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EVOLVING APPROACH TO THE CONDUCT OF CARDIOVASCULAR AND RENAL OUTCOME TRIALS IN DIABETES. HOW DO RECENT TRIALS INFORM FUTURE DRUG DEVELOPMENT?

Chairpersons: Bruce Neal (Sydney, AUS); Felipe Martinez (Cordoba, ARG)
8.00 am – 3.00 pm
 Regulatory agencies state that reduction of glycated haemoglobin (HbA1C) is an
appropriate primary endpoint in diabetes drug development, as it reflects glucose
control, and is known to be correlated with a reduced risk of micro vascular
complications.
 Until recently, data have not supported a beneficial effect of improving glycaemia in
diabetes on CV outcomes. Beneficial effects on macro-vascular complications can
only be evaluated properly in large scale and long-term controlled clinical trials, which
are not considered mandatory for marketing authorisation approval.
 In case it is considered necessary to perform a more in-depth assessment of the
cardiovascular safety profile of a new drug intended for the treatment of diabetes,
EMA recommends two approaches: a meta-analytic approach of outcome data
generated in the phase II/III studies, or a dedicated cardiovascular outcome study.
 The FDA guidance recommends a dedicated preapproval CV trial powered to
establish safety by establishing an upper bound of the two-sided 95% confidence
interval below 1.8 with the requirement for a subsequent trial to establish noninferiority
to rule out an upper bound confidence interval exceeding 1.3 for a new drug
intended for the treatment of diabetes.
 Would a more tailored approach, requiring a CVOT depending on the mechanism of
action of a specific drug and based on nonclinical and early phase clinical data be
more appropriate?
 The EMA’s and FDA’s preferred safety endpoint, is a composite of cardiovascular
death, non-fatal myocardial infarction, and non-fatal stroke. Heart failure events occur
with a similar frequency as myocardial infarction and with a greater frequency than
stroke in patients with type 2 diabetes mellitus at high cardiovascular risk. Regulatory
agencies should recommend including heart failure events as endpoints in diabetes
clinical trials, whether evaluating efficacy or safety. Should only heart failure requiring
hospitalization be the CHF endpoint? Should the focus on primary endpoint (3pt
MACE vs CHF) be a function of the mechanism of action of the drug under
development?
 Trials set in compliance with this guidance have occasionally been powered for
efficacy, or efficacy has been tested as part of the statistical hierarchy after CV safety
has been established. If efficacy (superiority over standard of care) has been
established in a trial (as for empagliflozin, liraglutide, and semaglutide), does this
have the same strength of evidence as a trial designed for superiority? Should
criteria for establishing CV efficacy based on a single trial be explicitly described and,
if so, what is an appropriate p value for superiority?
 Some molecules seem to impact atherosclerosis related endpoints, others improve
MACE events with mechanisms other than atherosclerosis, and/or heart failure
related endpoints.
 Trials using agents from the same pharmacological classes produced discrepant
results (LEADER and SUSTAIN6 vs. ELIXA and EXSCEL; SAVOR vs. other DPPIV

trials; EMPA-REG vs. CANVAS raising issues about class effect vs
structural/pharmacokinetic differences between molecules of the same class.
 There are emerging data suggesting an association between severe hypoglycaemia
and death, which should be taken into account in differentiating among new drugs
intended for the treatment of diabetes.
Endpoint related issues
· Non-inferiority cardiovascular safety endpoints in diabetes trials. Are efficacy
endpoint trials preferable.
Steven Nissen (Cleveland, USA)
o Cardiologist viewpoint
Naveed Sattar (Glasgow, USA)
o Diabetologist viewpoint
Steven Marso (Kansas City, USA)
· Should MACE be the primary endpoint in CV diabetes in CV efficacy/safety
outcome trials irrespective of the drug’s mechanism of action?
“Atherosclerosis” endpoints and/or heart failure endpoints.
Faiez Zannad (Nancy, FRA)
· Severe hypoglycemia and all cause mortality in CVOTs- What have we
learned?
Michael Farkouh (Toronto, CAN)
Patient population related issues
· Challenges of primary prevention (CV risk) and limitations of secondary
prevention (history of CV events) target populations?
Bruce Neal (Sydney, AUS)
· Addressing patients with CKD
Vlado Perkovic (Sydney, AUS)
· Going beyond diabetes. Non-diabetes trials of new drugs initially intended for
the treatment of diabetes.
Milton Packer (Dallas, USA)

Methodological issues
· The issue with non-inferiority design and interim analyses. Protecting
subsequent trial conduct during/following an interim analysis
Darren McGuire (Dallas, USA)
· Methodological refinements may help streamline future diabetes trials.
Cyrus Mehta (Boston, USA)
Industry viewpoint:
Elisabeth Björk (AstraZeneca, SWE), Mehul Desai (Janssen, USA), Stephen Gough
(NovoNordisk, DEN), Jyothis George (Boehringer Ingelheim, GER); Erica Caveney
(Quintiles, USA)
Regulatory viewpoint:
Robert Temple (FDA, USA),
NIH viewpoint
Yves Rosenberg (NHLBI, USA)
Payers’ viewpoint: How to value a diabetes drug with CV mortality benefit?
Lorenzo Mantovani (Milano, ITA)
Patient viewpoint : Patrick Gee (Chesterfield, USA)
Media Viewpoint: Ron Winslow (Wall Street Journal, USA)
The Forum. Moderated discussion with the audience
Refining the current regulatory guidance.
Chairpersons: Bruce Neal (Sydney, AUS); Felipe Martinez (Cordoba, ARG)
Panelists: Elisabeth Björk (AstraZeneca, SWE), Erica Caveney (Quintiles, USA), Mehul
Desai (Janssen, USA), Michael Farkouh (Toronto, CAN), Patrick Gee (Chesterfield,
USA), Jyothis George (Boehringer Ingelheim, GER), Stephen Gough (NovoNordisk,
DEN), Larry Husten (CardioBrief, USA), Darren McGuire (Dallas, USA), Lorenzo
Mantovani (Milano, ITA), Felipe Martinez (Cordoba, ARG), Cyrus Mehta (Boston, USA),
Bruce Neal (Sydney, AUS); Steven Marso (Kansas City, USA), Steven Nissen
(Cleveland, USA), Milton Packer (Dallas, USA), Vlado Perkovic (Sydney, AUS), Stuart
Pocock (London, GBR), Susan Quella (Rochester, USA), Yves Rosenberg (NHLBI,
USA), Naveed Sattar (Glasgow, USA), Dan Schaber (Medtronic, USA), Robert Temple
(FDA, USA), Ron Winslow (Wall Street Journal, USA), Faiez Zannad (Nancy, FRA)

Earlier Event: November 30
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Later Event: December 1
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