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Investigational Device Exemptions (IDEs) for Early Feasibility Medical
Device Clinical Studies Marybeth Gamber
Senior Regulatory Consultant Boston Biomedical Associates
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Agenda: Early Feasibility Program
• Background • What is the EFS program? • Structure & Intent • Application process • Investigational plan • After the EFS • Advantages & disadvantages of the program
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Background
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Background: Device Development • If your product requires a clinical study, prior to submitting an IDE,
preclinical testing must be performed to demonstrate the safety of the device
• Bench testing • Tensile, torque, simulated use, dimensional verification etc
• Animal testing • Use of the product in its indication to demonstrate safety prior to human use
• Typical IDE requires exhaustive testing to be completed prior to FDA review of the IDE
• Time and resource (manpower & $$) constraints for devices in early development
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Background: Regulatory
• Federal Food, Drug & Cosmetic Act recognizes that information required for an IDE may vary
• Section 520(g)(2)(C) provides “caveats,” including scope & duration of clinical study, number of subjects, and whether or not the clinical data will support a marketing application
• Provides FDA with some flexibility regarding amount of data required HOWEVER • Sponsors are still required to meet all the requirements of 21
CFR 812 (Investigational Device Exemptions) • Application, Investigational Plan, Report of Prior Investigations, etc.
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Why was the EFS Guidance written? • Perception (and reality) that early feasibility work is being
performed outside the U.S. due to the preclinical and regulatory burdens in the U.S.
• U.S. population was not gaining access to new and innovative therapies in clinical studies
• Significant lag time for new therapies to get to market in the U.S.
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What is the Early Feasibility Study Program?
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What is an Early Feasibility Study? • A limited clinical investigation of a device early in development, typically before
the device design has been finalized, for a specific indication (e.g., innovative device for a new or established intended use, marketed device for a novel clinical application). It may be used to evaluate the device design concept with respect to initial clinical safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) when this information cannot practically be provided through additional nonclinical assessments or appropriate nonclinical tests are unavailable. Information obtained from an early feasibility study may guide device modifications. An early feasibility study does not necessarily involve the first clinical use of a device.
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What is an Early Feasibility Study?
• Performed to obtain initial insights into: • Clinical safety of the device-specific aspects of the procedure • Whether the device can be operated successfully • Determine user technique/human factors challenges • Whether the device performs its intended purpose • Determine patient characteristics that may impact device performance • Therapeutic parameters
when additional non-clinical testing methods are not available or adequate to provide the information needed to advance the device development.
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Is an EFS Right for You? Early Feasibility Feasibility Pivotal
Device Design Not yet final Near final Final
Preclinical data provides all needed info RE: device design
No Yes Yes
Purpose of Study Guide device modifications
Preliminary S&E to help design Pivotal Demonstrate S&E
Understanding of Device Risks >Unknown Risks Risks Understood Risks Understood
Number of subjects ~10 15-45 100’s, depending on
indication, device type, etc.
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How is the EFS Structured?
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Early Feasibility Framework
• Application of risk/benefit principles throughout the FDA decision making process
• Allows for FDA to consider totality of risk/benefit profile for the device, inclusive of disease conditions and limitations & risks associated with currently-available therapies.
• Considerations set out in FDA’s Risk/Benefit guidance • Factors to Consider When Making Benefit- Risk Determinations in
Medical Device Premarket Approval and De Novo Classifications” • Use of risk mitigation strategies that appropriately protect study
subjects.
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Key Principle of the Guidance
• Less preclinical data may be used to support approval of an early feasibility study
• Recognition by FDA that exhaustive testing may not be necessary or possible, particularly if the device is likely to undergo further development
• Address basic device safety and characterize catastrophic failure modes/mitigations • Use of the device in a limited population to aid with further preclinical and
clinical testing strategies to support the final device design • Enhanced risk mitigation strategies and patient protection measures
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Intent behind EFS • Cannot determine how a device will perform without use in
patients • Early clinical experience increases efficiency in the device
design process • Amount of preclinical information available will limit the number
of subjects you can enroll • Increased patient exposure may be allowed with additional preclinical
data • Continuously provide more preclinical data into the process to
allow for study expansion • Increase enrollment with design iterations • Amass a body of evidence that supports your device safety
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The EFS Process
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Consider a Pre-Submission Meeting
• Provide your rationale for why your device is appropriate for EFS • Teach FDA about your device: Novel technology and/or
indication • Clinical context of the disease state • Device development milestone timeline
• Provide your draft Device Evaluation Strategy for feedback and initial agreement on testing requirements
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IDE: Report of Prior Investigations
• Standard IDE RPI based upon a comprehensive preclinical/clinical test plan
• Preclinical: Bench & Animal • Clinical: Previous human use • Bibliography & published articles relevant to the S&E of the device
• EFS IDE RPI structured differently to better capture EFS risk/benefit requirements
• Background, Executive Summary, Detailed Reports
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EFS: Report of Prior Investigations: Background Section • Clinical context for the EFS
• Clinical condition • Standard of care, including types & severity of risks • Justification of possible benefits with your device to justify the potential risks
• Design Concept: forms the basis for identifying testing • Device description, including principles of operation, key design features • Intended clinical use and conditions of use • Minimum design life of the device
• Summary justification regarding amount and type of information needed to support the EFS as compared to expectations of larger clinical study needs
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EFS: Report of Prior Investigations: Executive Summary Section • Summary of nonclinical testing performed and relevant clinical
information • Table summarizing testing planned and/or completed • Device Evaluation Strategy Table
• Justification of initiation of the study based upon available data and risk assessment
• Detailed information on device attributes, potential failure modes, and mitigation strategies (bench/animal testing, clinical study mitigations, etc).
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An Approach to the DES Table
• The Device Evaluation Strategy is not just your DFMEA • DES should focus on the possible harms and the data you have to
support the mitigations of those harms to support first human use • Not all harms will have the same data needs for mitigation
• Understand your device and how it functions • Focus on key safety and performance features • Risk mitigation strategies for key potential failure modes with clinical
impact will require greater mitigation strategies • And then educate FDA
• You know your device the best—be thorough and prepared
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EFS: Report of Prior Investigations: Detailed Reports Section • Test reports from bench, animal, and clinical (if available) testing • Summary of leveraged nonclinical data
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EFS Investigational Plan More Risk Management
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EFS Investigational Plan • Risk analysis and Mitigation
• Thorough risk analysis describing type & estimated severity of risks, risk minimization, and justification that the risks are reasonable in relation to the potential benefits
• Risk Mitigation Measures • Data Monitoring Committee • Identification of qualified investigators with adequate training in the specific area
to be studied • Collecting human factors information to modify the device based upon use • Increased number of follow-up assessments to closely monitor safety • Pre-specified plan for periodic patient outcome assessments and reporting prior
to enrollment of additional subjects (as frequently as after each use of the device)
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EFS Investigational Plan
• Comprehensive description of the subjects to be enrolled • Avoid enrolling subjects for whom success is unlikely due to general
health issues/comorbidities • Include subject risk tolerance (severity of condition, limitations of
current treatments) • Prospective definition of study success and pre-specified data
analysis plan are not necessary • Specific requirements for EFS informed consent
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Iterative Device Development Process • Information gained from the initial use of the device is fed back into
the study • Device modifications • Clinical protocol modifications
• EFS program provides flexibility during the IDE review process • More 5-day notifications which don’t require prior FDA approval
• Device modifications that don’t significantly change design or basic principles of operation • Clinical trial changes not typically allowed under a pivotal study as a 5-day
• Contingent approval • Approval of anticipated device changes obtained contingent on completion of agreed-upon
test plan
• Interactive review
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After the EFS
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What happens after EFS?
• Expansion of the Early Feasibility Study • Allow for investigation of further device iterations
• Move on to a traditional feasibility or a pivotal study • Device design is frozen • Early feasibility results support the safety and proof of principle • Full preclinical test suite will be expected to support either of these
applications
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Advantages to the EFS
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Potential Advantages of the EFS
• Provides FDA an opportunity to understand your device early • This may ease the transition to future studies beyond EFS
• Engage US physicians with direct participation • More engaged than talking to their EU / OUS colleagues who are
studying device today, and US physicians needs to wait 2 years until they have access to the device via an IDE
• Increase your podium presence in US
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Potential Advantages of the EFS
• The EFS studies the US population, which will be most applicable in terms of practice patterns, metabolic responses as would be seen in future trial, etc.
• Less extrapolation of data from OUS data
• For US based companies, possible resource and financial advantages • Avoid long plane rides to OUS countries • Significant time zone differences • Reduced or no translation costs • Shipping logistics of investigational devices easier, if devices manufactured/finished
goods housed in US
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Potential Disadvantages of the EFS
• EFS program is new at FDA. FDA has expressed their commitment to making this a success, but no long track record.
• Reviewers have been trained, but not all are calibrated • Some OUS countries may still offer advantages for data needs
and review times
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Conclusions
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Take-aways
• FDA wants innovation to stay in the U.S. and is working with manufacturers to make this happen
• EFS provides a mechanism to get early-stage devices in the hands of US physicians without the burden of all the testing that may be required for a traditional IDE
• Understand your device and the disease state to be able to demonstrate your risk mitigation strategies will be effective
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Guidance Documents
• Early Feasibility Guidance document: • http://www.fda.gov/downloads/medicaldevices/
deviceregulationandguidance/guidancedocuments/ucm279103.pdf • Benefit/Risk Determinations Guidance document:
• http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM296379.pdf
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© 2015 Boston Biomedical Associates Rev A Page 36
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