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
2. Lady Davis Carmel Cardiovascular Center
Trials that Changed Medicine: CHF
1987
5. • 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
6. Methodology and Trial Design -
Questions
• Randomized controlled trial (RCT)?
• Single or double blinding?
• Subgroup stratification?
• Choice of primary outcome?
• Predefined secondary outcomes?
7. 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?
8. 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
9. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. Clinical Trials: Site Enrollment
• Enrollment expectations and commitment
• Realistic commitment
• Competition for patients and resources must be taken into
account
• Track record
• Financial viability
17. Clinical Trials: Financing
• Non- funded
• Institutional, health system funding
• Research grant
• Contract research with a sponsor
• University sponsored
• Commercial entity or industry sponsored
18. 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
19. 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
20. 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
21. 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
22. Join the ESC Working
Group on Cardiovascular
Pharmacotherapy
Membership is FREE!
www.escardio.org/pharmacology
Modified Kaplan–Meier curves for traditional time-to-first-event, weighted composite endpoint, and severity-modified weighted composite endpoint by treatment arm. Pts, patients.
(A) Percentage use of events and types and relative importance of each event type by treatment. (B) Effective number and types of events used per 1000 patients enrolled by treatment expressed as percentage use. (C) Weighted non-fatal event type (%) by treatment arm for severity-modified weighted composite endpoint. AG, Andersen–Gill; MI, myocardial infarction; mod, moderate; WCE, weighted composite endpoint.
