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Clinical Trials PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Clinical Trials: How to do them?" by Basil S. Lewis, MD, FRCP, FACC, FESC.

This medical PowerPoint presentation is about clinical trials, scientific studies conducted to evaluate the safety and efficacy of new drugs, medical devices, or treatment strategies in human subjects.

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Published on : Jun 23, 2023 | Views : 1143 | Downloads : 0

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Slide 1-

Clinical Trials:How to do them? Basil S. Lewis, MD, FRCP, FACC, FESC Professor of Medicine Haifa, Israel Chairman-Elect, ESC WG on Cardiovascular Pharmacotherapy
Slide 2-

Trials that Changed Medicine: CHF 1987
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ACS: Cumulative Hazard Rates for CV Death/MI/Stroke RRR=20% ACC, Mar 2001
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AF: Stroke or Systemic Embolism Warfarin better Dabigatran better ESC, 2009
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Objectives should be relevant and important Objectives should be clear and well defined Do ACE-inhibitors improve survival in HF patients? Is DAPT superior to aspirin alone? Is dabigatran non-inferior to warfarin? Is dabigatran superior to warfarin? Your Clinical Trial: Trial Objectives
Slide 6-

Methodology and Trial Design - Questions Randomized controlled trial (RCT)? Single or double blinding? Subgroup stratification? Choice of primary outcome? Predefined secondary outcomes?
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Planning the Study: Statistical Aspects Superiority study? Non-inferiority study? Both? Alpha and Beta? What does this mean? Power calculations Based on what? Primary or co-primary endpoints? Event driven? Patient driven? Temporal design? Pitfalls Rapid recruitment but event rate then falls Adequate number of events but inadequate duration of exposure
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Trial Endpoints Clear endpoints Primary endpoint Secondary endpoints Clinical endpoints vs surrogate endpoints/mechanistic endpoints Example Do new lipid lowering drugs reduce LDL? (surrogate) Comparison with old Rx What components do they alter? (mechanistic) Do the changes translate into meaningful clinical benefit? (the real issue) What are the side effects, safety issues, price to pay?
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Primary Endpoint Primary endpoint Choose carefully Composite endpoints capture the effect of a new treatment on disease burden ACS trials: Death, non-fatal MI, non-fatal stroke Heart failure: Death, hospitalization for heart failure AF trials (SPAF): stroke, systemic embolism Wider composite end-point may increase power but could dilute the effect and lose the study! (TRACER-ACS example) Co-primary endpoint may be a useful solution
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Secondary Endpoints Secondary endpoints Examine in more detail components of the primary and other expected or exploratory findings Must be predefined How many? Not valid if primary end-point is not met? The CURRENT-OASIS 8 study example
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(A) Survival curves for traditional composite. Jeffrey A. Bakal et al. Eur Heart J 2015;36:385-392 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com
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Modified Kaplan–Meier curves for traditional time-to-first-event, weighted composite endpoint, and severity-modified weighted composite endpoint by treatment arm. Jeffrey A. Bakal et al. Eur Heart J 2015;36:385-392 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com
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(A) Percentage use of events and types and relative importance of each event type by treatment. Jeffrey A. Bakal et al. Eur Heart J 2015;36:385-392 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com
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Factorial Designs? Added Value Opportunity to study extra question Little extra cost Examples ISIS-4 studied ACE-I in acute MI + role of Mg ORIGIN studied lantus insulin in diabetes + role of Omega 3 HOPE 3 is looking at LDL cholesterol lowering + BP control
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Rosuvastatin + Candesartan/HCT HOPE-3: 2 x 2 Factorial Design N = 14,000 people at intermediate risk for CVD Rosuvastatin (10mg) Candesartan/HCT (Atacand plus 16/12.5mg) Placebo Rosuvastatin + Placebo Placebo Candesartan/HCT+ Placebo Placebo + Placebo Follow-up for an average of 6 years
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The Site – Patients and Staff Site should have access to appropriate patients Inpatient study (eg ACS, Acute HF) Outpatient study Referral base Properly trained staff PI, SI’s Research co-ordinator(s) – according to study needs Nurse Biotechnician Secretarial Other All personnel need to be trained in GCP
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The Site – Adequate Facilities Site facilities Working space Team and monitors Storage space Drug (IP), trial files, patient files Storage facilities Store IP – Pharmacy? Research unit? Refrigeration for IP Refrigeration for biologic samples - -20? -80? Equipment Routine equipment available - EKG, BP, scales, tapes, other Local labs may be required
Slide 18-

The Site – Administrative and communication Electronic communication essential for most trials Email, fax, scanners Web communication CRF and data transfer usually depends on Electronic data capture (EDC) Connection availability and speed (institutional firewalls can be challenging) Site training All personnel need to be trained in communication with discreet user IDs Paper based research trials for smaller/local trials
Slide 19-

Clinical Trials: Site Enrollment Enrollment expectations and commitment Realistic commitment Competition for patients and resources must be taken into account Track record Financial viability
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Clinical Trials: Financing Non- funded Institutional, health system funding Research grant Contract research with a sponsor University sponsored Commercial entity or industry sponsored
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Ethics Committee The ethics committee (EC; IRB; “Helsinki” committee) is responsible for ensuring patient safety Composition of IRB Scientists and researchers Experts in the field Public representative(s) Institutional administrators Legal opinion
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Role of the Ethics Committee The ethics committee is responsible for ensuring patient safety Ethics of the protocol Competence of the investigators and staff Informed consent language and process Ensure that there is an updated investigator brochure with proper information for investigators Reviewing trial progress Number of patients in trial Adverse and serious adverse events Input from DSMB Protocol violations Approval is usually renewable on an annual basis after review of trial progress
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Role of a Research Organization For most large-scale trials, a professional research organization is mandated by the sponsor to manage the trial Site selection and feasibility Contracts Submissions to IRBs Initiation visits Monitoring Ensure data authenticity by checking source data Ensure data completeness Problem solving
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Contract Research Organization (CRO) vs Academic Research Organization (ARO) CRO Very professional Independent Dedicated Attention to everything Business oriented Expensive ARO Scientific and professional Independent Lesser dedication and assistance to sites Cheaper
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Meta-analyses For: Low cost Gives overall picture Literature summary Adds publication to CV Hypothesis generating Against: Selection bias, ?misleading By data or study? Does not replace randomized trial
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Meta-analyses that “failed” Magnesium improves outcome in AMI ISIS 4 disproved (1995) DPP-4 inhibitors improve outcome in diabetes SAVOR-TIMI 53 disproved (2013)
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Amendments Costly Time consuming Limit amendments and bundle items
Slide 28-

Follow-up Plan well in the beginning ICF to allow tracking Contact persons E-treats and tricks inherent in study Watch out for missed or late visits Reliability? Drug supply problem Motivate investigators and patients TCs, meetings Patient groups – meetings and information
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Ethical Issues in “WC” or “lost pts” Tel contact Private investigator? To tell or not – what is public domain? What may affect the public good?
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Residents and Trainees Pros: Early access to latest treatment strategies Access to top investigators and lectures Exposure to research methods Protocol, ICF, GCP Criteria, definitions Statistics plan Attention to detail, CRF Cons: Less independent thought (done already by others) Less independent research and innovation (less time) Less critical questioning (do as you are told!) Fewer publications
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The Challenges and the Future Proper selection of topic and question Conflict of interest between parties Cost considerations – more bang for the buck RCT vs Meta-analyses, Registries and Registry based trials Added value trials (factorial design) CRO vs ARO? Maximize technology and e-possibilities eCRFs, networks, ipads, stats Dynamic trial design KEEP YOUR FINGER ON THE PULSE!
Slide 32-

Join the ESC Working Group on Cardiovascular PharmacotherapyMembership is FREE! www.escardio.org/pharmacology