Transcript MMR BY 12 months

Cancer Clinical Trials
- focused on leukemia research Dong-Wook Kim M.D., Ph.D.
Division of Hematology
Seoul St. Mary’s Hospital
The Catholic University of Korea
Steps in Drug Development
Research and Early development
Target
selection
Hit/Lead
generation
Discovery Phase
Phase
0
Clinical development
Phase
I
Phase
II
Exploratory Phase
Phase
III
Filing
Confirmatory Phase
Market
Sales/
Phase IV
Commercialization
Proof of
Concept
Biomarker (Target)
Development
Diagnostic Feasibility
& Utility: Pt. selection
Tailored prescribing
& monitoring
Approach to classifying clinical studies according to objective
Type of study
Objectives
Study examples
•Assess tolerance
•Pharmacokinetics/-dynamics
•Drug metabolism & interaction
•Activity to various conditions
•Dose-tolerance study
•Single and multiple dose
•PK/PD study
•Drug interaction study
Therapeutic exploratory
•Explore use for the targeted
indication
•Dosage for subsequent studies
•Basis for confirmatory study
design, endpoint, methodology
•Earliest trial of short
duration in well-defined
pts population
•Dose response exploration
study
Therapeutic confirmatory
•Demonstrate/confirm efficacy
•Establish safety profile
•Basis for assessing the benefit/risk
relationship to support licensing
•Dose-response relationship
•Randomized parallel
dose-response study
•Clinical safety study
• Mortality/morbidity outcome
• Large simple trials
•Comparative studies
Therapeutic use
•Refine the benefit/risk
relationship in general or
special population
•Identify less common AE
•Refine dosing recommendation
•Comparative effectiveness study
•Morbidity/mortality outcome
•Study of additional endpoint
•Large simple trials
•Pharmacoeconomic study
Human pharmacology
Phase I
Phase II
Phase III
Phase IV
Process of Clinical Trial
Site survey &
Initial Contract
Confidential agreement
Synopsis
Contact of Investigator
E-mail/
At Medical Congress/
Via local subsidiary/
KOL recommendation
IRB/FDA/EMEA
CRO selection
Formal Contract with
Study Sites
IND document
preparation
Investigator
meeting
Study Initiation Meeting
Cas
e
Enr
ollm
ent
Critical Points for Successful Clinical Trials
Drug
-. Efficacy & Toxicity
: management
-. Dosing
-. Route/Schedule
-. Target Disease
-. Response assessment
-. Data lock
: publication
-. FDA submission
-. Subgroup analysis
Data
Clinical
Study
Protocol
-. Phase planning
: 1/2/3, 1+2/3, 1+2/2+3
-. Study objective
-. Study duration
-. Assay: Response
-. Patient size
: IM/IM+NTKIs
-. PI experience/quality
-. GCP training
-. Monitoring/Inspection
Investigator
Who sponsors clinical trials?
• Clinical trials are sponsored or funded by a variety of organizations or
individuals
• physicians
• medical institutions
• foundations
• voluntary groups
• pharmaceutical companies
• government agencies such as the National Institutes of Health (NIH),
the Department of Defense (DOD), and the Department of Veteran's
Affairs (VA)
• Trials can take place in a variety of locations
• hospitals
• universities
• doctors' offices
• community clinics
Critical Factors: Investigator Networking
• Support Global Networking through Star Scientists
• Assessment of oversea Investigators and Patient pool
according to type of target disease
• LEAD Summit Meeting
: Pre-clinical to Phase 1 clinical study
Leading Experts Advising on Development
Communication between Scientists and Clinicians
: Bridge to Clinical Trial
Who is good investigator?
Specialty
Investigator
Qualification
Site
Experience
How do we know good investigators?
Publication
Investigator
selection
CRO
Principle
Investigator
Critical Factors: Pharmaceutical company-1
• Drug Investment Board (DIB): Phase 1 & 2
• review of pre-PoC (Proof of Concept) compound alliance
opportunities
• PoC decisions
• phase IIb investments for compounds passing PoC
• scientific review prior to PMB discussion of commit to phase 3
proposal
• review scientific activities for business development
• cross-therapeutic area reviews and prioritisation of indications
• Product Management Board (PMB): Phase 3
• phase III investiments and commitment to launch
• regulatory strategy
• phase IIIb/IV planning and additional investiments
• lifecycle management strategy for major products
• disease area strategies
• business development deals for discussion and approval
Critical Factors: Pharmaceutical company-2
• R & D capability: Finance/Strategy/Planning
• Employment of Clinical Research Specialists
• Networking/Partnership
- with domestic disease-specific expertise and institutes
• Operation of Global Advisory Board
- Scientific Study Committee/Publication Committee
- Global Safety Board
• Continuing Education
Other important considerations
• Selection of principle investigator
• Initial investigator Meeting
• CRO selection and qualification
• Logistics for study materials such as documents, samples
• Use of central or in-house laboratories for routine test
• Use central or in-house laboratories for biomarker test
• Interim review with investigators
• Publication plan: authorship of presentation and manuscripts
Site survey
eClinical Remote Data Capture Assessment Form
Protocol Number: 3160A4-200-WW
Form Completed By: Prof. Dong-Wook KIM
Investigator Name: Prof. Dong-Wook KIM
Reviewer Initials:
Computer and Internet Information:
Adobe Acrobat Reader is required. What is your version?
(Open Adobe Acrobat and select Help, About to determine your vers
Adobe Version:
ion.)
(preferred version = 5.0)
How do the computers at your site connect to the Internet?
(Select all that apply.)
Broadband (LAN, Cable, ADSL, DSL)
ISDN
Dial up
Other
Specify:
None
Do you have any monthly usage limitations on your access to the Int
ernet?
Yes
No
Has this connection been supplied by another sponsor?
(If Yes, we strongly recommend you inform the sponsor of your inte
nt to use the connection for another study sponsor.)
Yes
No
Do you have Internet security software installed on the computer? (E
xample: Virus software, Spyware blocker, etc.)
(If Not, we recommend you protect your computer. Wyeth is not re
sponsible for your machine and any security compromises which ma
y occur from general Internet usage.)
Yes
No
Investigator
Do you have any previous experience with electronic case
report forms?
How frequently do you use a computer?
How frequently do you access the Internet?
Is a computer at your site available for RDC data entry at al
l times throughout the whole term of the study?
Has your computer been provided by another sponsor?
(Computers supplied by other sponsors are not to be used
for Wyeth RDC.)
What are your computer’s Windows Operating System (OS)
and Service Pack (SP)? Refer to Instructions, Section I on l
ast page.
(Currently, RDC only supports the Windows Operating Syst
ems listed on the right.
RDC is not compatible with the Macintosh (MAC) Operating
System.)
What is your computer’s Processor Speed? Refer to Instru
ctions, Section I on last page.
What is your computer’s Memory (RAM)? Refer to Instructi
ons, Section I on last page.
Yes
No
Daily
Weekly
Monthly
Never
Daily
Weekly
Monthly
Never
Yes
No
Study
Coordinator
Yes
No
Daily
Weekly
Monthly
Never
Daily
Weekly
Monthly
Never
Site Support
(For data entry)
Yes
No
Daily
Weekly
Monthly
Never
Daily
Weekly
Monthly
Never
Yes
No
Windows 95
Windows NT 4.0 or above
Windows 98/98SE
Windows 2000
Windows XP
Speed:
Memory:
SP:
SP:
SP:
SP:
SP:
GHz (minimum required = 300 MHz)
MB (minimum required = 128 MB)
Resolution:
What is your Monitor’s Display resolution? Refer to Instru
(Minimum required = 1024 X 768 with a Super Video Graphics
ctions, Section I on last page.
Adapter (SVGA))
Yes
Do you have a CD-ROM drive?
No
What is your Internet Explorer (IE) version? Refer to Instru
ctions, Section II on last page.
IE Version:
(minimum version = 5.5)
(Currently, RDC only supports IE.)
Investigator meeting
Example of meeting agenda
Protocol AMN107A 2101 Investigator Meeting
The Grand Marina, Barcelona
February 20 - 21, 2005
Presentation Title
Presenter
Breakfast
Registration
Leila Alland
Welcome and Introduction
Leila Alland & Dr. Ottman
Clinical Overview
Anna Battaglia
Protocol Review & Procedures
All participants
Questions & Answers
Julie Koehler
Study Timelines and Patient Recruitment Plan
TBD
eCRF Review
Coffee/Tea Break
All participants
eCRF Workshop
William Torres
Biomarker Lab w/Quest
PK/PG procedures/Quintiles
Brian Rafter
eRT
Good Clinical Practice and Quality Assurance / SAE John Poustie
Reporting
Anna Battaglia
Publication Policy
All Participants
Questions & Answers
Anna Battaglia
Summary & Closing Remarks
Close
Buffet Lunch
Transfer back to the Airport
Start Time
(60)
- (60)
(10)
(45)
(60)
(10)
(15)
(45)
(20)
(45)
(30)
(20)
(50)
(10)
(10)
(5)
Interim Review
Example of meeting agenda
Protocol AMN107A 2101 Investigator Meeting
The Grand Marina, Barcelona
February 20 - 21, 2005
Presentation Title
Presenter
Breakfast
Registration
Leila Alland
Welcome and Introduction
Leila Alland & Dr. Ottman
Clinical Overview
Anna Battaglia
Protocol Review & Procedures
All participants
Questions & Answers
Julie Koehler
Study Timelines and Patient Recruitment Plan
TBD
eCRF Review
Coffee/Tea Break
All participants
eCRF Workshop
William Torres
Biomarker Lab w/Quest
PK/PG procedures/Quintiles
Brian Rafter
eRT
Good Clinical Practice and Quality Assurance / SAE John Poustie
Reporting
Anna Battaglia
Publication Policy
All Participants
Questions & Answers
Anna Battaglia
Summary & Closing Remarks
Close
Buffet Lunch
Transfer back to the Airport
Start Time
(60)
- (60)
(10)
(45)
(60)
(10)
(15)
(45)
(20)
(45)
(30)
(20)
(50)
(10)
(10)
(5)
Interim Review of Enrollment Progress
- Planned versus Actual Enrollment -
PACE Patient Management Forum: Biweekly report
Current Trial Status: Ponatinib (BY 15 May, 2011)
- 355 Patients in Rave (54 sites)
- 252 Patients Eligible
- 72 Screening
- 24 Discontinued/31 Screen Failures
- North America: 57%; EU: 29%; AP: 14%
Global Networking
Investigator Networking
Advisory
Board
• Scientific AB
• Study Design
• Data interpretation
Investigator
meeting
• Interim Data Review
• IIT Study proposal
• Clinical Application
Publication
• Publication committee
• Manuscript/presentation
• Subgroup study
Continuing
Activity
Investigator Networking = Multi-nationality
Global Opinion Leader Summit 2010; ‘Path to Cure’ 6 ~ 7th March 2010 by Novartis
Protocol design with new compounds
: sponsor & investigator considerations
• Design: number of patients/dosage/schedule
• What is the purpose of the study?: endpoints
• Who is going to be in the study?: indications
• What kinds of biomarkers and assessment tests will be applied?
: hematologic/cytogenetic/molecular/radiologic response?
• How do the possible risks, side effects, and benefits in the study
compare with current treatment?
• How long will the trial last?
• Who will pay for the experimental treatment/other expenses?
: control arm/routine tests
• Plan of long-term follow up care is part of this study?
Surrogate endpoints in cancer clinical trials
•
From the regulatory agency perspective, in 1992, the United States Food and Drug
Administration (FDA) introduced and applied the accelerated approval rule that a new
therapy can be granted marketing approval based on efficacy on a surrogate endpoint,
rather than the primary endpoint, in life-threatening diseases, i.e. cancer
•
A surrogate endpoint is defi ned as a measure or indicator of a biological process that
is obtained sooner, at less cost or less invasively than a true endpoint of health
outcome and is used to make conclusions about the effect of an intervention on the
true endpoint
Survivals variables (OS, DFS, PFS etc)
-. time to death, disease recurrence, and progression free from any cause
-. the most commonly used “gold standard” primary endpoint in cancer clinical trials
Tumor response
Disease recurrence
Disease progression
Laboratory variables (biomarkers)
Biochemical markers
Cellular markers
Cytokine markers
Genetic markers
Physiological results
Radiological measurements
Physical signs
Pathological assessments
Protocol comparison:
Trial Endpoints and Assessment Criteria
BY (BMS) vs AT (NVR & Pfizer)
Cytogenetic Response (BMS & Pfizer)
vs
Molecular Response (NVR)
Saglio G. et al, NEJM 2010;362:2251-2259
Kantarjian H. et al., NEJM 2010;362:2260-2270
Nilotinib and Dasatinib in Newly Diagnosed CML-CP:
Summary of Trial Endpoints and Assessment Criteria
Nilotinib
ENESTnd
(N = 846)
Dasatinib
DASISION
(N = 519)
Primary
Endpoint
MMR “AT” 12 months
(≤ 0.1% BCR-ABLIS)
Confirmed CCyR “BY”
12 months
Secondary
Endpoint
CCyR BY 12 months
MMR BY 12 months
(0% Ph+)
(< 0.1% BCR-ABLIS)
PCR testing
RT-PCR
MolecularMD
RT-PCR
MolecularMD
(Conversion factor 0.81)
(Conversion factor 0.81)
Study
IS, international scale; RT-PCR, real-time polymerase chain reaction;
FISH, fluorescence in situ hybridization.
Saglio G. et al, NEJM 2010;362:2251-2259
Kantarjian H. et al., NEJM 2010;362:2260-2270
(0% Ph+)
Nilotinib and Dasatinib in Newly Diagnosed CML-CP:
MMR “By” 12 Months
P < .0001
P < .0001
P < .0001
Percentage
by 12 Months
% MMR
60
55
51
50
46
40
27
30
20
ENESTnd
28
DASISION
10
0
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Dasatinib 100 mg QD
Imatinib 400 mg QD
Imatinib 400 mg QD
Saglio G. et al, NEJM 2010;362 (24):2251-2259/Kantarjian H. et al., NEJM 2010;362:2260-2270
Nilotinib and Dasatinib in Newly Diagnosed CML-CP:
Unconfirmed CCyR by 12 Months
P < .0001
P = .001
P = .0005
90
80
80
Percentage
by 12 Months
% CCyR
83
78
72
65
70
60
50
40
30
20
10
ENESTnd
DASISION
0
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Dasatinib 100 mg QD
Imatinib 400 mg QD
Imatinib 400 mg QD
Saglio G. et al, NEJM 2010;362 (24):2251-2259/Kantarjian H. et al., NEJM 2010;362:2260-2270
Nilotinib and Dasatinib in Newly Diagnosed CML-CP:
Overview of Clinical Trials
Study
Nilotinib
ENESTnd
(N = 846)
Dasatinib
DASISION
(N = 519)
Risk score
Sokal risk
Hasford score
Dose (mg)
300 BID
400 BID
100 QD
Dose Escalation
Not allowed
140 mg/day
QTc criteria
< 450 msec
< 450 msec
Cardiac I/E criteria
Yes
Yes
Saglio G. et al, NEJM 2010;362:2251-2259
Kantarjian H. et al., NEJM 2010;362:2260-2270
Cardiac Exclusion Criteria
DASISION
ENESTnd
MI within 6 months
History of clinically documented MI
Unstable angina within 3 months
Unstable angina during last 12 months
CHF within 3 months
Other clinically significant heart disease
(e.g. CHF, uncontrolled hypertension)
QTc >450 ms
QTc >450 ms
History of ventricular arrhythmia (ventricular
tachycardia/fibrillation)
History or presence of clinically significant
ventricular or atrial tachyarrhythmia
Nilotinib Label:
8.6 Cardiac Disorders
In the clinical trials, patients with a history of
uncontrolled or significant cardiovascular disease,
including recent myocardial infarction, congestive
heart failure, unstable angina or clinically significant
bradycardia were excluded. Caution should be
exercised in patients with relevant cardiac disorders.
[see Boxed Warning and Warnings and Precautions
(5.2)].
Clinically significant resting bradycardia
Use of ventricular pacemaker
Complete left bundle branch block
LVEF <45%
BELA Study Design: Wyeth study
Phase 3 open-label trial in
newly diagnosed chronic
phase CML
N = 502
139 sites
31 countries
Randomization is stratified based on Sokal risk score
and geographical regions.
R
A
N
D
O
M
I
Z
E
Bosutinib
500 mg/day
n = 250
8-year follow-up
Imatinib
400 mg/day
n = 252
8-year follow-up
1-year analysis
•
Key eligibility criteria: cytogenetic diagnosis of Ph+ CP CML 6 mo prior, with
no prior therapy other than hydroxyurea or anagrelide
•
Primary endpoint: complete cytogenetic response (CCyR) at 12 months in the i
ntent-to-treat (ITT) population
•
Key secondary and exploratory endpoints:
– MMR at 12 months, duration of CCyR and MMR, time to and incidence of tra
nsformation to AP/BP CML, event-free survival, and overall survival
– Safety and tolerability
Complete Cytogenetic Response Rates
ITT Population
● CCyR rate at 12 months was 70% (95% CI, 64%-76%) for bosutinib
compared with 68% (95% CI, 62%-74%) for imatinib
● Patients achieved their first CCyR faster with bosutinib (median, 12.7
weeks; 95% CI, 12.6-13.3 weeks) compared with imatinib (median, 24.6
weeks; 95% CI, 24.3-25.6 weeks; P 0.001)
P = 0.598
P = 0.665
P = 0.024
P = 0.229
P = 0.051
P 0.001
P values displayed except Month 12 were exploratory and provided for descriptive purposes only.
Development of Radotinib (SupectTM)
: Comparison to Global Pharma-1
BMS
Factor
NVR
IY
Frequently
change
Study Director
No change
No change
Irregular
Investigator
Meeting
Regular
Regular
Limited
IIT Application
Open
NA
less
Publication
more
1 global/
2 local
Development of Radotinib (SupectTM)
: Comparison to Global Pharma-2
BMS
Factor
NVR
IY
Same (2010)
Phase3
publication
Same (2010)
NA
Same (IHOP)
Global AB
meeting
Same (GOLS)
2 AP AB
meeting
active
IIT Application
active
NA
low
Price access
high
low
Development of Radotinib (SupectTM)
: Luncheon symposium of Radotinib in Thai 2010
Use of an "expanded access" program
: A treatment IND or treatment protocol is a relatively unrestricted study
• For patients who may benefit from the drug use but don't qualify for the
clinical trials because of other health problems, age, or other factors
• For people with a life-threatening or serious disease
• To generate additional information, i.e. drug safety
• Only if clinical investigators are actively studying the experimental
treatment in well-controlled studies, or all studies have been completed
• There must be evidence that the drug may be an effective treatment
and the drug cannot expose patients to unreasonable risks
• Expanded access protocols are generally managed by the
manufacturer, with the investigational treatment administered by
researchers/doctors
CRO selection
Check Lists (16 lists)
Q
C
R
P
A (Korea)
10
10
68
4
4
10
1 (MM)
2
1
X
O
O
O
O
X
O
local
20
O
1-2
O
local
28
O
1-2
O
local
22
O
2-3
O
local
13
O
1
X
Local
3
O
1-2
IVRS-randomization
By Tel
Oracle by both
Vendor
Vendor
By Web
e-CRF development
Global branch?
4-8 wks
AP
4-8 wks
AP
X
AP
4 wks
AP
8 wks
X
China
China
China
India
Korea
China
Korea
Indonesia/China
China
Korea
US
China
Korea
X
India
Korea
X
Korea
Korea
Korea
TNT
Any
Any
Any
Any
2.6 M USD
4.0 M USD
2.6 M USD
2.6 M
USD
1.0 M USD
KFDA trials - ongoing
cancer trials
FDA Inspection in specific
area
Audit experience by
sponsor
Site selection experience
CRA education
CRA number
Separate contract ?
No. of project of CRA
DB location
DM location
Project manager
Lab kit supply
Courier
Price
(n=240 pts in AP
countries)
•화이자(36위), 노바티스(62위), 사노피(81위), 로슈(89위),애보트(127위) 등
500대 기업 중 16개가 제약기업
•국내 기업 중 12개가 500대 기업에 포함
Astellas
AstraZeneca
Bayer
BI
BMS
Eli Lilly
GSK
Janssen
J&J
MSD
Novartis
Novo Nordisk
Otsuka
Pfizer
Roche
Sanofi-Aventis
Wyeth
Ahn-Gook
Chong Kun Dang
ChoongWae
CJ
Daewoong
Dong-A
Green Cross
Handok
Hanmi
Hanwha
ILYang
Jeil
Kuhnil
LG
SK
Yuhan
Korean clinical trials by Pharma sponsors
Of 926 trials conducting in Korea
120
109
100
99
80
75
60
20
0
75
61
63
53
59
53
40
35
10
15
http://clinicaltrials.gov/ct2/search
39
14
35
37
24
1
6
9
6
2
4
2
8
9
1
2
3
2
4 10 1
서울성모병원 만성골수성백혈병 연구팀
1st CML DAY 9.22