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Confidential | © 2014 Premier Research, LLC | Version 1.0
Rare Oncology Research
in the 21st Century
29 MARCH 2016
Agenda

Definitions and Epidemiology

Rare Oncology as a Rare Disease
 Patient Perspective
 Trial Design Considerations

Regulatory Options
 Expedited Review Pathways
 Legislative Updates
Summary
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
Definitions and Epidemiology
FDA
EMA
 Rare Disease: Disease or disorder that affect
fewer than 200,000 people in the United
States1
 Rare Disease: A disease or disorder is
defined as rare in Europe when it affects
less than 1 in 20003
1 http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm
2
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789814/
3 http://www.eurordis.org/about-rare-diseases
4 http://www.rarecancerseurope.org/About-Rare-Cancers
 One rare disease may affect only a handful
of patients in the EU, and another touch as
many as 245,000
 Rare Cancers: Defined as those cancers that
have an incidence of less than
6 per 100,000 in the population4
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 Rare Cancers: Defined as those cancers that
have an incidence of less than 15 per 100,000
in the population2
The Burden of Rare Cancers
27% in US
22% in EU
http://www.rarecancerseurope.org/
Cancer Res Treat. 2015 Oct; 47(4): 591–599
Eur J Cancer. 2011 Nov;47(17):2493-511. doi: 10.1016/j.ejca.2011.08.008. Epub 2011 Oct 25
Survival Rates (Europe)
Incidence of Rare Cancers (Europe)
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Rare cancers account for of all new cancer diagnoses
annually
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http://www.rarecancerseurope.org/About-Rare-Cancers/Families-and-List-of-Rare-Cancers
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Rare Cancer Types
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Rare Oncology Research:
Current Topics and Patient Input
Rare Cancer from a Patient’s Perspective - Challenges
Lengthy Diagnosis Process
Coordinating Care
Lack of Data
 Pathology considerations
 Location of specialists
 Genetic testing limitations
 Availability of treatments in
local setting
 Natural history not well
characterized
Limited Treatment Options
Sparse Support Options
 No known treatment options
 Access to patient support
groups for rare and ultra-rare
cancers
 “Best guess” treatments
based on similar cancers
 “Sharing the burden”
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 Lack of prognostic indicators
What Do Rare Cancer Patients Want?
Innovation in terms of
clinical research standards
for treatments for their
cancer
Input into clinical
research process
Options to accept higher
levels of risk than some
other patient populations
Support from industry
and regulatory agencies
to recognize and address
their needs
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HOPE
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Rare Cancers are
Rare Diseases
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As oncology research becomes more focused on the genetics of
cancer, there will be increasing focus on conducting research in
smaller populations that exhibit a certain genetic characteristic,
thus the considerations for how to conduct these trials in “rare”
populations are becoming more and more important.
Rare Disease Challenges
Unknown/Sparse
Natural History
What controls to use?
How to access
patients?
Research Naïve Sites
How to guarantee
data integrity?
Lack of Defined
Biomarkers
Lack of Surrogate
Endpoints
How to measure
activity?
How to define
success?
Obstacles to Patient
Retention
How to get all the
data?
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Small Population
How to find patients?
Geographically
Widespread
Challenges in Rare Cancer Research
In addition to the challenges associated with rare disease
research in general, the following are additional challenges
inherent in rare cancer research:
 Late or incorrect diagnosis delays access to trials and
treatment
 Lack of local clinical expertise with a rare cancer diagnosis
 Primary oncology team as limited research experience
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http://www.rarecancerseurope.org/About-Rare-Cancers/The-Burden-and-the-Challenges-of-Rare-Cancers
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 There are few available tissue banks or registries to support
research
Lessons from Rare Disease Trials


Assess patient population
Define patient pathways


Social Media
Patient Advocacy Groups
Patient
Engagement
and Retention
Investigative
Site Selection
Investigative Site
Team
Engagement




Give the patients a voice
Tailor communications
Share updates throughout study
Invite investigator feedback
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Patient
Identification
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When working in rare oncology treatment development, just as in
non-oncology rare disease research, every data point counts.
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Rare Oncology
Trial Design Considerations
Adaptive Trial Designs
A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design
and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of these accumulating
study data are performed at pre-planned time-points within the study, with or without formal statistical hypothesis testing.
Adaptive Parallel Simon Two-Stage Design
Multi-Arm, Multi-Stage (MAMS) Design
Entire Population
Entire Population
Biomarker +
Biomarker -
Biomarker 1+
Biomarker 2 -
Experimental
Experimental
R
R
No
Control
Experimental 1
Preliminary
efficacy in both
Biomarker + and
Biomarker -
Preliminary
efficacy in
Biomarker +
Enroll additional
Unselected
Population
Enroll additional
Biomarker +
Experimental
Experimental
Interim Analysis 1
on Intermediate Outcome
Experimental 1 Superior?
Yes
No
Drop
Experimental 1
Experimental 2
Interim Analysis 1
on Intermediate Outcome
Experimental 2 Superior?
Yes
No
Drop
Experimental 2
Antoniou M, Jorgensen AL, Kolamunnage-Dona R. Biomarker-Guided Adaptive Trial Designs in Phase II and Phase III: A Methodological Review. Soyer HP, ed. PLoS ONE. 2016;11(2):e0149803.
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Interim Analysis
Efficacy of
Experimental
Treatment?
Clinical Trial Designs for Rare Diseases
From the International Rare Cancers Initiative:
 Utilize a phase II design (anal cancer)
 Accept a greater type I error (salivary gland cancer)
 Abandon a trial early for lack-of-benefit (uterine leiomyosarcoma)
 Test only research treatments with early discontinuation for lack-of-activity in absence of standard
(metastatic uveal melanoma)
 Balance scientific value and feasibility (high-grade undifferentiated uterine sarcoma)
 Incorporate Bayesian elements to quantify resulting level of information (small bowel adenocarcinoma)
 Bayesian design with reverse philosophy (squamous carcinoma of the penis [InPACT])
 Multi-arm selection without assumption (Ewing sarcoma)
Bogaerts, J et al. Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative. European Journal of Cancer. 51(3), 271–281.
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 Multiple concurrent treatments, interim analysis based on merit
Basket Trial Design
 Test the effect of a single drug or drug combinations
on a specific mutation in a variety of cancer types
(‘baskets’), allowing researchers to analyze each
cancer type individually, as well as assess the impact
of the drug or drug combinations as a whole.
 Examples: VE-BASKET, I-SPY 2, BATTLE, ALCHEMIST
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 Using this approach, it is possible to combine what
would have been multiple Phase 2 trials into a single
study, thus greatly speeding up the development
process and improving our understanding of the
different types of cancer and expediting the delivery
of an effective treatment to the patient.
Basket Design: VE-BASKET
Cholangiocarcinoma
All Others*
ECD / LCH**
Anaplastic Thyroid
Breast
Ovarian
Vemurafenib Monotherapy
Primary end point
 Response rate at week 8
Secondary end points
 Progression-free survival
 Time to progression
 Best overall response
 Time to response
 Duration of response
 Clinical benefit rate
 Overall survival
 Safety
Multiple Myeloma
Colorectal
* All others included cervical cancer, brain
tumors, head and neck cancer, esophageal,
gastric, and pancreatic cancers, sarcomas,
cancers of unknown primary
N Engl J Med 2015;373:726-36. DOI: 10.1056/NEJMoa1502309
Vemurafenib
Monotherapy
Vemurafenib +
Cetuximab
**ECD/LCH = Erdheim-Chester
Disease and Langerhans-cell
Histocytosis are orphan diseases
with no approved therapies
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BRAF V600 testing via local methods
NSCLC
Umbrella Trial Design
 Test the impact of different drugs on different
mutations in a single type of cancer (‘under the
umbrella of one disease’), for example, NSCLC.
 Patients are randomized based on the genetic
mutation most prominent in their tumor and
treated with a number of medicines known to
target this specific mutation.
 Examples: AGILE GBM, NCI-MATCH
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http://www.bhdsyndrome.org/forum/bhd-research-blog/genetic-sequencing-approaches-to-cancer-clinical-trials/
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 Given that identification is based on histology
this type of trial is not likely to be seen often in
rare oncology research.
AGILE: Adaptive Trial in Glioblastoma Multiform
 Glioblastoma is listed as a "rare disease" by the Office of Rare
Diseases (ORD) of the National Institutes of Health (NIH). This
means that Glioblastoma, or a subtype of Glioblastoma,
affects less than 200,000 people in the US population.
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http://www.nbdabiomarkers.org/sites/default/files/GBM%20AGILE%20Press%20Release%20-%20Final%20%28002%29.pdf
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 Orphanet currently defines a condition rare when if affects 1
person per 2,000. They list Glioblastoma as a "rare disease".
AGILE Study Characteristics
 > 130 neurologists,
neurosurgeons, neurooncologists, statisticians,
pathologists, etc. from all
over the globe are
participating in the design of
the master protocol
 Global coalition including
Australia, China, the EU and
the US
Adaptive Design
 Will utilize Bayesian statistics
to incorporate information
from patient experiences as
the progresses
 In the US the AGILE study will
Concurrent Biomarker
Development
 Study design includes the
evaluation and validation of
biomarkers as there are no
validated biomarkers
available for GBM research
follow some of the same
principles as those identified
in the I-SPY 2 master protocol
in breast cancer
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http://www.nbdabiomarkers.org/sites/default/files/GBM%20AGILE%20Press%20Release%20-%20Final%20%28002%29.pdf
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“Crowdsourcing Knowledge”
Rare Cancers and Alternative Study Designs
Comprehensive review of adaptive phase I clinical trials in oncology
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http://jco.ascopubs.org/content/32/23/2505.full
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53 Phase I trials
Continuous
reassessment
method (CRM)
CRM using escalation
with overdose control,
time to event
parameters
Risk-Benefit
Treatment
 Patients treated at MTD = 39%
 Patients treated at MTD or adjacent level = 74%
Outcome
 Observed DLT rate = 18% (range 0%-75%)
 Lower observed DLT rate than acceptable 26%
 All levels above the MTD; avg. DLT rate = 36%
Conclusion
 Confirms safety
 Confirms generalizability
http://jco.ascopubs.org/content/32/23/2505.full
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 ‘3 + 3’ design has a DLT rate > 33% in doses above MTD
Non-Traditional
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Defining Endpoints
Traditional
Quantifiable
Diagnosis
Prognosis
Pharmacodynamics/
Pharmacokinetics
Treatment
response
Recurrence of
disease
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Selection of Biomarkers
Surrogate Biomarkers Considerations
 Specific - Biomarker should be involved in process that causes the cancer
 Changes in biomarker should correlate with changes in the disease
 Measurable - Levels of biomarkers should be high enough that they can be measured easily and reliably
 Accurate - Levels or presence of biomarker should readily distinguish between normal, cancerous, and
precancerous tissue
 Effective treatment of the cancer should change the level of the biomarker
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 Level of the biomarker should not change spontaneously or in response to other factors not related to the
successful treatment of the cancer
Key Questions for Alternative Model Designs
 Are model-based dose-escalation designs safe?
 Are model-based designs treating patients at sub
therapeutic levels?
 Do model-based phase I trials result in longer trial
duration?
 Is sample size too large?
 Are these designs flexible enough to deal with different
schedules, patient populations, or drug combinations?
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http://jco.ascopubs.org/content/32/23/2505.full
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 Do designs recommend counterintuitive escalations?
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Expedited Review Pathways for
Potential Rare Cancer Treatments
FDA Expedited Programs for Serious Conditions
Fast Track
Breakthrough
Therapy
Accelerated
Approval
Priority
Review



Serious condition
Potential unmet medical need
Based on clinical and nonclinical data


Serious condition
Substantial improvement on a clinically significant endpoint vs
available therapy



Serious condition
Meaningful advantage vs available therapy
Shows an effect on a surrogate endpoint


Serious condition
If approved would represent significant improvement in safety or
efficacy
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Designed for products designed to address an unmet medical need in the treatment of a serious condition
Accelerated
Assessment
(AA)
Conditional
Marketing
Approval (CMA)
Exceptional
Circumstances
(EC)
Effective as of
March 2016
PRIority
MEdicines
(PRIME)

Medicinal product is expected to be of major public health interest,
particularly from the point of view of therapeutic innovation

Seriously debilitating or life-threatening diseases, emergency
threats or orphan medicinal products
Benefit/risk ratio is positive
Comprehensive data to be provided post-marketing



Applicant unable to provide comprehensive clinical data due to:
rarity of disease, present state of scientific knowledge and ethical
constraints


Major therapeutic advantage over existing therapies
Benefits patients without treatment options
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EMA Expedited Review Programs
Comparison of Expedited Review Programs FDA and EMA
Common Characteristics
EMA Expedited Review Program
Breakthrough Therapy
Unmet Medical Need
Agency Support
PRIority MEdicine (PRIME)
Priority Review
Advantage Over Existing Therapies
Reduced Review Timelines
Accelerated Assessment
Accelerated Approval
Unmet Medical Need
Limited Data / Surrogate Endpoints
Requirement for Post-Marketing Studies
Conditional Marketing
Approval
Fast Track
N/A
None
None
N/A
Exceptional Circumstances
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FDA Expedited Review Program
2015 FDA Expedited Approval Pathway Utilization
Expedited Reviews
56% of the novel drugs approved by the FDA in 2015 utilized
one or more expedited designations:
 Fast Track
 Breakthrough
 Priority Review
 Accelerated Approval
Non-Expedited
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM485053.pdf
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Expedited
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Breakthrough Therapy
22%
Accelerated Approval
Fast Track Designation
13%
31%
Breakthrough
Accelerated Approval
Fast Track
Total Approvals
Total Approvals
Total Approvals
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http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM485053.pdf
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2015 FDA Expedited Review Pathway Utilization – Novel
FDA Accelerated Novel Drug Approvals in 2015
Generic Name
Indication
Basis of Accelerated Approval
Alecensa
alectinib
ALK+ NSCLC
 2 open-label studies
 Tumor response rate
 Duration of response
Darzalex
daratumumab
Multiple myeloma – failed 3 previous
treatments
 2 open-label studies
 Reduction in tumor load
 Duration of response
Farydak
panobinostat
Multiple myeloma after 2 prior
therapies
 Subgroup analysis from 1 study
 Progression-Free Survival
Tagrisso
osimertinib
EGFR T790 mutation positive NSCLC
 2 open-label studies
 Tumor Response Rate
 Duration of Response
Ibrance
palbociclib
Advanced (metastatic) breast cancer
 Single open-label study (adjuvant)
 Progression-Free Survival
Praxbind
idarucizumab
Emergency reversal of dabigatran’s
blood-thinning effects.
 3 studies in healthy pts taking dabigatran
 1 study in pts on dabigatran needing
emergency surgery
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM485053.pdf
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Brand Name
Things to Come
The 21st Century Cures Act
TITLE II - PATIENT-FOCUSED DRUG DEVELOPMENT
•
•
The idea behind the proposal is that different patients—even those suffering from the
same disease—have varying levels of risk they are willing to accept.
The bill would require FDA to establish a structured framework for the meaningful
incorporation of patient experience data into the regulatory decision-making process,
including the assessment of desired benefits and tolerable risks associated with new
treatments.
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Title II of the legislation seeks to build on FDA's recent launch of a Patient-Focused Drug
Development (PFDD) program, which was launched in 2012 under the Food and Drug
Administration Safety and Innovation Act (FDASIA), is meant to incorporate patient
preferences into FDA's regulatory decision-making.
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Summary
Summary

Rare Cancers – What are they?
 Definition, epidemiology and potential future shifts in both

Rare Cancer Patients
 Treat like non-oncology rare disease patients

Putting words into actions for rare cancer patients
 Trial designs to reflect changing molecular aspects of cancer research

Regulatory accommodations for expedited approval of treatments for rare cancers

Pending legislation changes that could potentially change the research environment for rare cancers
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
Increasingly vocal through advocacy groups
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Questions?
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