Design of Experiments for IMI2 Strategic Research

Agenda “The Right Prevention and Treatment for the

Right Patient at the Right Time”

Vlad Dragalin, PhD

VP, Scientific Fellow
Quantitative Sciences

Design and Analysis of Experiments in Healthcare

Isaac Newton Institute | Cambridge | Thursday 9th July 2015
IMI2 provides a platform to accelerate
outcomes focus in Europe
Access to funding, expertise and
data IMI2 – Europe’s partnership for health

✓ Leverage in unique consortia

involving top teams from industry,
academia, SMEs, regulators, and
others
• Multi stakeholder effort required as
proof of concept for scalable solutions
and healthcare system changes of
paradigm €3.276

✓
bn1
Benefit from the expertise, databases,
and infrastructures of consortium
partners
€1.638 bn Partnership €1.425 bn
• Access to databases and best funds - in-kind
practices cash 2014 - 2024 invest-

✓
ments
Credibility and visibility of IMI's
projects in Europe and globally
• Enviable platform to promote change
and best practices to healthcare
Average resources for projects: ~20-40M€ +
systems across the world matching in-kind investments from
collaborating pharma companies
IMI2 vision – towards integrated healthcare solutions

• Addressing healthcare priorities identified by the WHO 2013

report and Horizon 2020 health objectives
• Strategic Research Agenda aimed at progressing the vision of
stratified medicines: prevention, treatment and health
management
• Entire product cycle from discovery, through development to
healthcare delivery and access models
• Collaboration across sectors to harness all knowledge and
technologies which can contribute to IMI2 vision - diagnostics,
imaging, IT, medical devices, …

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IMI2 - Major Axes of Research

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 New models: Paradigm shift in R&D,
licensing, access and healthcare delivery
1. Re-engineer Conditional 2. Clarify/align data/methodology
Authorisation mechanism for all stakeholder B/R assessment
needs, pre- and post-approval
Confirmatory trials
Submit &
Review &
Explore R&D design
Confirm
approval

Early access on
condition of
Initial access data collection

3. Develop new trial design and

statistical analysis methodologies Effectiveness/comparative studies
4. Adapt framework to
new science and products, esp Rx-Dx
and RX-Rx combos
Global Considerations and Operational Excellence

5. Enhance Global Medicines 6. Ensure Regulatory 5

Development operational excellence
The concept of Strategic Governing Groups
• Objective: Full potential of IMI2 will only be exploited with good
planning, management and coordination across all programmes and
beyond

• Challenge 1: not to create new “silos”

• Challenge 2: composition which reconciles “all inclusiveness” (input

from all necessary perspectives, e.g. public health, clinical, ...) with
operational efficiency

• Challenge 3: to prevent conflicts of interest when reaching out to

scientific community

• Challenge 4: transparency mechanisms that do not create

unnecessary bureaucracy (charter, Rules of Procedure, ...)

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7 priority themes and enablers = 7 SGGs

 Neuro-degeneration
Leads: Janssen, Lilly, Abbvie
 Immune-Mediated diseases
Leads: GSK
 Metabolic Disorders
Leads: Sanofi, Lilly, Servier
 Translational safety
Leads: Sanofi, Bayer, Janssen, Novartis
 Data and Knowledge Management
Leads: Janssen, Pfizer
 Medicines Adaptive Pathways to
Patients
Leads: Amgen, Janssen
 Infection control
Leads: AstraZeneca

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SGG DKM WS2 - Therapeutic Development Optimization

Members

Lead: Vlad Dragalin, Janssen: vdragali@its.jnj.com

Nima Behkami, Merck: nima.behkami@merck.com
Vitali Proutski, AZ: Vitali.Proutski@astrazeneca.com
Clive Bowman, Daiichi-Sankyo: cbowman@dsd-eu.com

Jerry Schindler, Merck: jerald_schindler@merck.com

Ohad Amit, GSK: Ohad.Amit@gsk.com
Andy Preece, GSK: andrew.f.preece@gsk.com
Alun Bedding, Roche: alun.bedding@roche.com
Inna Perevozskaya, Pfizer inna.perevozskaya@pfizer.com

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 SGG DKM WS2 - Therapeutic Development Optimization

• Focus on one of the 4 IMI2 Major Axes of Research “Innovative clinical

trial paradigms”

- Innovative methodologies to evaluate treatment effect: use and

develop appropriate methodology for patient population stratification and
treatment prediction, explore potential biomarkers predictive of treatment
effects or validate proposed candidate markers.

- Adoption of innovative clinical trial designs: build the seamless

adaptive designs on the program and portfolio level and needed
statistical methodology as well as the specifications of the infrastructure
for their implementation

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Expected outputs from the new SGG process

• Improvement of internal processes for getting commitment

and speeding up the idea maturation process
• Coordinated strategic approach within and across portfolios of
existing projects and programmes
• Coherent planning and exploitation of results
• Structure for review and integration of proposals from
industry and third parties
• Interacting as appropriate with other sectors and key
stakeholders

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SGG DKM is aiming at defining an ambitious program and initiatives
related to Adaptive Designs in Drug Development to launch calls in
2016

Topic definition
Stage 1 Stage 2 Negotiation phase
phase

Academic
research Hospitals
teams Applicant
consortium
Industry Mid-size
Regulators
enterprises
consortium
Industry
Patients’ consortium
SMEs
organisations

Submission of Preparation of full

Identification of proposals by public proposal &
topics and consortia Signature of Project
evaluation by
willingness to Agreement and
& evaluation by independent
collaborate by Grant Agreement
independent experts/ethical
industry partners
experts panel

Selected team Definition of

Call
launch
merges with contractual Project
industry terms
launch!

Source: IMI 11
 Adaptive Design Refresher
Adaptive Design is defined as a multistage study design that uses
accumulating data to decide how to modify aspects of the study
without undermining the validity and integrity of the trial
Trial Level Program Level Portfolio Level
Seamless Adaptive
Designs: Combining
• Number of Subjects Conventional Phases in • Compound Finder
• Study Duration a Single Trial
• Indication Finder
• Treatment Duration
• Basket Trial
• Patient Population • Seamless Phase I/II

• Number of Treatments • MAD and POC • Umbrella Trial

• Randomization Ratio • POC and ADRS (Adaptive • Platform Trial

Dose Ranging Studies)
• Number of Interim
Analyses • Seamless Phase II/III

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Seamless Adaptive Designs

• Seamless AD - adaptive design, applied on the program level

of a compound that achieves efficiency by combining in a
single trial, objectives that are usually addressed in two
separate conventional studies
• Such a strategy provides the obvious benefit of
– reducing the timeline by running the two studies seamlessly
– under a single protocol, with the same clinical team, the same centers
and
– achieves trial efficiency by combining the information from subjects in
both studies in the final analysis

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Types of Adaptive Designs at the Program Level
• SAD or MAD combined with Biomarker-based Efficacy
Phase I/II Design • To identify the Optimal Safe Dose

• Two-stage adaptive approach in patients

MAD and PoC • 1st stage – to identify MTD
• 2nd stage – to select dose and exposure levels

• Start with the highest feasible tolerated dose and placebo

PoC and ADRS • If a pre-specified futility condition is satisfied=> stop
• Otherwise, open enrollment to lower doses

•Design combining the objectives of Phase II dose ranging

Phase II/III Design study and confirmatory Phase III trial in a single protocol
•Dose selection at the interim analysis

•Placebo run-in; Active control run-in; Dose titration

Population •Adaptively enrich the population at the interim analysis
Enrichment Design •Enrich based on biomarker or clinical endpoint response

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Types of Adaptive Designs at the Portfolio Level

• The fixed aspect of the trial is the indication (e.g., breast cancer) and the
Population Finder treatment (e.g., epidermal growth factor receptor inhibitor)
• The design aims to establish which subset of the population benefits most

• The fixed aspect of the trial is the compound

• The competing options are different indications
Indication Finder • The design aims to establish which of the indications show therapeutic
benefit

• The competing options are several different compounds for the same
indication
Compound Finder • The design aims to identify the compound with the most impressive
therapeutic index

• Multiple development candidates are assessed in parallel and matched

Compound / with biomarker signatures of different subpopulations

Population Finder • The design aims to dynamically change the allocation of new patients with
a given signature to different compounds

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Adaptive Platform Benefits

• Match drugs with biomarker signatures

• Savings from common control
• Better therapies move thru faster
• Drug/biomarker pairs graduate to small, focused, more
successful Phase III based on Bayesian predictive
probabilities

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 Alzheimer’s
GBM Global
LUNG-MAP

Ebola
UK MATRIX
BATTLE
I-SPY 2
MICAT
On-going Platform Trials

• Many cancers
• Alzheimer’s
• Ebola
• Antibacterials
• CVOT for testosterone
gel
• Community acquired
pneumonia
• Scleroderma

Acknowledgement to Don Berry

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 Basket Trials
• Targeted therapy
• Trial Population: Restrict to
tumors expressing target
• Simultaneously develop
across organ-specific
tumors
• Sample sizes tiny, borrow
but don’t “pool”
• “Equivalent sample size”
• Formalizes “Gleevec
phenomenon”

*Berry DA. The Brave New World of clinical cancer research: Adaptive biomarker-driven trials
integrating clinical practice with clinical research. Molecular Oncology 9(2015):951-959.
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U.S. Congress bill:
21st Century Cures
One pager: TITLE III – MODERNIZING CLINICAL TRIALS
• “Encouraging broader utilization of efficient, flexible trial designs
… would help modernize the development and assessment of
potential new treatments”

Subtitle B—Broader Application of Bayesian Statistics and Adaptive

Trial Designs

http://energycommerce.house.gov/sites/republicans.energycommerce.house.gov/
files/114/Analysis/Cures/20150127-Cures-Discussion-Document.pdf
One pager: http://energycommerce.house.gov/sites/
republicans.energycommerce.house.gov/files/114/Analysis/Cures/20150127-Cures-
Discussion-Document-One-Pager.pdf

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Summary
• Adaptive designs offer much more than just sample size re-
estimation and early stopping
• Adaptive designs enable more effective decision-making
throughout the whole development process of a compound
• Adaptive designs assist and enhance the decision on which
compound to develop for which population
• The adoption of an adaptive design strategy across the drug
development process brings a number of important benefits:
– increased R&D efficiency,
– increased R&D productivity,
– increased probability of success at phase III

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