Clinical Trials:How to do them?

Basil S. Lewis, MD, FRCP, FACC, FESCProfessor of MedicineHaifa, Israel

Chairman-Elect, ESC WG on Cardiovascular Pharmacotherapy

Lady Davis Carmel Cardiovascular Center

Trials that Changed Medicine: CHF

1987

CURECURE

Months of Follow-up

Cu

mu

lati

ve

Ha

za

rd R

ate

s

0.0

0.0

20

.04

0.0

60

.08

0.1

00

.12

0.1

4

0 3 6 9 12

ACS: Cumulative Hazard Rates for CV Death/MI/Stroke

p <0.001

Clopidogrel

Placebo

Cum

ulat

ive

Haz

ard

Rat

es

Months of Follow-up0 3 6 9 12

6303

6259

5780

5866

4664

4779

3600

3644

2388

2418

Plac

Clop

No of Pts

RRR=20%

ACC, Mar 2001

AF: Stroke or Systemic Embolism

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs. Warfarin

Dabigatran 150 vs. Warfarin

Non-inferiorityp-value

<0.001

<0.001

Superiorityp-value

0.34

<0.001

Margin = 1.46

HR (95% CI)Warfarin betterDabigatran better

ESC, 2009

• 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

Methodology and Trial Design - Questions

• Randomized controlled trial (RCT)?

• Single or double blinding?

• Subgroup stratification?

• Choice of primary outcome?

• Predefined secondary outcomes?

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?

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

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

(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

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

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

PlaceboCandesartan/HCT+

PlaceboPlacebo +Placebo

Follow-up for an average of 6 years

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

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

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

Clinical Trials: Site Enrollment

• Enrollment expectations and commitment• Realistic commitment• Competition for patients and resources must be taken into

account• Track record• Financial viability

Clinical Trials: Financing

• Non- funded

• Institutional, health system funding

• Research grant

• Contract research with a sponsor• University sponsored • Commercial entity or industry sponsored

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

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

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

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

Join the ESC Working

Group on Cardiovascular

Pharmacotherapy

Membership is FREE!

www.escardio.org/pharmacology