This webinar will address emerging trends in clinical trial methodology for orphan disease drug development

1. Barbara Zupancic, MBA, MSc
Director, Global Patient Recruitment and Retention
Lorna Graham, BSc, MSc
Associate Director, Project Management, Evidence
Necessity is the Mother of Invention
The Impetus for Observational Research in Orphan Drug Development
Michael Murphy, M.D., Ph.D.
Chief Medical and Scientific Officer
Josie Measures
Vice President, Biostatistical Operations

2. Michael Murphy, M.D., Ph.D.
Chief Medical and Scientific Officer

3. CONFIDENTIAL
Agenda
3
• Introduction
Dr. Michael Murphy
• New Perspectives in Patient Centered Recruitment and Care
Barbara Zupancic
• Observational Research: An Operational Approach
Lorna Graham
• Statistical Considerations in Observational Studies
Josie Measures
• Q & A

4. CONFIDENTIAL
Physicians
Governments
Insurers
Regiona
l
Variatio
n
Basic
Researchers Employers
Neither orderly nor rational, multiple stakeholders impact R&D with conflicting data needs.
Financial Markets
Academia Insure
d
Childre
n
Assisted
Living
Patients
Pharma
CMS,
State Medicaid
4
Responding to the “Other Stakeholders”
Intermediaries
Care Providers
Products & Services
Consumers
Global
Regulation

5. CONFIDENTIAL
Many Options for Interventional Studies
•Minimizing sample
– Adaptive randomization
– Longer trials, more events/ patient
– Risk stratification
– Continuous and composite measures,
repeated measures
– “relaxed alpha’s” within Bayesian
frameworks
•Maximizing treatment
– Parallel groups
– Crossovers and permutations
– Factorial
– “n-of-one”
– Randomized placebo
– Stepped wedge and variations
– Randomized withdrawal
Period 1 Period 2 Period 3 Period 4 Period 5 Period 6
A B B A A B
Sequence 1 Sequence 2 Sequence 3
Time periods
Placebo Active
Treatment
adverse event
withdrawal
screen
titrate to
effect with
active
randomise
contr
ol
Assesment
lack of
efficacy
withdrawal
activ
e
Comparison: B vs
placebo
Comparison:
Avsplacebo
Treatment
B
n=200
Placebo B
n=200
Treatment
A
Treatment
B
n=100
Treatment
A
Placebo B
n=100
Placebo A
Treatment
B
n=100
Placebo A
Placebo B
n=100
Treatment
A
n=200
Placebo A
n=200
Period 1 Period 2
Group A
Group B
Placebo
Active
Treatment
Placebo
Active
Treatment
Time
Time
Trial
starts
Trial ends
A: parallel groups
Group 1
Group 2
R
Dose 1
Dose 2
R
Placebo
Dose 2
B: cross-over
C: fractorial
D: N-of-1
E: randomised placebo phase
F: stepped wedge
G: randomised withdrawalSee Cornu et al, 2013; Gagne et al 2014

6. CONFIDENTIAL
…But Other Arrows in the Quiver
6
Hypothesis Generation Hypothesis Testing
Shah, N. Evidence standards in the era of comparative effectiveness. AHDB.2(1): s41-s48, 2009.
Case StudyDescriptive Exploratory Experimental
Cross-sectional
Case-Control
Serial cross-sectional
Retrospective Cohort
Prospective Cohort
Nested case control
Quasi-Experimental
RCT

7. CONFIDENTIAL
…That Can Answer Diverse Questions
7
To inform protocol design?
As a complement to a submission strategy?
To shape formulary & reimbursement decisions?
With many objectives
• Natural history of disease
• Burden of illness
• Treatment Pathways
• Disease Management
• Usage (on & off label)
• Comparative effectiveness

8. CONFIDENTIAL
For Today’s Presentation
• What questions are amenable to
observational methods, and who is asking?
• How has R&D in orphan diseases shaped
patient, family, and payer expectations?
• What are the options and the challenges in
implementation?
• What are opportunities and limitations in
analysis and interpretation– as a standalone
study, or integrated with interventional trials?
8

9. POWERED BY HONEYCOMB
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