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Risk Assessments in 510K
Clinical Studies
John McLane, Ph.D.
COO & Vice President Clinical and Regulatory Affairs
Clinquest, Inc.
[email protected]
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Clinical Trial Preparation
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Do your homework:
• Start with the regs
• Literature
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Budget appropriately for R&D
Form a solid team of experts –
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Scientific Advisory Board
Clinical Expertise
Careful Planning and Conduct are Key to
Obtaining Useful Data and Assuring Human
Subject Protections
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Medical Device Risk Regulations
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Medical Devices Directive (MDD), 93/42/EC – covers
all general medical devices except:
Active Implantable Medical Devices (AIMD),
90/385/EC –in humans
In Vitro Diagnostic Devices (IVDD), 98/79/EC
ISO regulations
• ISO 14155 (clinical)
• ISO 14971
21 CFR Parts 812, ICH GCP,
Japan GCPs, GHTF guidelines
EU MEDDEVs (2.7.1)
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ISO 14971 Risk Management
Risk Management standard
 Must have that particular defined and
documented RM Process that
addresses
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• risk analysis
• evaluation and control,
• collection of production
• post-production data to validate or change
previous risk determinations
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ISO 14155:2011 Newly Released
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Harmonize the ISO standard with the ICH-GCPs and MedDev
guidances on clinical trials
Clarify the responsibilities of investigator, sponsor, monitor, and
IRB/EC more thoroughly and consistently
Clarify risk and risk assessment with regard to the subject rather
then device design
Update the literature review section to match MedDev and any
developing GHTF documents: Investigator’s Brochure
Clarify the responsibilities of sponsors, monitors, investigators,
institutions, IRBs/ECs, DSMB, auditors, and other parties
Clarify details of the Investigator ‘s Brochures, final report,
adverse event handling, case report forms, and data mgmnt
Distinguish between adverse events, devise deficiencies, and
deviations
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ISO 14155: 2011 key items
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Definition of Clinical Data not included
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Risk of Use Error (ref: ISO 14971) includes training
Use of selected literature allowed if meets similarity
requirements
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Intended use
Population
Conditions of use
Note: similarity differs from MDD “demonstration of equivalency”
(Article 1)
Requires assessment of significance and weight of studies
including published and unpublished studies
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Development of clinical data is in Annex A
Note: FDA PMA require unpublished and published data
All AE (not just SAE) to be reported to all countries where trial
conducted
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ISO 14155 Med Device Clinical
Step-by-step methodology, recordkeeping, and reporting requirements
 Ethical and legal approval requirements
 Steps to construct a protocol
 Risk assessment
 Case report (data collection) forms
 Instructions for preparing a final report
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Global Harmonization Task Force
(GHTF)
Study Group 5
 Harmonize clinical definitions
 Review applicable GHTF & ISO/ICH
documents, to assure terminology is
consistent and interfaces are clear
 Develop guidance on how to conduct
and document the clinical evaluation
 Harmonise the content and format for
clinical investigation reports.
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GHTF Essential Principles
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Essential Principles of Safety and
Performance of Medical Devices (Summary
Technical Document (STED)
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Classification and complexity of the device;
If it incorporates novel technology
If it is an already marketed device type that w/ intended
use different from original use
If it is new to the manufacturer
Device type associated w/ significant number of adverse
events/ user errors, novel or potentially hazardous
materials, or raises specific public health concerns
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STED Premarket Use
General description and list specific
features
 Set of labels and language variants
 Summary tech docs and design
 Essential principles checklist
 Risk analysis and control summary
 Summary of V&V
 Clinical Evaluation Report
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Principles of GHTF SG5
MORE
REQUIRED
NO
Are Essential
Principles
met?
YES
Clinical investigation
Literature searching
-----Processes
CLINICAL
EVALUATION
Clinical use
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Outputs
CLINICAL INFO
- Literature
-Clinical experience
-Clinical Investigations
-Other?
DECLARATION
OF
CONFORMITY
REPORT
CLINICAL EVIDENCE
ISO14155
STED
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NON CLINICAL
EVIDENCE
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Clinical Design
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Clear statement of objectives
Appropriate subject population(s)
Minimization of bias
• randomization, blinding
Confounding factors
• concurrent medications, co-morbidities
Appropriate controls
• cohort, sham, historical
Design configuration
• parallel, crossover, factorial
Type of comparison
• superiority, non-inferiority, equivalence
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Conclusion
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Consider the Clinical Trial as a
comprehensive process
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Get Experts (Reliance Medical Association)
Know your target product profile
Be prepared
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Have the evidence
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Preclinical
QSR
Work with the FDA and IRBs
Be realistic on potential risks
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GHTF Documents to Consider
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SG1/N011:2008 Summary Technical Documentation for
Demonstrating Conformity to the Essential Principles of Safety
and Performance of Medical Devices (STED)
SG1/N029:2005 Information Document Concerning the
Definition of the Term “Medical Device”
SG1/N041:2005 Essential Principles of Safety and Performance
of Medical Devices
SG1/N040:2006 Principles of Conformity Assessment for
Medical Devices
SG1/N43:2005 Labelling for Medical Devices
SG5/N1R8:2007 Clinical Evidence – Key definitions and
Concepts
SG5/N2R8:2007 Clinical Evaluation
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Backup slides
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Classification Basis
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Classification depends on intended use and
indications for use, and level of risk
Intended use- What disease, symptom, or condition
is the device intended to treat? How will the device
be used?
Indications for use- What kinds of patients should this
be used on? Can be based on age, disease state,
medical history, allergies, etc.
Level of risk-Is the device life-saving? Is the device
life-sustaining? Is there an unreasonable risk of
illness or injury associated with use of the device?
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Device Classification
Class I
 Safety & effectiveness are well-established
 Subject only to “General Controls” (registration, device
listing, GMPs)
Class II
 Need “Special Controls” (guidances, postmarket
surveillance, labeling, preclinical testing)
Class III
 General and special controls are insufficient to assure
safety and effectiveness
 Devices that are life-sustaining, life-supporting, or
present unreasonable risk of illness or injury
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Protocol Deviations
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CFR 812.150(a)(4) require prior approval from the
sponsor of all planned deviations, including
administrative and minor deviations.
Planned deviations requested of a sponsor must be
submitted for IRB review as a “Change in Research”
prior to instituting any IDE research planned
deviations
For device research, the PI must keep on file a copy
of the written approval document from the sponsor
and IRB when a deviation is granted.
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Medical Device Clinical Paths
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Core Principles
When is Clinical Data Needed To
Assure That Essential Principles are
Met?
 Clinical Evaluation Process
 Justification for Clinical Investigation
 What Type / Design of Clinical
Investigation is Appropriate?
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Studies Exempt from IDE Regulation
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Legally marketed device when used in accordance
with its labeling
Diagnostic device if it complies with the labeling
requirements in §809.10(c) and if the testing:
• Noninvasive
• Does not require an invasive sampling procedure
• Does not introduce energy into a subject
• Has “back-up” approved confirmatory diagnostic tests
Consumer preference testing, testing of a
modification, or testing of a combination of devices if
the device(s) are legally marketed device(s)
Device intended solely for veterinary use or
laboratory animal use
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Non-significant Risk Device IDE
Applications
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Abbreviated IDE application submitted to IRB:
• Device Labeling :
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CAUTION - Investigational Device. Limited by Federal (or
United States) law to investigational use
• Informed Consent –Investigators must obtain and document
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informed consent from each subject
Monitoring - All investigations must be properly monitored to
protect the human subjects and assure compliance
Records and Reports - Sponsors and Investigators are
required to maintain specific records and make certain
reports as required by the IDE regulation
Prohibitions –Commercialization, promotion, test marketing,
misrepresentation of an investigational device, and
prolongation of the study are prohibited (§812.7)
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Test for Safety
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Biocompatibilty
• ISO 10993
• Rabbit epidural study
Implant – Tissue interface
Mechanical Performance
• ASTM testing
Biomechanical Performance
• Cadaveric, animal??
• Expulsion, subsidence, catastrophic failure
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Example: Implant Assessments
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Static / Fatigue – endurance – 10M
Wear debris – amount & characterization
Long term creep
Quantity of Motion
Quality of Motion
How much work does the implant have to do – will
affect lifespan of implant
Interface with tissue
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FDA Meeting Preparation
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Prepare a target product profile
• Key efficacy and safety objectives
• Potential pt and user group description
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Plan on submission questions
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Keep questions focused
Don’t ask question of what you can easily find in
the regulations
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Plan on providing support documentation
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Can ask question to clarify approach to a regulation
Evidence-based information most persuasive
Be prepared
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Reports of Prior Investigations
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Provide all data that is relevant (whether
adverse of supportive)
• Including laboratory/animal data
Provide data on previous versions (models)
of the device.
 Explain what conclusions where reached
from the clinical experience with previous
device designs.
 For each clinical investigation:
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Rationale for subject selection
Statistical justification for N
Description of the study methods and endpoints
Efficacy and safety results (summary table AEs)
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Device Description
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Description of each important component,
property and principle of operation of the
investigational device
Identify Human Factor tests
If applicable, state any anticipated change(s)
in the investigational device during the course
of the study
Identify potential device-related risks
• Differentiate from clinical risks
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Investigational use instructions
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Investigational Plan
Purpose
 Protocol
 Risk analysis
 Description of device
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• Label to be on device
Monitoring Procedures
 CRF
 Patient information materials
 Informed consent template
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Feasibility Clinical Study
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Simple trial design to provide
• Support for a future pivotal study
• Answer basic research questions
Often not primary support for a
marketing application
 May be required by FDA prior to pivotal
study to assess basic safety and
potential for effectiveness
 Endpoints and sample size generally
not statistically driven
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• N=10-50 subjects
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FDA 1976 Medical Device Regulations
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Prompted by Dalkon Shield IUD contraceptive
device – caused injury, miscarriage, infertility
Established three classes of medical devices
Required safety and efficacy of all medical
devices including diagnostic products
Required manufacturers to register with FDA
and follow quality control procedures
Required pre-market approval for devices
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Pivotal study
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Generally intended as the primary clinical
support for a marketing application
Endpoints and sample size statistically driven
Assess both safety and effectiveness
• Reasonable study conceptually?
• Adequate preclinical validation of device?
• Appropriate mitigation of potential risks?
• Appropriate enrollment criteria?
• Patients adequately informed?
• Sample size appropriate?
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Key Components of Clinical
Protocol
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General study design
Proposed subject population
Anticipated number of subjects
Inclusion criteria
Exclusion criteria
Screening procedures
Study treatment (allocation, breaking the
blind)
Follow-up assessment methods including the
schedule of testing
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Biometrics Sections of Protocols
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Identify primary effectiveness endpoint
• Avoid composite or ambiguously defined terms
• Describe how measured
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How will safety be assessed and monitored
(safety endpoint)
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Not just well tolerated
Objective performance criteria
Sample size determination
Data and Safety Monitoring Committee
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Objective Performance Criteria
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Type of comparison in medical device trials
• Requires statistical pooling of prior investigations
• Underlying disease and pt population well described and
stable
Fixed Target(s) Positive Tx effect expected
Objective and Meaningful Standard
Provides Comparison in Evaluating Safety and Effectiveness
Usually a Rate
Surrogate for Control Group
Benchmark for Minimally Acceptable
Values
Not a Control Group
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Statistical Analysis Plan
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Justification for sample size calculations
Type-1 error and multiplicity
Missing data handling
Assessment of critical endpoint covariates
Interim analyses and early stopping rules
Data handling
Contingency analysis
Provide enough detail to avoid ambiguity
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Anticipated and Unanticipated Safety
Events
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Use prior studies to clearly identify potential
and anticipated risks
• Similar devices
• Engineering, animal, and human factor testing
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Define how study design mitigates risk
• Clinical training necessary?
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Define how different safety events to be
reported
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Patients
Patient’s Investigator and all investigators
IRB
FDA
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Unanticipated Adverse Device
Events (UADE)
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UADEs must be reported by investigators to
sponsors and reviewing IRBs as follows:
As soon as possible, but in no event later than 10
working days after the investigator first learns of the
event
Sponsors must immediately conduct an evaluation of
a UADE and must report the results of the evaluation
to FDA, all reviewing IRBs, and participating
investigators within 10 working days after the sponsor
first receives notice of the effect
Guidance for Clinical Investigators, Sponsors, and
IRBs. Adverse Event Reporting to IRBs—Improving
Human Subject Protection Jan 2009
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Shared regulations with drugs
Part 50 – Protection of Human Subjects
 Part 56 – Institutional Review Boards
 Part 54 – Financial Disclosure by
Clinical Investigators
 Part 58 – Good Laboratory Practices for
Nonclinical Laboratory Studies
 Part 11 – Electronic Records; Electronic
Signatures
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Adequate Monitoring
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Trained monitors
Qualified investigator sites
Following the written procedures in the protocol
• Collection of essential documents
Obtaining a signed investigator agreement from each
participating investigator (can use FDA form 1572)
Provide investigators with the information they need
to conduct the investigation properly
• Documented training of all study personnel
• Delegation log
Ensuring subjects sign informed consent form
Device quality check and accountability
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Questions for audience
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Does “risk analysis”mean risks of the device or the risks of study participation?
•Is it always necessary to keep records of all the potential subjects screened?
•Must all data be copied into or collected in Case Report Forms vs. hospital
records?
•Must marketed products that are studied for new uses have
“Investigational”labeling?
How to integrate quality assurance for the study into the overall quality system of
the Sponsor? Investigator or CRO?
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