Connecting the Dots for Rare Disease Studies

FOCUSED. TRUSTED. GLOBAL.
Discovery Series: Connecting the
Dots for Accelerated Rare Disease
Studies
Pirouz Shamszad, MD
Alexander Artyomenko MD, PhD
Derenda Nichols

Introduction to Rare Disease
Pirouz Shamszad, MD

Pirouz Shamszad, MD, FAAP
o Board-certified in cardiology and pediatrics
o Clinical expertise treating children with rare cardiac
disease and research experience utilizing registries
and databases to better describe the epidemiology,
safety, and outcomes of patients with rare disease

Overview
o Introduction to Rare Disease
 Definitions and Epidemiology
o Regulatory basics
 FDA and Pathways
o Clinical Trials in Rare Disease
 Challenges and considerations to trial design
 Ethical considerations
 Pediatric considerations

A Field of Zebras
“When you hear hoof beats, think horses, not zebras.”

Definition
What is Rare Disease?
o There is no single, widely-accepted
definition for rare disease
o Current definitions are prevalence-based
and vary by geography and local
governing regulatory bodies

Countries with Rare Disease Legislation
 United States
 Japan
 Australia
 European Union
 Singapore
 Russia
o Anticipated introduction of orphan legislation:
 Canada
 Turkey
 China

Definition - USA
o In the US, rare disease status is defined by
designations set forth in the Orphan Drug Act
(ODA) of 1983 and Rare Disease Act of 2002
o Defined as any disease:
 Affecting < 200,000 people in the US
• ~1 in 1,500 people
 Affecting >200,000 in the US and no expectation that
drug development costs for such disease will be
recovered from sales in the US of such drug

Europe and Japan
o Europe:
 A life-threatening or chronically debilitating disease
with such low prevalence that special combined
efforts are needed to address them
• 1 in 2,000 people
o Japan:
 Disease affecting <50,000 people in Japan
• 1 in 2,500

Not quite the same
Orphan Diseases
o Rare Diseases are sometimes referred to as
Orphan Diseases
o Not necessarily the same
 Orphan diseases can encompass other diseases that:
• Are “neglected” with regards to treatment options or
availability of treatment
• More common in developing countries

Clinical Examples and Epidemiology of
Rare Disease

Rare Doesn’t Have To Mean Unheard Of
Clinical Examples of Rare Disease
o Amyotrophic lateral sclerosis (ALS)
o Cystic fibrosis
o Progeria
o Hemophilia
o Homozygous familial hypercholesterolemia

Clinical Examples of Rare Disease
o Metachromatic leukodystrophy
o Fibrodysplasia ossificans progressiva (Stoneman)
o Glomuvenous malformations plaque type
Rare Can Be Quite Rare

Rare Disease – The Numbers
Once diagnosed with a rare
disease, it’s not so “rare”
anymore

Rare Disease – The Numbers
Not as Rare As One May Think

A Special Focus
Children with Rare Disease
o 50% affected by Rare Diseases are children
 Responsible for 35% of deaths in first year
 30% will not live past 5 years of age
o 33% of treatments with orphan designation
are developed for children

Regulatory Basics

An Important Effort
Treating Rare Disease
o Continual need for therapies among Rare
Diseases
 Opportunity to make meaningful, innovative
contributions
 Must balance against financial concerns
o Market for Rare Disease compounds is growing
at twice the rate of the balance of R&D
 Driven by development incentives

Orphan Drug Designation
Treating Rare Disease
o FDA Office of Orphan Products Development
(OOPD) established in 1983 via ODA
o Orphan Drug Designation program provides
orphan status and associated incentives
o Mission:
 Advance the evaluation and development of
products that demonstrate promise for the diagnosis
and/or treatment of rare diseases or conditions
 Provides incentives for sponsors to develop products
for rare diseases

Essential Concepts
Expedited Pathways
o Serious Condition
 Morbidity impacting day-to-day functioning
 Typically progressive
o Available Therapy
 FDA approved/licensed product for same
indication or relevant to current SOC
o Unmet Medical Need
 Treatment not addressed by available therapy

Designed for Serious Conditions
Expedited Development Pathways
1. Fast Track
2. Breakthrough Therapy
3. Accelerated Approval
4. Priority Review

Accelerate Development for Serious Disease
o Fast Track:
 Preclinical/clinical data demonstrate potential to fill
unmet medical need
 Rolling review
o Breakthrough Therapy:
 Preliminary clinical data demonstrate improvement
over available therapy
 Fast Track provisions plus intensive guidance

Accelerate Development for Serious Disease
o Priority Review:
 Application providing significant advancement OR
proposes a pediatric labelling change
 FDA makes this designation at time of application
 Application is reviewed in ~6 months vs. ~10 months
o Accelerated Approval:
 Provides meaningful therapeutic advantage AND
demonstrates effect on a surrogate endpoint predicting
earlier benefit
 Eligibility assessed early in development by FDA
 Requires post-market study to verify and describe clinical
benefit or effect on irreversible morbidity or mortality

Type Fast Track Breakthrough Therapy Accelerated Approval Priority Review
Program
Nature
Designation Designation Approval Pathway Designation
Qualifying
Criteria
Intended to treat a serious
condition AND nonclinical
or clinical data that
demonstrate potential to
address unmet need OR
designated as a QIDP
Intended to treat serious
condition AND early data
suggests substantial
improvement on a clinically
significant endpoint(s) over
available therapies
Treats a serious condition AND
provides meaningful
advantage AND
demonstrates an effect on a
surrogate endpoint likely to
predict earlier benefit OR can
be measured earlier
An application that treats a
serious condition AND would
provide significant
improvement OR proposes a
pediatric labelling change
[505A] OR QIDP OR submitted
with a PR voucher
Timing of
Request
With IND or after; NLT pre-
BLA or pre-NDA meeting
With IND or after; NLT EOP2
meeting
Discuss with review division
during development,
With original BLA, NDA, or
efficacy supplement
FDA Response
Timelines
Within 60 calendar days of
receipt of the request
Within 60 calendar days of
receipt of the request
Not specified Within 60 calendar days of
receipt of original submission
Features Actions to expedite
development and review;
rolling review
All FT features, plus Intensive
guidance on efficient drug
development; organizational
commitment; rolling review;
other actions to expedite
review
Approval based on an effect
on a surrogate endpoint or an
intermediate clinical endpoint
that is reasonably likely to
predict a drug’s clinical
benefit
Shorter clock for review of
marketing application (6
months compared with the
10-month standard review)
Additional
Considerations
Designation may be
rescinded if it no longer
meets qualifying criteria for
fast track
Designation may be
rescinded if it no longer
meets qualifying criteria for
breakthrough therapy
Promotional materials;
confirmatory trials to verify
and describe the anticipated
effect on IMM or other clinical
benefit; subject to expedited
withdrawal
Designation will be assigned
at the time of original BLA,
NDA, or efficacy supplement
filing
References Section 506(b) of the FD&C
Act, as added by section
112 of the FDAMA and
amended by section 901 of
FDASIA
Section 506(a) of the FD&C
Act, as added by section 902
of FDASIA
21 CFR part 314, subpart H
21 CFR part 601, subpart E
Section 506(c) of the FD&C
Act, as amended by section
901 of FDASIA
Prescription Drug User Fee
Act of 1992
After: Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (US FDA; May 2014); by s.johnson1@medpace.com

Successes
OOPD Orphan Drug Designation
o Since 1983:
 Successfully enabled the development and marketing of
more than 3,000 products, including 460 drugs, and 500
clinical trials resulting in 50 approvals
• <10 products supported by industry betwen1973 – 1983
o In 2013 alone:
 Approved 33 orphan drugs
 Approved 27 new molecular entities:
• 9 were for orphan products and approved after 1 review
• 2 used the breakthrough therapy pathway
• 5 used fast track pathway
• 4 used the priority approval pathway

Clinical Trial Design in Rare Disease

The Basics Are The Same
Clinical Trial Design
o Clinical trials in Rare Disease have similar
requirements to those of general clinical trials:
 Study design (sample size, endpoints)
 Regulatory submissions
 Site selection
 Patient recruitment
 Data collection/measurements
 Allotted funds and study personnel

The Execution is Challenging
Clinical Trial Design in Rare Disease
Despite similar requirements to general clinical
trials, clinical trials in rare disease are complicated
by small sample size

Challenges – Small Sample Size
Clinical Trials in Rare Disease
o Patient populations will be limited in Rare
Disease clinical trials
 Variable disease sub-types
 Varying presentation and progression
 High inter-subject variability (heterogeneity)
o Limited number of sites and investigators
 Consolidated to large academic centers

Considerations – Mitigating Small Sample Size
o Utilize alternative trial designs and statistical techniques
that maximize data from a small, heterogeneous group
 Examples: Crossover, n-of-1, Adaptive, Historical control
 FDA has greater risk tolerance with existing precedent for
approval of orphan dugs based on NON-randomized,
placebo-controlled, or double blind trials
o Capitalize on resources:
 OOPD Small Clinical Trials course
 Direct pre-IND guidance from FDA about design and
outcomes
 Protocol working groups (disease-specific working groups)

Considerations – Mitigating Sample Size (cont.)
o Possible “all-inclusive” strategies
 Companion or extension protocols
 Expanded access programs
• For excluded patients that may benefit from use
o Enrichment strategies (using genetic subtyping)
 May make results less generalizable

Challenges – Lack of Outcome Assessment
o Natural history and clinical features of Rare
Disease are not always understood
o Challenge in determining outcome assessment
 Endpoints and biomarkers difficult to identify
o Duration of trial difficult to determine
 Especially true for chronic disease that cross from
childhood to adulthood

Considerations– Mitigating Lack of Assessment
o Current push to better understand natural histories
and clinical features of these disease
o Expand foundational science (pre-clinical)
 Aid in identifying biomarker profiles and describing natural
history of disease
o Endpoint identification
 Capture patient recorded outcomes utilizing patient
advocacy/support groups
 Adapt Phase 2a designs to test endpoints
 Development of global patient registries

Challenges – Ethics
o Higher risk tolerance due to these life-
threatening illnesses or lack of current therapies
 Both from patients and FDA
o Limited patient population contributes to
significant “trial fatigue”
 Burden on patients looking for treatment options
 Burden on study teams working for each data point

Challenges – Ethics of Controls
o Controls strengthen trial design by addressing
variability
o In the setting of life-threatening or shortening
disease, the ethics of a control arms are
heightened
 Patients or parents of patients may be reluctant to
receive control or there may be no
 Greater urgency to receive active treatment, before
therapeutic window is lost

Considerations– Ethics
o For any given product, the following must be
weighed:
 Desired clinical benefit
 Risk to benefit probability
 Amount of tolerable uncertainty
o In situations where no preclinical or clinical data
is available, “… it is important for FDA and
sponsors to partner early in the product
development process and reach agreement
on potential paths forward” (FDA, 2014)

Considerations– Ethics
o Incorporation of an open-label extension and
use of rescue medications can be used to help
justify placebo-controlled designs
 Add-on to standard of care therapies
o Stabilization may be seen as a reasonable
benefit
 Risks for harms may be acceptable given the
potential for slowed progression of the disease versus
absolute cure

Challenges – Research Involving Children
o 50% of rare diseases affect children usually due to
genetic etiology of most rare diseases
 Children represent a small percentage of the overall general
population, adding to recruiting difficulty
o Evolving approach to pediatric research from a
“vulnerable” population in the 1970’s to our “moral
imperative” in the 2010’s
o Children are not little adults
 If adult data exist, may not apply to children
o Pediatric institutions generally have less developed
research infrastructure than adult counterparts

Considerations – Research Involving Children
o Support the family decision to include (or
exclude) their child in a clinical trial
 Acknowledge the disruption to daily life
 Facilitate travel/lost work
o Address safety and benefits of a trial vs.
standard of care or no therapy
 Full disclosure/transparency; Assent
o Provide patient support systems /team
relationships geared to the child

Success Lies In A Team Approach
Clinical Trial Execution in Rare Disease
Medpace Rare Disease Team
A team of dedicated individuals across all functional
areas contributing to a collective experience
 Disease/trial specific insights and lessons learned from
past trials to foster creative strategies
 Internal/External Rare Disease Training Programs
 Strong partnership and collaboration with Sponsor,
Investigators, and Patient Groups

Resources
o FDA OOPD
o NIH Office of Rare Diseases
o National Organization of Rare Diseases (NORD)
o European Organization for Rare Diseases
(EURODIS)

Real-World Evidence
in Rare Diseases
Alexander Artyomenko MD, PhD
Webinar Spotlight:

Alexander Artyomenko, MD, PhD
o Cardiologist with > 13 years of experience in Late
Phase clinical research
o Unique background encompassing medicine, clinical
trials and project management, with a highly
successful track record in developing strategies and
executing global phase IIIb-IV and observational
studies

Alone we are rare…together we are strong!

o “Data used for
decision-making that
are not collected in
conventional RCTs…”
o i.e., collected in an
observational, non-
controlled, non-
experimental setting
What is Real-World Evidence?
Garrison,L.P.,et al,(2007).Using RWD for coverage and payment decisions: the ISPOR RWD task force report. International
Society for Pharmacoeconomics and Outcomes Research(ISPOR), Value in Health,Vol10,No5.

Real-World Evidence
Outcomes
research
Resource
use and
treatment
options
analysis
Patient
experience,
compliance
and
preferences
evaluation
Effectiveness
and benefits
review across
treatment
options

Why we need RWE in rare diseases?
o Address research questions
 Natural history of the disease/condition
 Influence of lifestyle, environment, genetics
 RCTs may not always be feasible for very
rare diseases
o Support the market access and pricing
strategy
 Healthcare resources and product utilization
o Further research on safety and
comparative effectiveness of the
product
 Support treatment decisions

Aligning the Stakeholder Needs
Pharma
• Address data gaps
• Feedback from payers
and patients
Providers
• Maximum treatment
safety and effectiveness
• Reduced treatment
costs
Payers
• Evidence of positive
clinical, humanistic and
economic outcomes
Patients
• Minimal side effects
• Cure the disease
• Improve quality of life
• Affordable care

Patient-Reported Outcomes in Rare Diseases
o Out of 69 orphan medicines approved by
EMA as of Nov 2013, 20.3% had a PRO claim
o Various PRO concepts were assessed (i.e.,
symptoms, function, and QOL), with QOL
representing almost 30% of the PRO claims
Patient-reported outcome (PRO) claims in products indicated for the treatment of rare diseases and approved by the
European Medicines Agency (EMA). Laure-Lou Perrier, Catherine Acquadro, Benoit Arnould, ISPOR May 2014

Health Economics in Rare Diseases
o The National Institutes of Health reports that
about 6,000 rare diseases affect approximately
30 million Americans each year
o Even at a modest annual estimate of $15,000
per person for biologics targeting rare diseases,
the annual bill for rare diseases would amount
to $450 billion, nearly half of the global
pharmaceutical market of $990 billion in 2012
http://rarediseases.info.nih.gov/files/Rare_Diseases_FAQs.pdf
IMS Health, IMAP

Recent EU changes in evidence requirements for the
reimbursement of orphan drugs
Country Major changes
United Kingdom • New responsibility for assessment of ultra orphan drugs for NICE
(1st of April 2013)
• New appraisal mechanism developed by NICE for ultra orphan
drugs (1st of April 2013)
• Value-based pricing system (1st of January 2014)
France • Economic evaluation in national reimbursement assessment
(Autumn 2013)
• Early dialogue pilot system
Germany • AMNOG (1st of January 2011)
• Responsibility for assessment of orphan drugs passed from IQWIG
to the G-BA – No clinical added benefit assessment
• Threshold reduction for annual budget from 50 million to 30 million
Euro
Belgium • Discussion about appropriate study designs for orphan drug
assessment
• Orphan drugs will be subject to contract negotiations
• Discussion guided by ethical arguments
Austria • Transparency directive changes
• Current Austrian health reform
An European overview of the future changes in evidence requirements for the reimbursement of orphan drugs
A stakeholder analysis. Lisa J. Krüger, Johannes J Tamminga, Ben F.M. Wijnen, Mickael Hiligsmann, Silvia M.A.A. Evers, accessed via http://www.ispor.org/research_pdfs/46/pdffiles/PSY72.pdf

The Varied Sources of RWE
•Routinely Collected Primary and
Secondary Care Datasets
•Retrospective Chart Review Datasets
•Medical Claims Datasets
•Electronic Medical Records
Retrospectively
collected data
•Prospective chart review datasets
•Large pragmatic trials
•Patient and population surveys
•Registries
Prospectively
collected data

Retrospectively Collected Data
o Routinely Collected Primary and Secondary
Care Datasets
 Explore evidence of safety, effectiveness and health
outcomes improvement and support clinical
innovation efforts
 No international standard approach to coding and
classification
 Examples:
• US: Veterans Health Administration database
• UK: Clinical Practice Research Datalink

Retrospectively collected data
o Retrospective Chart Review
 Information not originally
collected for research purposes
 Well-defined research questions,
inclusion/exclusion criteria, CRF
and data collection procedure
 Training and monitoring for data
abstractors
 Should address inter-rater and
intra-rater reliability,
confidentiality and ethical
considerations

o Medical Claims Datasets
 Initially created for financial administrative purposes
 Patient-level information on diagnosis, treatment
types, providers and costs
 Standardly coded
 Examples
• PharMetrics®
• Medicaid
• Truven Health MarketScan

o Electronic Medical Records
 More comprehensive clinical data
 Includes info on non-prescription drugs
 Additional healthcare info (labs, risk
factors, nurses etc.)
 Not limited to insured only population
 Not widely adopted

US
PharMetrics
LabRx
MarketScan
WellPoint
Medicare
HRTX/DoD
Australia
GPRN
Taiwan
National Health
Insurance Research
Database
Italy
HealthSearch
Pedianet
France
In Fine PHARMA
EGB / SNIIR-AM
Canada
RAM-Q
SWO
Saskatchewan
Europe
IMS Disease Analyser (AT, DE, FR, UK)
PharmAccess (FR, GE, IT, UK) Denmark
ODS
OPED
PDNJ
Sweden
Swedish
registries
Finland
Finnish
registries
UK
GPRD
THIN
MEMO
Netherlands
Pharmo
ICPI
• Electronic Health Records
• Pharmacy Databases
• Medical Claims Databases
• National Registries

Prospectively Collected Data
o Prospective Chart Review Datasets
 Robust site feasibility is essential
 Protocol, CRF and training required
o Large Pragmatic Trials
 Interventional trials
 Relaxed eligibility criteria
 Closest to the standard of care

Natural History Studies
o The natural course of the disease from the time
immediately prior to its inception, progressing
through its presymptomatic phase and different
clinical stages to the point where it has ended
and the patient is either cured, chronically
disabled or dead without external intervention
Posada de la Paz M, Groft SC. 2010. Rare diseases epidemiology. Vol. 686

NH Study Types
o Retrospective chart review
o Prospective cross-sectional
o Prospective longitudinal

NH Study Goals
o Define the disease
o Identify knowledge gaps
o Understand patients needs
o Improve diagnosis
o Identify potential biomarkers and outcome
measures
o Develop centres of expertise
o Raise disease awareness

Patient and Population Surveys
o Primarily used for epidemiological information
o Should be well designed, structured standardized
and validated
 Satisfaction and experience type surveys
o May have questionable validity and generalizability
of the results
 Population sampling
 Voluntary response bias
 Convenience sampling
 Length and structure
Are patient surveys valuable as a service improvement tool in health services? An overview. A. Patwardhan,
C. Spencer, Journal of Healthcare Leadership, May 2012.

One of the most widely used data sources
Registry
o …a patient registry is an organized system that
uses observational study methods to collect
uniform data (clinical and other) to evaluate
specified outcomes for a population defined by
a particular disease, condition, or exposure,
and that serves one or more predetermined
scientific, clinical, or policy purposes.
Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. 2nd ed.
Agency for Healthcare Research and Quality. September 2010.

Types of Registries
o Disease/condition
registry
 Research the natural
history of the disease
 Study treatment
patterns
o Product registry
 Follow up long terms
outcomes for patients
using a new therapy
 Pregnancy registries

A total of 641 registries*
Geographical coverage of rare disease
registries
Orphanet database, January 2014 report
European,
6.2%
Global,
11.5%
National,
69.6%
Regional,
12.0%
Undefined,
0.6%

Addressing Scientific and Commercial Objectives
Registries
o To understand clinical practice, identify unmet clinical
need, disease natural history and treatment.
o To evaluate the effectiveness of treatments, meet post-
marketing commitments in terms of quantification and
characterization of safety endpoints
o To generate supportive data for new indications,
product position, label extension and reimbursement
o To demonstrate the economic value, quality of life
benefits of a particular treatment/product
o To develop positive relationships with clinicians / patients
and develop product advocacy
o To obtain relevant information on prescribing (i.e.
physician behaviour and patterns)

Registries
Main Strengths
•Flexible design and lower cost
•Information on normal clinical
care
•Information on long term
outcomes
•Good for hypothesis generation
•High external validity when
appropriately designed
•Feasible for broader range of
practice environments
Main Weaknesses
• Confounding and other forms of bias
are common features
• Recruitment challenges due to larger
sample sizes
• Weaker causal inference as regards
effectiveness and safety assessments
• Physician motivation and patient
retention can be challenging
• Possibility of variable data quality
• Absence of threshold for defining good
practice standard

The Future: RWE stakeholders meet Big Data
o Increasing volume of
patient-level
information and our
ability to analyze it
 EMRs, claims data
 Patient communities,
social media
 Individual sensors and
wearables
 Medication compliance,
behaviours, functional
parameters (respiratory,
cardiovascular,
metabolic etc.)

Executing Rare Disease Studies
Derenda Nichols

Derenda Nichols
o > 24 years experience in the CRO industry with 13
years in post marketing and peri-approval research
o Successfully participated in planning and execution of
large, multi-country projects in a variety of
therapeutics areas

(A few) Operational Considerations
o Multiple stakeholders with differing interests
o Limited numbers of patients
o Scant knowledge about the pathophysiology or
natural history of the disease
o Few investigators who typically are experts in
their field, but may be naïve in conducting
industry sponsored research
o Pediatric population may need to be followed
to and beyond age of consent
o Little data to support study design decisions

Aligning Stakeholder Understanding
o Identify all stakeholders
o Delineate objective(s) and scope at the earliest
planning stages
o Consider national / regional interests
o Define operational roles / responsibilities
o Communicate frequently and transparently
o Make no assumptions

Registry
•“Real world”
•Observational
•Hypothesis generating
•Large “N”
•Flexible
•GCP “light”/GRACE
•Relatively long duration
Clinical Trial
•Randomized
•Selective entry
•Hypothesis driven
•Small “N”
•Powered
•GCP required
•Typically short duration
Registry ≠ Clinical Trial

Differences Between Registries and RCTs
Activity Registries RCT
Sites May include research naive sites Experienced sites
Site visits Variable Yes
Site honoraria Variable Substantial
Case report forms Usually simpler, shorter Complex, extensive
Protocol Simple, straightforward Comprehensive
Duration Long term Short term
Sample size
Variable
Relatively small based on
disease under study
Investigator agreement Simple Complex
Investigator motivation
Scientific or clinical practice
value
Scientific value
Patient motivation
Scientific or clinical practice
value
Scientific value
Patient consent Usually Yes
Data quality control Variable Comprehensive
Outcomes Final Intermediate
Statistical analysis Usually descriptive Hypothesis testing
Design Observational Structured

Why include Registries In Rare Disease Drug
Development?
o Increases the likelihood for developing a treatment
for the disease in question
o Establishes a standard of care
o Improves patient outcomes and life expectancy
o Provide insights to potential clinical endpoints and
variability in clinical progression among subsets of
patients
Orphanet. Report on Rare Disease Research, Its Determinants In Europe and The Way Forward, May 2011
ll

Getting It Right The First Time . . .
o Registry studies need careful planning
 Expensive to conduct
 Often long in duration (5, 10, 15+ years)
 Regional regulatory requirements can differ substantially (e.g.
data protection laws, EC submission process)
 Clinical development may drives natural history registry
timelines
 Marketing approvals / insurance reimbursement drive
timelines for product registries
 Sites are managed remotely
 Need to balance simplicity with adequate data
capture/integrity
 Sites/patients need to stay interested and motivated
o Poor planning in year 0 can haunt you in year 5, 10…

Registries - “Monitoring” from a Distance
o Risk-based, centralized monitoring is the norm
o Routine field monitoring is not typical for
registries
o Site performance can be evaluated using a
standardised checklist reviewed in regular calls
with sites
o Pre-defined triggers for escalated on-site
monitoring

Triggers for Registry On-site Monitoring
o Triggers that may justify on-site monitoring:
 Failure of the site to obtain appropriate Patient
Informed Consent
 Suspected data integrity issues
 Sites enrolling greater than a pre-determined number
of patients
 Excessive staff turnover
 Unresolved/excessive outstanding data queries
 Lack of understanding and/or non-compliance of
study procedures by site staff
 Non-compliance with safety reporting procedures
(e.g. delayed or incomplete SAE/AEI reporting)

Lessons Learned

Common Study Execution Needs
o Increased collaboration between Sponsor and
selected vendors and partners
o Frequently required vendors
 Travel Centers – Colpitts, NORD
• Patient costs, on-site translators
 Call center
 Home healthcare nurses
 On demand training services

Common Study Execution Needs
o Supply management of site equipment for
novel endpoints
o Training on novel endpoints
o PIs typically experts in their field, but industry
sponsored research naïve
 Tailor a training plan for good clinical practice, good
documentation practice and basic adverse event
reporting

Site Selection and Feasibility
o Differences between typical site selection and
feasibility:
 Sponsors usually have pre-selected investigators
 Registries are often the key to understanding where
population is treated along with identifying and
tracking key inclusion/exclusion data

Site Selection and Feasibility
o QVs are conducted to identify issues and solve
these challenges rather than evaluating site’s
ability to participate
o Highly motivated but very busy - study-specific
tools, training, and monitoring support are vital
 Reminders/refreshers regarding GCP/GDP
o Varying requirements for navigating IRB/EC
approval, contracting, etc.
 Leverage past experience and PI commitment to
reduce timelines

Regulatory Submissions
o Ratio of countries to number of sites is skewed
 Many countries and relatively few sites
 Nearly all sites are local EC/IRB sites
 Multiple review committees are common due to
patient age or novel therapy
o Patients may request to travel to existing site
locations across country borders
 Establish process/checklist to ensure necessary
resources and documentation are in place

Regulatory Submissions
o Lower the risk of lengthy back and forth
 Review past experiences with each site
 Discuss the EC/IRB review process and expectations
with each Investigator prior to submission
 Complete ICF Preparation Early
• Identify types of ICFs/Patient Information (according to
age groups) needed for each site
• Tailor ICFs to IRB/EC mandatory expectations based on
previous experience
 Investigator involvement in the process is key

Conditional Marketing Approval
o Authorization may be granted if certain specific
obligations, are met and approved annually by the
Agency for the following:
 Seriously debilitating or life-threatening diseases
 Emergency threats (WHO, EU Commission)
 Orphan medicinal products
o Granted when all requirements are met:
 Benefit/Risk balance is positive
 It is likely that comprehensive clinical data will be provided
 Unmet medical needs will be fulfilled
 Benefit to public health of immediate availability outweighs
risks that additional data are still required

Recruitment Strategies
o Generate excitement about your trial
 Presence at scientific meetings
 Engage the PIs and CRCs in the study through
strategic outreach/team building
 Utilize registries to understand what sites to target for
referrals and participation in the study
 Collaborate with advocacy groups
• Significantly improves study and medication awareness
and further enhance site and patient
interest/enthusiasm

Patient Retention
o PI and CRC involvement and encouragement is
critical for patient retention in this study
o Request that the PI discuss study expectations
and all possible outcomes with
patient/guardians during the screening process
o Engage subjects
o Reminders (phone calls, text messages or
emails) about what to expect

Social Media
o Social media can have many positive
and negative effects on your trial
 Potential for unblinding
 Misinformation
 Boosted awareness of trial positively impact
recruitment
 Support
 Advocacy
 Learning – important insights
can be gained

Monitoring Strategies
o Create a strong site support plan
 Bolus recruitment is commonplace
• Dry runs may be necessary based on complexity of
protocol
• Increased monitoring visit frequency
 CRC support tools/funding; CRCs in hospitals are
overworked
 Site specific recruitment plan for patients based on in-
house database review
 Individualized CRA-CRC interaction plan – maintain
interest, discuss recruitment efforts, keep the
relationship positive

Ensuring Data Integrity - Monitoring
o Strategies for conducting on-site monitoring
may include:
 Selecting a pre-determined number of patients for full
clinical monitoring
 Performing Source Document Verification for all
patients on critical data fields
• Patient demographics
• SAE information
• Adverse events of interest data
• Concomitant medications

Safety Monitoring
o Unique anatomy/physiology
 Typical physiology and effects on safety assessments
(labs, ECGs, radiographic studies, etc) may be largely
unknown or poorly characterized
 Safety assessments may be significantly abnormal at
baseline, making detection/interpretation of changes
more challenging
• Consider how safety signals may be uniquely
manifested in the patient population
• Define safety flags in the context of the disease (ex: LFT
increases in patients with myopathy)
• Tailor safety monitoring algorithms

Factors for Success
o Strong, inclusive planning effort
o Collaborative team (sponsor, partners, other
stakeholders) sharing common vision
o Well-defined processes and communication
pathways
o Knowing the “ins and outs” of FDA approval
requirements
o Engaged Investigators
o Motivated Patients
o Proactive assessment of study performance
and risks

THANK YOU!

Connecting the Dots for Rare Disease Studies

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Connecting the Dots for Rare Disease Studies