A brief overview of Challenges in conducting Trial of medical devices. My small endeavor in understanding #clinicalTrials of MDs. Includes Medical Device rule 2017 too.

1. Special Issues In Conducting Clinical Trials On Medical
Devices
Dr. Shakeeb Dhorajiwala
1st Year DM Resident,
Department of Clinical Pharmacology

2. Overview
Conclusion
Potential Approaches to Mitigate Problems in Device Trial- Tabular form
Regulatory Pathway For Device Approval
Post-marketing device studies
Challenges in randomizing device trials and their alternatives
Sham Procedures : Their limitations and ways to overcome
Challenges in Process of Blinding and suitable measures
How clinical trial of MD differs from Pharmaceutical
Introduction
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3. Introduction
All substances intended for internal or external use in:
• Diagnosis
• Treatment
• Mitigation
• Prevention
of disease/disorder in human beings
notified by the government from the time to time
Indian Government introduced the Medical Device Rules (MDRs), 2017 (“2017 Rules”) made
with intention to distinguish medical devices from pharmaceuticals for purpose of regulation
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4. How are Clinical trials of MDs different?
Blinding more challenging
• Subjective endpoints e.g. threshold for revascularization
Procedural learning curve play an important role
• Implication: poor outcomes in early phases
Underpowered for major morbid events/ mortality
Compliance not an issue
Pre-market approval supplement pathway
• for new models of devices already approved
No precise rule governing what degree of change warrants new CTs
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5. Challenges In Blinding Process
Blinding requires sham procedure
Sham procedures: a procedure that simulates the
device implantation, but no device is implanted
• violate ethical principles d/t lack of potential for individual benefit
• Mostly deemed UNETHICAL RISK outweighs potential BENEFIT
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Zannad F, et al, Current challenges for clinical trials of cardiovascular medical devices, Int J Cardiol (2014), http://
dx.doi.org/10.1016/j.ijcard.2014.05.021
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6. What To Do If BLINDING Is Not Possible?
Can bias outcome  overestimating the treatment effect
Design studies with hard objective end-points (e.g. all-cause mortality in place of cause-specific
mortality)
Subjective endpoints assessed by blinded CEC (PROBE design)
Use PRO/ HRQOL questionnaires as secondary endpoints to address patients perspective and
know preferences
Also data collected rigorously and potential sources of bias be acknowledged
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CEC: Clinical events committee
PROBE: Prospective Open with blinded evaluation
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7. Unblinded Investigators
Adjust therapies and alter patient management during an ongoing study
accidental unblinding affect pts’ care in treatment arms
Investigators reporting AEs more frequently in investigational arm or under-reporting AEs
if the investigator bias favors study device also common
Plausible solution: blind study personnel
operator should not participate in study-related patient assessments
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8. Blinded placebo control and limitation of sham
Sham procedure+OMT Analogous to active control in drug trial
Implantation procedure exert greater placebo/negative effect on the patient's
condition than a placebo in drug trial
Invasiveness of the sham procedure directly proportionate placebo effect
affects validity of conclusion
discontinuation (drop outs) or drop-ins (switch to “on” mode) raises problems
with statistical power, data quality, safety, and the interpretation of study results
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9. Overcoming limitations of Sham-Procedures
Between-group comparison between device ‘on’ and device ‘off’- assesses true
effects
Establish post-procedural baseline assessment quantify incremental benefit of
device fn above immediate effect of procedure
• However post-procedural confounders like anesthesia effects, wound healing, Hawthorne effect
skews assessment
placebo effects wanes over time in chronic diseases e.g. CVS ds
• extended follow-up may help assess true treatment effects
Soln for drop-outs: Adjust for drop-out in sample size calculation
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10. What to do if Sham procedures aren’t feasible?
• OMT as the comparator
• E.g.
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Approach assesses incremental benefit over conventional therapy

11. Challenges in Randomization
Reduces potential bias by ensuring that confounders are evenly distributed among
treatment groups
If not randomized: limits data interpretation and confidence of asserting results
randomized trials are time consuming incompatible with many device life-cycles
new generation of the device may be engineered by the time the trial has concluded
FDA’s instructions if randomized trials not feasible: Considers only those alternative
designs that are “based on sound arguments that they will provide sufficiently robust
data”*
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* Chen E, Sapirstein W, Ahn C, Swain J, Zuckerman B. FDA perspective on clinical trial
design for cardiovascular devices. Ann Thorac Surg 2006;82:773–5.
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12. FDA’s Stance on Alternative Non-Randomized designs
FDA is flexible in approach
Encourages early direct interactions with sponsors
Considers such trials only on Case by Case basis
Device-specific recommendations i.e.
• an approach acceptable for one device type may not be applicable to other device types.
FDA’s only intent: Study to generate sufficient e/o device safety and effectiveness
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13. Alternative approaches (1/3)
Non-randomized controlled:
Control groups derived from contemporary registry data
Useful only if data collection procedures comprehensive, complete,
and ideally concurrent
CHALLENGE: achieving population with similar risk profile to those
treated with the study device
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14. Objective Performance Criteria (2/3)
Defn: a numerical target value derived from historical data from clinical studies/ registries
used by FDA for comparison of safety or efficacy end points
developed for an established device technology using patient-level data collected from pooled
data
ADV.: OPC as a comparator substantially reduces sample size because it assumes a fixed
number with no variability
Limitations:
• Inadequate to support claims of superiority by regulators
• represent minimal acceptable outcomes
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15. Observational Studies (3/3)
Non-randomized observational studies alternative when randomized trials are not feasible
provide data on device performance in a day-to-day clinical practice environment
patient enrollment is often faster in observational studies lower complexity and study burden
evidence generated is less robust than data from RCTs
raise questions about the benefits and risks of new device vs current standard of care
not fully informative with regard to the mechanisms of effectiveness.
Selection bias is a major drawback
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16. Post-Marketing Device Studies (1/2)
Highly essential in MD trials; for reasons being
• Trials highly underpowered small sample size
• provide an opportunity to address issues posed by regulators but answered by pivotal trial
provide increased precision around point estimates for rates of key events viz mortality
FDA grants conditional pre-market approval to class III (highest-risk) devices in return for post-
marketing data
Sponsors too design prospective clinical trials conducted under an investigational device exemption
(IDE) nested within post-approval studies to generate data supporting new future indications
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17. Post Marketing Studies- Observational (2/2)
Non-randomized, observational studies are commonly used for post-market surveillance
inherent limitations (e.g., unmeasured confounders, selection bias)
Provides opportunity to confirm findings of randomized controlled trials
help to inform reimbursement and health policy decisions
Generate hypotheses
FDA's MedWatch system-
• maintains vigilance over post-approval marketing studies and encourages groups of investigators and patients to
report adverse events
• Important initiatives: Unique Device Identifier (UDI) system and Sentinel initiative
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18. Regulatory Pathway For Device Approval
Global differences in standards for regulatory device approval
FDA requires demonstration of a reasonable assurance of safety and effectiveness for class III
(highest risk) devices
In European Union (EU) process differs as
• medical device approvals are processed by Notified Bodies designated by government Competent Authority in each
member country
• Notified Bodies determine approval (grant the Conformité Européenne [CE] mark) based on reliability testing and a
demonstration that the device performs as intended, rather than on safety and effectiveness data
Regulatory requirements for approval of medical devices in the United States are vastly different
from those in Europe, causing difficulties in harmonizing research requirements globally.
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19. Potential Approaches to Mitigate
Problems in Device Trial
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20. Problem Suggested approach and potential
advantages
Potential disadvantages
1. Placebo effect for sham control arm
2. Bias introduced to endpoint
assessments in open label trials
i. potential influence of immediate
post-procedural factors (e.g., pain,
wound healing, anesthesia, temporary
increased compliance to background
medical therapy, Hawthorne effect) to
be considered  Establish post-
procedural baseline after the patient
has stabilized from the procedure.
ii.Consider randomizing to sham in only
part of control group, to quantify the
placebo effect provide information
about influence of sham procedures in
trials and contribute to totality of
information about need for blinding.
Use objective endpoints over subjective
e.g. total hospitalization preferred over
cause specific hospitalization.
Post-procedural baseline not true
baseline procedure has already
occurred
Randomizing only part of control group
to a sham procedure require a larger
sample size.
Use of all-cause mortality may require a
larger sample size
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21. Problem Suggested approach and potential advantages Potential disadvantages
3. Bias introduced to patient reported
outcome or HRQOL endpoints in open-
label trials
4. Investigator bias in open-label trials
i. Instruments should be administered
by blinded study personnel/ completed
by patient independently of study
personnel in trials in which the patient is
blinded but investigator is not
ii. HRQOL /PROs not be used as pivotal
endpoints in open-label trials, except
when no effective therapies exist
i. Routine addition or titration of
therapies  prespecified in the
protocol& not at the discretion of
investigator to prevent differential use
of therapies in investigational and
control arms
ii. Study personnel responsible for
ascertaining and reporting AE should be
blinded to fullest extent
iii. Physicians/operators not blinded to
treatment assignment should not
participate in study-related assessments
or evaluations after the index procedure
Validated instruments that are accepted
by regulatory agencies are lacking
Monitoring investigator adherence to
these protocol specifications is difficult.
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22. What is CAPA?
Purpose of
CAPA
subsystem
is to:
collect & analyze information
identify and investigate product and
quality problems
measures to prevent their recurrence
Verify/validate CAPA communicating
to responsible people
providing relevant information for
management review, and documenting
these activities
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23. Conclusion
For many medical devices, adherence to standard practices of blinding and control groups is not
possible
Both randomized trials and non-randomized observational studies play key roles
keen awareness of the potential for bias when blinding or randomization is not possible, and
implementing measures to reduce bias such as use of hard endpoints and blinding CEC members
and other study personnel
No single solution or research design will be appropriate for every device or target patient
population
combination of different trial designs that complement each other might be a viable option
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