Transcript S8-1_E. Rand Sutherland_Global Clinical Development in Rare

Kali MPS I Disease USA
Global Clinical Development in Rare Diseases
Challenges and Opportunities
E. Rand Sutherland, MD, MPH
3-November-2016
Head, Rare Diseases Development
Sanofi Genzyme
Pioneer of treatment for rare diseases
Portfolio of marketed products for LSDs,
substantial R&D portfolio
Employees in 40 sites worldwide, serving
patients in over 100 countries
Acquired by Sanofi in 2011
Four business units
Rare diseases
Multiple sclerosis
Oncology
Immune mediated diseases
2015 revenue $4.14 B
“When you get it right, when
you do something meaningful,
when you transform a life, in
fact you can create a
sustainable business. ”
David Meeker, MD
Orphan Drug Designation
• In US, treatment, for diagnosis or prevention of diseases that affect fewer than
200,000 people in the U.S., or that affect more than 200,000 persons but are not
expected to recover the costs of developing and marketing a treatment drug
• Regulatory strategy to advance development and evaluation of drugs for
treatment or diagnosis of rare conditions, often through financial incentives and
market protections
• Successfully enabled the development and marketing of more than 500 drugs
and biologic products for rare diseases since 1983
Japan
EU
S Korea
1
9
8
3
1
9
9
1
1
9
9
3
USA
Singapore
1
9
9
7
1
9
9
9
2
0
0
0
Australia Taiwan
2
0
0
3
2
0
1
2
Canada
Growing Number of Orphan Drug Designation
Requests to USA FDA from 1983-2015
Kurt R. Karst, http://www.fdalawblog.net, Feb 9, 2016
Orphan Drug Approvals in US from 2006-2011
Other
Oncology
17%
Hematology
33%
8%
8%
Rheumatology
17%
Neurology
17%
Gastrointestinal/
Inborn Errors of Metabolism
Melnikova I, Nat Rev Drug Disc 2012;11:267-268
Worldwide Orphan Drug Market is Projected
to Reach $176B in 2020
What Are the Challenges in Rare Diseases?
• R&D Challenges for Orphan Diseases
Small, heterogeneous, and geographically dispersed
populations
Natural history of disease often not well-characterized
Need to find new approvable endpoints with large effect
sizes
Many affect children, adding extra considerations
Many are chronic, slowly progressive, and have
irreversible damage
Many are serious life-threatening, and have no treatment
Small Patient Numbers
• Orphan disease affects < 200,000 people in US, but many
diseases affect < 100 to 5000 people
• Solutions for patient recruitment
Identify centers of excellence as central clinical sites
Engage patient organizations to raise awareness of trials
Notify specialists of trial through professional societies
Increase a patient’s chance to receive drug with weighted
randomization or no control arm, and offer drug to all patients in
extended treatment period
Implement multinational participation early on
Establish a disease registry
List studies on www.clinicaltrials.gov
Collaboration Opportunities with Public Groups
Patient
Advocacy
Groups
Sanofi
Genzyme
Disease
Research
Foundations
Public Health
Labs,
Other
Agencies
Geographically Dispersed
• Diseases prevalence often 1/10,000 - 1/1,000,000
• Solutions
Identify geographic or ethnic
predilections
Set up multinational sites early on
Reimburse patients for travel to
central site
Use central sites for primary
analysis period, transition patients to
local sites with infrequent return
visits during follow-up period
Natural History of Disease not Well-Characterized
• Given rarity of diseases, there is often inadequate literature
and clinical experience to rigorously describe the natural
history of rare disorders
• Solution
Use literature and chart reviews to establish burden of disease,
pharmaco-economic impact, and disease progression based on
symptoms, major clinical milestones, and health care utilization
Conduct a cross-sectional or preferably a longitudinal natural history
study to characterize the range of frequency of abnormalities that could
be suitable endpoints for a clinical trial
Chart review or observational study could form basis of historical
control group
Use established as well as disease-specific questionnaires, if possible,
as outcome measures (e.g. PRO, ORO)
Biology May Drive Clinical Variability
• In LSDs, there can be a broad clinical spectrum based
on amount of residual gene/protein function, often
resulting in infantile (severe), juvenile (intermediate),
and adult (less severe) forms of disease that may have
different organs affected (e.g. CNS and heart)
• Solutions
Entry criteria for primary endpoint should maximize chance of
enrolling potential responders, taking into account baseline value
of primary endpoint, disease stage, and rate of disease
progression
Patient subgroup should have unmet need that is responsive to
treatment, whether it be stabilization (compared to declining
control group) or reversal of disease (improvement)
Collaborative Opportunities with Academic Sector
Investigator
Sponsored
Studies
Clinical
Studies
Research
Collaborations
Sanofi
Genzyme
Disease
Registries
Centers of
Excellence
Broad Age Range of Patients
• Pediatric and adult patients, with potentially variable severity,
clinical manifestations and natural history
• Solution
Establish positive risk/benefit of drug in adults before
children (could be safety alone or pharmacodynamics)
Identify a common endpoint across a mixed age range or
conduct two or more studies, e.g. adults and children>5
years in one study and children <5 years in a second study
Efficient Clinical Trial Designs Often Employed
• Overcome small patient numbers with efficient trial design
 Choose a clinically relevant primary endpoint with large
treatment effect
 Enrich for subgroup of patients most likely to show a
treatment difference – rely on natural history data and
Phase 1/2 results
 Optimal dosing for safety and efficacy
 Unconventional control groups (historical, standard of
care, and patient as own control) to reduce numbers
 Adaptive designs to dose escalation, combining phases,
and shortening trial duration
 Accelerated approval pathways
Often Debilitating with No Available Treatment
• Ethical pressure to enroll seriously ill patients who do not
meet entry criteria of trial
• Patients receiving placebo may suffer irreparable harm
• Solutions
Clear-cut entry criteria backed by strong clinical science
Offer extended treatment after primary analysis period to both groups of
patients (drug and placebo)
Add rescue criteria in trial to offer drug to patients who decline
Incorporate adaptive trial design to minimize study duration if results are
strongly positive before study completion
Consider N of 1 design or historical control so all patients are treated
with drug
Consider separate expanded access program for patients who do not
qualify for the trial, especially if larger safety database is desired or for
patients with advanced/end stage disease
Summary
• Rare diseases present unique challenges
Understanding the natural history of the disease
Selection of appropriate endpoints
Validation of surrogate endpoints as “reasonably likely
to predict clinical benefit” based on limited data
Limited opportunities to conduct multiple clinical
studies
Identifying patients and centers of excellence
Sustainability of orphan drugs will require
demonstration of value of treatment and partnering
with key stakeholders