Preparing for an IDE Application

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Preparing for an IDE Application
John McLane, Ph.D. COO Vice President Clinical
and Regulatory Affairs Clinquest, Inc.
jmclane_at_clinquest.com
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Importance of Medical Devices

• 11,000,000 Americans have at least one medical
  device implant
• In the U.S. annually
• gt290,000 hip replacement surgeries
• gt300,000 knee reconstructive implants
• gt151,000 pacemaker implants
• gt2,000,000 lens implant surgeries

Hippocrates
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IDE Preparation

• Do your homework
• CYA avoid possible liabilities
• Budget appropriately for RD
• 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
• Dont 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
• N10-50 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
• Patients 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