fulfilling the promise of medicine together preparing for an ide application john mclane, ph.d. coo...
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Fulfilling the Promise of Medicine Together
Preparing for an IDE Application
John McLane, Ph.D.COO & Vice President Clinical and Regulatory AffairsClinquest, Inc. [email protected]
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Importance of Medical Devices
11,000,000 Americans have at least one medical device implant
In the U.S. annually:
• >290,000 hip replacement surgeries
• >300,000 knee reconstructive implants
• >151,000 pacemaker implants
• >2,000,000 lens implant surgeries
Hippocrates
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IDE Preparation
Do your homework CYA – avoid possible liabilities Budget appropriately for R&D
• Lawsuits cost more Form a solid team of experts –
• Scientific advisory Board
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Differences between Drugs and Devices
Pharmaceuticals Molecular entities Limited shelf life Long life cycle Long development
time Potential for
interactions with other drugs
Wrong drug/dose issues
Devices Complex
components Many = durable
equipment Short product cycles
– “tweaking” of design
Device malfunctions User errors
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FDA 1976 Medical Device Regulations
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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Classification Basis
• 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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General Routes for FDA Approval
For a new device: Pre-market Approval or PMA:
• Manufacturer must show safety and effectiveness of new device
Laboratory and Animal Research Clinical Research
For a “Me Too” device:510(k) Notification:
• Manufacturer must show substantial equivalence to marketed device
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Valid scientific evidence
Well-controlled investigations• Human factor testing
• Animal testing
• Component testing
Partially controlled studies or studies without matched controls
Well-documented case histories by qualified experts
Reports of significant human experience with a marketed device
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Why an IDE?
Studies on “significant risk” devices require an Investigational Device Exemption (IDE) (21 CFR 812)
Sponsors must usually complete bench, animal testing before proceeding to human IDE trials
An IDE helps assure good study design Data from IDE studies are used to
support PMAs and sometimes 510(k)s
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Medical Device Clinical Paths
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Studies Exempt from IDE Regulation
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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Type of IDE Devices: Risk Based
Significant Risk (SR) Devices (21 CFR 812.3M)
• Requires FDA approval
• Presents potential for serious risk
• Use for support or sustain life
• Substantial importance diagnosing, or treating Non-significant Risk Devices (812 and 812.2(b)
• Abbreviated IDE
• Sponsor to provide rationale for NSR
• IRB can act as FDA surrogate
• IRB usually asks FDA for ruling on SR/NSR
FDA Guidance
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Test for Safety
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
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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Pre IDE FDA Meetings
Informal Guidance Meeting
• Meeting with ODE to discuss IDE development plans Significant and non-significant categories ODE team
Formal Guidance Meetings
• Determination Meeting Broad outline of clinical design
• Agreement Meeting Request and summary information
On-going preclinical programs Protocol design Risk assessments
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FDA Meeting Preparation
Prepare a target product profile• Key efficacy and safety objectives
• Potential pt and user group description
Plan on submission questions• Keep questions focused
• Don’t ask question of what you can easily find in the regulations
Can ask question to clarify approach to a regulation
Plan on providing support documentation• Evidence-based information most persuasive
• Be prepared
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Non-significant Risk Device IDE Applications Abbreviated IDE application submitted to IRB:
• Device Labeling : CAUTION - Investigational Device. Limited by Federal (or
United States) law to investigational use
• Informed Consent –Investigators must obtain and document 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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Complete IDE Application Name and address of sponsor Complete report of prior investigations of device Summary and completed investigational plan Description of methods, facilities, and controls used
for manufacture, processing, packaging, storage , installation of device (Quality System Regulations)
Example of investigator agreements Names and addresses of investigators List of names, address, and chairperson IRB Institution(s) participating Investigational labeling for device Reimbursement charges for device Patient informational materials and forms provided
to patients to obtain consent Clinical protocol
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Reports of Prior Investigations 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: 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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Good Manufacturing Processes and Systems Material controls Design controls Production and process Equipment and facility controls Records, documents, and change
controls Risk assessments
• Hazard Identification Risk management programs
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Quality System Regulations
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Investigational Plan
Purpose Protocol Risk analysis Description of device
• Label to be on device Monitoring Procedures CRF Patient information materials Informed consent template
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Device Description
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
Investigational use instructions
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Feasibility IDE clinical Study
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• N=10-50 subjects
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Pivotal study
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 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
Identify primary effectiveness endpoint• Avoid composite or ambiguously defined terms
• Describe how measured
How will safety be assessed and monitored (safety endpoint)• Not just well tolerated
• Objective performance criteria
Sample size determination Data and Safety Monitoring Committee
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Objective Performance Criteria 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
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 Use prior studies to clearly identify potential
and anticipated risks• Similar devices
• Engineering, animal, and human factor testing
Define how study design mitigates risk• Clinical training necessary?
Define how different safety events to be reported• Patients
• Patient’s Investigator and all investigators
• IRB
• FDA
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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
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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IDE Supplements
Required if changes significantly affect:• Validity of data
• Scientific soundness of study
• Rights, safety, or welfare of subjects
Examples:
• Different type of study control
• Alternative primary endpoint
• Reduction in study population size
• Change in method of evaluation
• Early termination of the study
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5-Day FDA Notice to Protocols
• Additional measurements• More targeted subject criteria• More frequent follow-ups• Change in secondary endpoints
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Protocol Deviations
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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Conclusion
Consider the IDE as a comprehensive process• Get Experts (Reliance Medical Association)
Know your target product profile Be prepared
• Have the evidence Preclinical QSR
Work with the FDA and IRBs Be realistic on potential risks