double-Blind trials: neither the patient nor those responsible for care and evaluation know which treatment they are receiving. University ofGalway.ie When is blinding feasible? Ethics: The double-blind procedure should not result in any harm or undue risk to a patient. Strong connection between ethics and high scientific and organizational standards Practicality: For some treatments it would be totally impossible to arrange a doubleblind trial. Avoidance of bias: One needs to assess just how serious the bias might be without blinding Compromise: Sometimes partial blinding (e.g. independent blinded evaluators) can be sufficient to reduce bias in treatment comparison. University ofGalway.ie Patient Protection The Belmont Report principles: Respect for persons, the requirement to treat individuals as autonomous agents, and the requirement to protect those with diminished autonomy. Beneficence, maximizing possible benefits and minimizing possible harms. Justice, as demonstrated by fairness in distribution of the opportunity to participate in research. University ofGalway.ie A trial should avoid… • Bias: exaggeration of benefit of new therapy. Too few patients. • No published findings: publication furthers medical knowledge. • Each trial requires a balance between individual and collective ethics. Informed patient consent. University ofGalway.ie The size of a Clinical Trial “How many patients are necessary?” Statistical methods can be used to determine the required number of patients to meet the trial’s principal scientific objectives. The standard statistical approach involves power calculations University ofGalway.ie Multi-centre Trials Advantages: Patient accrual faster, any conclusions have a broader more representative base, collaboration should raise standards. Disadvantages: planning more complex, expensive, all must follow same protocol, standardised training, a well-organized centre for data essential, motivation of all participants, some participants may only enter occasional patients University ofGalway.ie Publication of findings Writing a Trial report • • • • • • Title Summary Introduction: Why did you start? Methods: What did you do? Results: What did you find? Discussion: What does it mean? University ofGalway.ie Critical Evaluation • Careful scrutiny of the methods section • Potential for distorting results (too few patients, failure to account for all patients, inappropriate statistical methods, confusing presentation of results) • Check that conclusions are justified from the results given University ofGalway.ie Registering of Clinical Trials • Now, it is expected that all clinical trials are registered • For example in the Clinical trials website of the FDA (https://www.clinical trials.gov/) Overall conclusions • Weighing up the efficacy (therapeutic benefits) and safety (harms) of the treatment • Sufficient evidence to enable the regulatory authorities to grant a licence, i.e. that it has a “place in therapy” • Follow-up postmarketing surveillance Case study University ofGalway.ie University ofGalway.ie SURMOUNT-1 Trial Jastreboff, Ania M., Louis J. Aronne, Nadia N. Ahmad, Sean Wharton, Lisa Connery, Breno Alves, Arihiro Kiyosue, Shuyu Zhang, Bing Liu, Mathijs C. Bunck, and Adam Stefanski. "Tirzepatide Once Weekly for the Treatment of Obesity." The New England Journal of Medicine 387.3 (2022): 205-16. Web. Research question. Clinical need for effective pharmacotherapy for obesity. Tirzepatide — a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist recently approved in the United States to treat type 2 diabetes — induced clinically relevant weight reduction in phase 2 studies of people with diabetes. Its efficacy for weight reduction in those without diabetes is unknown. Funding: Eli Lilly. Design, PICO A phase 3, randomised, double-blind, placebo-controlled, multicentre trial at 119 sites in 9 countries. P – 2539 adults with a body-mass index of 30 or higher, or 27 or higher with at least one weight-related complication I – once-weekly subcutaneous tirzepatide at one of three doses (5 mg, 10 mg, or 15 mg) C – placebo O – co-primary endpoints: percentage change in weight from baseline to week 72 and weight reduction of at least 5% by week 72 University ofGalway.ie Patient Characteristics 1 Patient Characteristics 2 Results - efficacy Results – safety 1 Results – safety 2 Gastrointestinal events, including nausea, diarrhea, and constipation, were the most common adverse events seen with tirzepatide; the majority of events w transient and mild to moderate in severity. Conclusions In the present trial, adults with obesity had average weight reductions of 19.5% and 20.9% with 10-mg and 15-mg doses of tirzepatide, respectively, as compared with a 3.1% weight reduction with placebo (treatment-regimen estimand). All three doses of once-weekly subcutaneous tirzepatide led to clinically meaningful and sustained weight reduction in obese adults who did not have diabetes. The incidence of adverse events was similar in the 10-mg and 15-mg groups. This finding suggests that the 15-mg dose may confer additional benefits in some patients, without added safety concerns. University ofGalway.ie Conclusions 2 For perspective: the average placebo-adjusted weight reductions with older anti-obesity medications that are currently approved by the FDA for the treatment of obesity are approximately 3.0 to 8.6%, whereas a recently introduced anti-obesity medication, semaglutide (2.4 mg), resulted in a placeboadjusted weight reduction of 12.4%, with nearly one third of persons having a weight reduction of 20% or more. Limitations: • • • The enrolled participants with obesity and overweight may represent a subpopulation with a greater commitment to weight-management efforts than the general population with obesity. The measured baseline cardiometabolic risk factors in the trial population, such as blood pressure and lipids, were relatively normal, possibly attenuating the potential to show improvement, though meaningful changes in these variables were observed. Overall, only 5.5% of trial participants with overweight (BMI of 27 to <30) were included University ofGalway.ie Summary • Since the 1960s, Phase I-III trials have become the means by which new drugs enter the market • Clinical trials require extensive planning and execution • It is essential that both positive and negative trials are published • Databases are ways in which findings on all trials can be interrogated University ofGalway.ie Systematic Reviews and meta-analysis University ofGalway.ie Systematic Reviews A review of a clearly formulated question that uses systematic and explicit methods: • to identify, select, and critically appraise relevant research, and • to collect and analyse data from the studies that are included in the review Involves collating all of the experimental evidence, i.e. “A study of studies” The Cochrane Collaboration glossary (https://community.cochrane.org/glossary Rationale Often individual studies may not be large enough to produce answers on their own There may be conflicting results across studies resulting in different conclusions Hierarchy of evidence Evidence based medicine pyramid: Clinical opinion: based on experience/expertise Case reports: a finding from a single patient Case series: a number of cases Case-control studies: a retrospective study that compares subjects who have a condition (cases) with patients who do not (controls) Randomized controlled trials (RCTs): prospective investigations of effects where groups are assigned before treatment begins Meta-analysis It is an optional part of a systematic review They are often necessary as most treatments are only moderately effective Thus, to demonstrate or refute moderate treatment effects we need reliably to avoid: 1. Moderate random errors (fluctuations from the “truth” due to the play of chance) 2. Moderate biases (i.e. systematic differences from the “truth” due to e.g. study design) University ofGalway.ie Prof. Sarah Lewington, University of Oxford, UK When to conduct a Meta-analysis • When more than one study has estimated an effect • If the patients, interventions and outcomes are sufficiently similar to produce a clinically useful and meaningful result • When the data are available • The effect size with 95% confidence intervals is constructed for each study and these are lined up as a Forest Plot University ofGalway.ie Prof. Sarah Lewington, University of Oxford, UK The Forest Plot and the Cochrane logo We call this representation a "forest plot". This forest plot within our logo illustrates an example of the potential for systematic reviews to improve health care. It shows that corticosteroids given to women who are about to give birth prematurely can save the life of the newborn child. The circle formed by two 'C' shapes represents our global collaboration The lines within illustrate the summary results from an iconic systematic review. Each horizontal line represents the results of one study, The diamond represents the combined result, our best estimate of whether the treatment is effective or harmful. From the Cochrane Library Website University ofGalway.ie Some examples of meta analyses University ofGalway.ie University ofGalway.ie Steroids in the treatment of critically ill patients with COVID-19 • • • • COVID-19 provokes a significant immune response in certain patients Is life-threatening and requiring hospitalisation Critically ill patients often need ventilation Glucocorticoids (dexamethasone, hydrocortisone, methylprednisolone) are strong anti-inflammatory agents that are being examined for their effects • Several studies have been published University ofGalway.ie From: Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis JAMA. Published online September 02, 2020. doi:10.1001/jama.2020.17023 Figure Legend: Association Between Corticosteroids and 28-Day All-Cause Mortality in Each Trial, Overall, and According to Corticosteroid DrugThe area of the data marker for each trial is proportional to its weight in the fixed-effect meta-analysis. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial result is for patients who were receiving invasive mechanical ventilation at randomization. CAPE COVID indicates Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease; CoDEX, COVID-19 Dexamethasone; COVID STEROID, Hydrocortisone for COVID19 and Severe Hypoxia; DEXA-COVID 19, Efficacy of Dexamethasone Treatment for Patients With ARDS Caused by COVID-19; REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; Steroids-SARI, Glucocorticoid Therapy for COVID-19 Critically Ill Patients With Severe Acute Respiratory Failure. aThe random-effects analysis estimates both the average and variability of effects across studies. The 95% CI for the average effect (shown here) is wide because there is a small number of studies, some of which have very small sample size. The prespecified primary analysis was the fixed-effect analysis, which should be used to guide clinical interpretation of the results. Date of download: 10/5/2020 Copyright 2020 American Medical Association. All Rights Reserved. Concerns with SSRI antidepressants • • • • • “SSRIs are no better than placebos” There is no dose-response relationship The effect of SSRIs is so small as to not be clinically meaningful SSRIs are only of benefit in severe depression The beneficial effects are due to side effects augmenting the placebo effect University ofGalway.ie Examining the concerns • In April 2018, Cipriani et al published a systematic review and meta analysis of 21 antidepressants • Consisted of 522 trials comprising nearly 120,000 subjects • All antidepressants had a greater efficacy than placebo Cipriani, A. et al. (2018): Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391: 1357–66 Summary • Systematic reviews are a very important means of bringing a range of experimental findings together • Meta analyses are an extension of a systematic review that summarise the effects of a range of studies • These methodological approaches can be continuously added to as new findings emerge to help in identifying a drug’s place in therapy University ofGalway.ie