Thrilling U20 Women get ready for battle

Two-Arm Double Randomised
Clinical Trial Using Drugs and
Devices
Dr Sunita Ahir
Regulatory Affairs Manager
D-Target SA
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Contents
1. What is STEMI?
2. Regulatory Requirements for Global
Clinical Investigations
3. Conclusions of this Clinical Investigation
4. Importance of Clinical Investigations to
establish evidence based medicine
3
ST Elevation Myocardial Infarction
STEMI
4
ST Elevation Myocardial Infarction
STEMI
5
ST Elevation Myocardial Infarction
STEMI
6
ST Elevation Myocardial Infarction
STEMI
20 mins
t = 30
7
ST Elevation Myocardial Infarction
STEMI
12
7
6
1
hour
4
3
10
hours
5
2
8
t = 11
9 hours
hours
8
ST Elevation Myocardial Infarction
STEMI
9
ST Elevation Myocardial Infarction
STEMI
R
P
Q
10
ST Elevation Myocardial Infarction
STEMI
11
ST Elevation Myocardial Infarction
STEMI
12
ST Elevation Myocardial Infarction
STEMI
13
STEMI
The treatment options for vessel occlusion
are:
 Anticoagulants
 Percutaneous Coronary Intervention
 Or both
14
Study Design
 Drug and device commercialized but
investigational for their intended use
 3604 randomized (3602 enrolled) patients
with ST segment Elevated MI (within 12
hours of symptoms onset) in whom a
primary PCI strategy was intended
15
Clinical Study
A dual arm double randomized trial in
patients with STEMI comparing:
ARM A: RANDOMIZATION 1:
Anticoagulant B
Anticoagulant A
16
Clinical Study
ARM B: RANDOMIZATION 2:
Bare Metal Stent
Drug Eluting Stent
17
Randomization Schedule
RANDOMIZATION 1 - pt. 1:1
Anticoagulant A
Anticoagulant B
BMS
BMS
DES
RANDOMIZATION 2 - pt. 1:3
(if indicated for PCI)
18
DES
Study Design
Arm A: Pharmacology – 30 days
 Primary Endpoint:
• The composite of major adverse ischemic
events and major bleeding (net clinical benefit
endpoint)
 Major Secondary Endpoints:
• Major adverse ischemic events (death, reinfarction,
stroke or ischemic target vessel revascularization)
• Major bleeding
19
Study Design
Arm B : Stent – 1 year
 Primary Efficacy Endpoint:
• Ischemic target lesion revascularization
 Primary Safety Endpoint:
• The composite rate of death, reinfarction, stent
thrombosis or stroke
 Major Secondary Endpoint (13 months):
• Binary restenosis (angiographic subset)
20
Regulatory Requirements for a global
clinical investigation
21
FDA Status Update
Prospective, single blind, multi-center trial with FDA approval
Initial IDE
submission
14 Oct 2004
Enrollment
Begins…
25 March 2005
IDE resubmit
IDE resubmit
IDE resubmit
25 May 06
20 Sept 06
13 Apr 06
DSMB Findings
Safety – 500 Pts
Safety – 250 Pts.
FDA
Approval
12 Nov 04
250 patients
25 sites
FDA
Approval
07 Jan 05
1000 pts
200 sites
FDA
Approval
18 Apr 06
FDA
Approval
02 Aug 06
1400 pts
200 sites
2600 pts
200 sites
22
Regulatory Requirements
The study was conducted in compliance with:
 the CIP (protocol),
 the sponsor`s standard operating procedures,
 the United States Food and Drug Adminisation
requirements
 the International Conference on Harmonisation (ICH)
GCP guidelines
 the Declaration of Helsinki
 local regulations where applicable
23
Participating Countries
North & South
America
Europe
24
Israel
European Union and Israel:
Clinical Trial Requirements
Clinical Trials must be approved by Ethics
Committees/Competent Authorities before
the start of the trial
Medical Devices Directive: Article 15, Annex VIII;
ISO 14155
25
Device Clinical Trial Submissions:
Competent Authority requirements
Medical Device
Directive
Annex VIII
section 2.2
Proof of payment
Notification forms
ISO 14155
Investigator
Brochure
Clinical
Investigation
Plan
Clinical investigation
of medical devices
for human subjects
Part 1 General
Requirements
Confirmation
of Insurance
CA
submissions
Place, starting date
List of sites
Informed
Consent
Documents
Case Report
Forms
Ethics
Committee
Approval
Agreements between
Sponsor, Investigator
and site
CVs of investigators
26
Device Clinical Trial Submissions:
Competent Authority requirements
Medical Device
Directive
Annex VIII
section 2.2
Proof of payment
Notification forms
ISO 14155
Investigator
Brochure
Clinical
Investigation
Plan
Clinical investigation
of medical devices
for human subjects
—
Part 1 General
Requirements
Section 7.3; Annex B
Confirmation
of Insurance
CA
submissions
Place, starting date
List of sites
Informed
Consent
Documents
Case Report
Forms
Ethics
Committee
Approval
Agreements between
Sponsor, Investigator
and site
CVs of investigators
27
Device Clinical Trial Submissions:
Competent Authority requirements
Medical Device
Directive
Annex VIII
section 2.2
Proof of payment
Notification forms
ISO 14155
Investigator
Brochure
Clinical
Investigation
Plan
Clinical investigation
of medical devices
for human subjects
Part 1 General
Requirements
Section 7.3; and 9.1
Confirmation
of Insurance
CA
submissions
Place, starting date
List of sites
Informed
Consent
Documents
Case Report
Forms
Ethics
Committee
Approval
Agreements between
Sponsor, Investigator
and site
CVs of investigators
28
Device Clinical Trial Submissions:
Competent Authority requirements
Medical Device
Directive
Annex VIII
section 2.2
Proof of payment
Notification forms
ISO 14155
Investigator
Brochure
Clinical
Investigation
Plan
Clinical investigation
of medical devices
for human subjects
Parts 1 and 2
Confirmation
of Insurance
CA
submissions
Place, starting date
List of sites
Informed
Consent
Documents
Case Report
Forms
Ethics
Committee
Approval
Agreements between
Sponsor, Investigator
and site
CVs of investigators
29
Device Clinical Trial Submissions:
Competent Authority requirements
Medical Device
Directive
Annex VIII
section 2.2
Proof of payment
Notification forms
ISO 14155
Investigator
Brochure
Clinical
Investigation
Plan
Clinical investigation
of medical devices
for human subjects
Part 1 General
Requirements
Confirmation
of Insurance
CA
submissions
Place, starting date
List of sites
Informed
Consent
Documents
Case Report
Forms
Ethics
Committee
Approval
Agreements between
Sponsor, Investigator
and site
CVs of investigators
30
Device Clinical Trial Submissions:
Competent Authority requirements
Medical Device
Directive
Annex VIII
section 2.2
Proof of payment
Notification forms
ISO 14155
Investigator
Brochure
Clinical
Investigation
Plan
Clinical investigation
of medical devices
for human subjects
Part 2 Clinical
Investigation Plan
Confirmation
of Insurance
CA
submissions
Place, starting date
List of sites
Informed
Consent
Documents
Case Report
Forms
Ethics
Committee
Approval
Agreements between
Sponsor, Investigator
and site
CVs of investigators
31
Drug Clinical Trial Submissions:
Competent Authority requirements
Pharmaceutical
Directive
Proof of payment
Covering Letter
Clinical Trial
Application
EMA
Decision
2001/20/EC
Protocol
CA
submissions
Scientific Advice
IMPD Dossier if needed
Investigator
Brochure
IMPD
Ethics
Committee
Approval
QP Declaration on GMP and site
Manufacturer`s authorisation
32
European Union:
similar but different!
Data
Protection:
Required in
France
Netherlands
Belgium
Denmark
Legal
Representative:
Required by France
Radiation
Protection:
Germany
33
Drug and Device Clinical Trial Submissions:
Ethics Committees
Submission
Form
Confirmation
of Insurance
Clinical
Investigation
Plan
Summary
Informed
Consent/
Clinical
Investigation
Plan
Patient
Information
Sheet
Ethics
Committee
Approval
Patient
Diaries
Investigator
Brochure
Advertising
Material
Agreements
between
Sponsors,
Sites and
Investigators
34
Case
Report
Forms
Regulations in Israel
Israel
Regulated by the Ministry of Health
(MoH); Legislated by national laws
 MoH has two departments:
• Device – ISO 14155 for the conduct of
clinical trials
• Drug
trials
– ICH GCP for conduct of clinical
Combination products are usually reviewed by the drug
department of the MoH
35
Study progression
36
Site Selection
 Site selection is normally an activity of the
sponsor although it is discussed with the
CRO.
 In this case study, based on their
experience, the sponsor identifies good
centers and investigators who can provide
reasonable patient numbers.
37
International Clinical Sites
Norway
Netherlands
UK
Sweden
Poland
Germany
Austria
France
Spain
Denmark
Italy
Israel
38
Patient Enrollment
4000
3500
3000
2500
Total
2000
EU
1500
US
1000
500
0
2005
2006
39
2007
Patient Enrollment

Poor patient enrollment in the US

Europe and Israel enrolled 72% of patients

Conclusion: site selection, patient enrollment
can be difficult – proper site assessment,
qualification, ability to generate good quality
data and experience is necessary.
40
Monitoring Visits
Follow-Up Visits Required:
 1, 6, 12 months, and then yearly up to 5 years
total, for all patients undergoing at least
primary randomization
 Angiography at 13 months for 1,500 stent
randomized patients only
41
Study Close Out
 The study was terminated early (truncating the
study from 5 years to 3 years). The FDA, IRB,
competent authorities, and ethics committees
were informed.
 The study outcome was achieved within 3 years.
42
Final Report
 The database was locked on 4 November 2010.
 The final report was submitted to the FDA
on 11 November 2010.
43
Study Conclusions
44
Study Conclusions:
Safety reports: Drug and Devices
Bare Metal
Stent (BMS)
Anticoagulant A Anticoagulant B
Drug Eluting
Stent (DES)
Net Adverse Clinical Events
27.60%
25.50%
Net Adverse Clinical Events
28.0%
24.50%
MACE 1
21.80%
21.90%
MACE 1
24.0%
20.0%
MACE 2
16.00%
13.40%
MACE 2
12.9%
13.6%
7.70%
5.90%
6.6%
5.6%
- cardiac
5.10%
2.90%
- cardiac
3.8%
3.2%
- non cardiac
2.80%
3.10%
- non cardiac
2.90%
2.4%
2.00%
1.70%
Ischemic TVR
17.6%
12.4%
10.50%
6.90%
Ischemic TLR
15.1%
9.4%
5.10%
4.50%
Death
Stroke
Major bleeding
Any stent thrombosis
Death
45
Study Conclusions
 A significant 34% reduction in major bleeding
and a significant 24% reduction in reinfarction,
with comparable rates of stent thrombosis, target
vessel revascularization and stroke is
maintained to three years.
46
Study Conclusions
 The improvement in survival in patients treated
with anticoagulant B is maintained to three years
with a significant 44% reduction in cardiac
mortality and a 25% reduction in all-cause
mortality.
47
Study Conclusions
 The DES group continues to show superiority for
the primary efficacy endpoint of ischemic target
lesion revascularization (TLR) with a 40%
reduction and no evidence of late catch-up at
three years.
48
Study Conclusions
 The DES showed superiority over the
BMS when used in combination with
anticoagulant B.
49
Importance of Clinical Investigations to
establish evidence based medicine
50
Clinical Regime
This has resulted in a change in clinical
regime for patients with ST Elevated MI and
incorporated into:
“ACC/AHA Guidelines for the Management
of Patients With ST-Elevation Myocardial
Infarction.”
51
The Lancet
 December 2011 Volume 378, Issue 9807,
 Bivalirudin for patients with ST-elevation
myocardial infarction
 Gregg Stone and colleagues assessed the sustained benefit of
bivalirudin monotherapy at 3 years for patients with ST-elevation
myocardial infarction (STEMI) who underwent primary percutaneous
coronary intervention. Stone and colleagues report that the long-term
benefit in the bivalirudin group was consistent with delayed effects from
reduction in major bleeding.
52
Combining mechanical reperfusion and
pharmacologic therapy to improve
myocardial perfusion
 Establishes Primary Percutaneous Coronary Intervention (PCI) to
restore coronary blood flow as the current standard of care for STelevation myocardial infarction Now additional resources are utilized by
hospitals and clinicians to achieve this goal.
 Door-to-balloon time of less than 90 minutes as one of the core
performance measure to motivate clinicians and hospitals to adhere to
this important class IA recommendation of American College of
Cardiology (ACC)/ American Heart Association (AHA) guidelines.
53
The future ……
54
The future ……..
% fractionated heparin
Prasugrel
eptifibatide
abciximab
unfractionated
heparin
tirofiban
55
Collaborate to Innovate
56
Thank you
for your attention
Dr. Sunita Prem Ahir
Regulatory Affairs Manager
DTarget SA
11 Avenue Des Sciences
Yverdon-les-bains
Switzerland
phone: + 41 24 424 2688
[email protected]
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