n this free webinar, Medpace partners with Michelle Eagle of ATOM International, a provider of CE training for clinical trials across the world, to discuss approaches and steps that can be taken to ensure quality and integrity.

1. PART 3: RARE DISEASE CLINICAL
RESEARCH – STRATEGIES FOR ENSURING
ENDPOINT INTEGRITY

2. PROTECTING TRIAL ENDPOINTS
ATOM INTERNATIONAL
MASTER PHYSIOTHERAPIST
MEREDITH JAMES

3. M A K I N G T H E C O M P L E X S E A M L E S S
TABLE OF CONTENTS
Who is
ATOM
Our
Story
What We
Do
Outcome
Measures
Quality
Control
Results
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4. M A K I N G T H E C O M P L E X S E A M L E S S
OUR PEOPLE
• Founded by Michelle Eagle, PhD,
PT in Newcastle, UK
• Michelle has over 10 years
experience training evaluators for
commercial therapeutic trials and
over 30 years as a Physiotherapist
• 18 Physiotherapist team members
• Several team members are global
key opinion leaders in
neuromuscular disorders and
clinical endpoints
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advice
training
quality
control

5. M A K I N G T H E C O M P L E X S E A M L E S S
INDICATIONS
• Neuromuscular disorders
‒ Duchenne Muscular Dystrophy (DMD)
‒ Becker Muscular dystrophy (BMD)
‒ Spinal Muscular Atrophy (SMA)
‒ Limb girdle muscular dystrophy (LGMD)
‒ Fascioscapulohumeral muscular dystrophy (FSHD)
‒ Myotonic dystrophy
• Glycogen Storage disorders
‒ Pompe disease
‒ Farber disease
• Mitochondrial disease
‒ Thymidine kinase 2 deficiency (TK2d)
• Achondroplasia/ skeletal dysplasias
• Acute trauma/ Intensive care unit
• Autism
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6. M A K I N G T H E C O M P L E X S E A M L E S S
OUR STORY
• Began with Michelle Eagle, a global leader in Neuromuscular
disorders and developer of critical functional outcome measures for
this population.
• The first clinical trials in NMD commenced around 2007
‒ Disease specific endpoints were not available
‒ Training consisted of an investigator meeting and manual only
Difficulty achieving primary endpoints- variability in data, variation in how sites performed tests, no standardized
training
ATOM established as the industry leader in Advancing Trial Outcome Measures
Needed re-thinking of choice of endpoints, training and data collection methods
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7. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT WE DO
• ATOM is involved at all stages of a clinical trial
‒ Protocol development
‒ Endpoint information and guidance
‒ Clinical evaluator manual of operations
‒ Training of study clinical evaluators
‒ Source documentation
‒ Data quality control via video review
‒ Support for evaluators through personal ‘buddy system’
‒ Data review
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8. M A K I N G T H E C O M P L E X S E A M L E S S
QUALITY CONTROL-WHY?
• Evaluation of end points/outcome measures in trials are a serious
and expensive business
• A good outcome measure is reliable, repeatable and standardised
• A good outcome measure is sensitive enough to measure change
• Data collection is dependent on high quality, reliable, standardised
evaluations by a Physiotherapist/Clinical Evaluator
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How does ATOM facilitate these factors so that we can trust
our data?

9. M A K I N G T H E C O M P L E X S E A M L E S S
PROTOCOL INPUT
• Consultancy on protocol design and
endpoints/outcome measures
• Advice on
‒ population choice
‒ endpoints- primary/secondary
‒ inclusion criteria
‒ exclusion criteria
‒ schedule of events
‒ training plan and IRB implications
‒ quality control measures
‒ eCRF and source documentation
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10. M A K I N G T H E C O M P L E X S E A M L E S S
ROLE OF THE PHYSIOTHERAPIST IN
CLINICAL TRIALS
• The Physiotherapist clinical evaluator is a key person
• They gather the functional trial endpoints
• Physiotherapists have developed many of the outcome measures/
ClinROs used in current trials or standardized their application in
clinics and trials
• Level of education and autonomy is variable globally
• Standardised procedures for clinical trials essential
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11. M A K I N G T H E C O M P L E X S E A M L E S S
OUTCOME MEASURE TRAINING
• Standardized, reliable and repeatable clinical evaluation is central to
the success of trials
• Minimisation of variability between endpoint assessments
• Clinical Evaluators are responsible for collection of data based strictly
on the CE manual of operations.
• Following the manual is essential to decrease internal validity risks
associated with effort dependent tests
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12. M A K I N G T H E C O M P L E X S E A M L E S S
METHODS FOR OUTCOME
MEASURE TRAINING
Training is delivered by a number of methods, but always
individualized to the needs of the clinical evaluator whilst
being delivered with standardized content.
• Investigator meeting
• Physiotherapist only meeting - in country
site or US/UK
• Site visits
• Webex
• ‘Buddy’ support
• Manual of operations
• Source documentation
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13. M A K I N G T H E C O M P L E X S E A M L E S S
OUTCOME MEASURE TRAINING
• Disease specific and general functional scales
• Walking tests
• Timed tests
• Strength testing (HHM, MMT, QMT)
• Tests of upper limb dexterity and function
• Respiratory function testing
• Anthropometric measures (Height, ulna length,
arm span)
• Clinical experience ≠ perfect assessment
• Every CE must follow the manual to the letter
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14. M A K I N G T H E C O M P L E X S E A M L E S S
DOCUMENTATION
• eCRF collaboration
• Source documentation
• Training materials
• Manual of operations
• Certificates of training
• Video QC of assessments
• Data review meetings
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15. M A K I N G T H E C O M P L E X S E A M L E S S
VIDEO QUALITY CHECKS
Video of the Clinical evaluator performing the assessments help
reduce variability and quality control the assessment and the data
• Confirm trained CEs completing assessments correctly
• Provide feedback to evaluators on administration technique
• Provides continuation of training, positive reinforcement
• Reduce variability between assessments
• Capture invalid assessments/data
• Critical at screening visit to correct errors prior to
baseline/randomization
• Chilipharm utilization
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16. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT ISSUES ARE PICKED UP BY VIDEO
QC AND WHAT DO WE DO ABOUT IT?
Untrained evaluators
doing assessments
Wrong starting
positions
Unsuitable
testing area
Invalid tests
Incorrect order
of evaluations
Set-up
training
Give advice/reminders
on correct positions
Alert site, assist in
finding better areas
Document and inform
Find out why? Assist in
resolving any problems
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17. M A K I N G T H E C O M P L E X S E A M L E S S
COMMON ERRORS SEEN ON VIDEO
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18. M A K I N G T H E C O M P L E X S E A M L E S S
ERRORS PICKED UP BY VIDEO QC
• Minor Errors
‒ Deviations from the procedures outlined in the user manual, but are
unlikely to affect the results of the test
‒ CEs will correct before next testing session
‒ Persistent errors may require re-training
• Major Errors
‒ Deviations which may potentially compromise the validity or reliability of the
resulting data
‒ ATOM will initiate a discussion with the Sponsor to determine the appropriate
follow-up actions
‒ ATOM will contact the CE to schedule re-training
‒ Depending on the major error and the visit time point at which it occurred,
a participant may be asked to repeat the functional testing
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19. M A K I N G T H E C O M P L E X S E A M L E S S
INTERNATIONAL REACH
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20. DATA MANAGEMENT

21. M A K I N G T H E C O M P L E X S E A M L E S S
ATOM DATA REVIEW MEETING
• Subject Profiles and Listings
‒ Demographics
‒ Physical Function Tests
‒ Adverse Events
‒ Concomitant medications
‒ Additional procedures that may confound Clinical Evaluator testing
• Data Visualizations
‒ Spotfire
‒ Excel
‒ Tableau
• Data Quality
‒ Source Data verified
‒ Electronic edit checks
• Timing
‒ Look at data early and often
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22. M A K I N G T H E C O M P L E X S E A M L E S S
SITE 001 SUBJECT 001
• 6-minute walk distance
shorter over time
• All timed function tests
taking longer over time
• No indication of Clinical
Evaluator error
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23. M A K I N G T H E C O M P L E X S E A M L E S S
SITE 2 SUBJECT 001
• 6-minute walk
• Distance trending longer
• V3 Decreased 58 m
• V4 Increased 83 m
• Time function Tests
• Trending shorter
• Review video V3 6
Min Walk
• Data entry error?
• Review additional
subjects at site
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24. M A K I N G T H E C O M P L E X S E A M L E S S
SITE 002 ALL SUBJECTS
• V3
• Decrease 6MWT
• Quicker 10 meter
• Was test order
switched?
• Was course location
changed?
• Were subjects not
wearing shoes?
• Different Clinical
Evaluator?
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25. OPERATIONAL
CONSIDERATIONS

26. M A K I N G T H E C O M P L E X S E A M L E S S
KEYS TO SUCCESSFUL PARTNERSHIP
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Early Protocol
Collaboration Communication
Planning
Training and
Equipment

27. M A K I N G T H E C O M P L E X S E A M L E S S
HIGHLY TRAINED STAFF
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ATOM team comprised of PTs with
approximately 200 years of industry
sponsored trial experience
Medpace Rare Disease Certificate program
Clinical Research Associate training
• Understand equipment and space needs
• Swift alerts for impactful changes in staff
• Partner in keeping site on track

28. M A K I N G T H E C O M P L E X S E A M L E S S
STUDY EQUIPMENT
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Ensuring global standards
Site Space
Regulatory
and
Importation
Contractual
setup

29. M A K I N G T H E C O M P L E X S E A M L E S S
EXECUTING PROPER TRAINING AND OVERSIGHT
Effective
meetings
Complexities
of equipment
Unique
space
requirements
Managing
multiple
languages
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30. M A K I N G T H E C O M P L E X S E A M L E S S
IMPROVING ENDPOINTS
• Reducing variability in endpoints through years of strategic collaboration
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Training
Oversight
Technology
Operational
Strategies
Continuing
Education

31. QUESTIONS
THANK YOU