investigational plan workshop on fda product life cycle of an
TRANSCRIPT
Investigational Plan
Workshop on FDA Product Life Cycle of an Investigational Device Exemption
NHLBI
June 24, 2010
Tara A. Ryan, MD, MS, MBAInterventional Cardiology Devices Branch
ODE/DCD
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Types of IDEs
Feasibility study– May provide support for a future pivotal study or
may be used to answer basic research questions– Not intended to be the primary support for a
marketing application– Endpoints and sample size generally not
statistically driven– Often required by FDA prior to pivotal study to
assess basic safety and potential for effectiveness– Generally ~10-40 patients but may be larger– FDA review is primarily focused on safety
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Types of IDEs
Pivotal study– Generally intended as the primary clinical
support for a marketing application– Endpoints and sample size statistically
driven– Designed to assess both safety and
effectiveness– FDA review is much more complex
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FDA’s Feasibility IDE Review
Focused on safety Critical issues
– 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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FDA’s Pivotal IDE Review
Focused on safety and plan for collecting and evaluating study data
Additional critical issues– Trial endpoints– Randomization, blinding, etc– Study conduct and monitoring– Statistical analysis plan
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Investigational Plan(21 CFR 812.25)
• Name and intended use of the device • Objectives and duration of the investigation • Protocol • Risk analysis • Device description • Monitoring procedures • Labeling• Consent materials • IRB information• Other institutions • Additional records and reports
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Objectives of the clinical investigation
For example, if the study is a feasibility study, tell us what is being looked at:
Initial evaluation of the device in humans or a certain population
Evaluation of potential safety issues Evaluation of device design Assessing certain human factors (patient or
operator)
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Study Design
General study design Proposed subject population Anticipated number of subjects Inclusion criteria Exclusion criteria
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Study Procedures
Screening procedures Study treatment (allocation, breaking
the blind) Follow-up assessment methods
including the schedule of testing
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Study Outcome Measurements
What is the primary effectiveness endpoint? What is the primary safety endpoint? Are there secondary endpoints? If so, clearly
state these and describe methods for analysis.
Sample size determination Adverse events Data and Safety Monitoring Committee
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Risk Analysis
What are the potential risks to the patient?
Does the study mitigate the risks where possible?
Adverse Events: How will they be recorded and reported to FDA and the IRB?
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Device Description
Description of each important component, property and principle of operation of the investigational device.
If applicable, state any anticipated change(s) in the investigational device during the course of the study.
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Monitoring Procedures
Two major issues:
– Who can be a monitor?
– What constitutes adequate monitoring?
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Who Can Be A Monitor?
Applicable FDA Regulation:
A sponsor shall select monitors qualified by training and experience to monitor the investigational study in accordance with this part and other applicable FDA regulations.
» 21 CFR 812.43(d)
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What Constitutes Adequate Monitoring?
No universal tool or master template policy– Following the written procedures for monitoring included in the
investigational plan {21 CFR 812.25(e)}– Obtaining a signed investigator agreement from each participating
investigator {21 CFR 812.43(c)}
– Providing investigators with the information they need to conduct the investigation properly (21 CFR 812.40)
– Ensuring subjects signed an IRB-approved informed consent form prior to instituting study activities
– Device accountability:• Maintaining accurate, complete, and current records of
disposition that describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal {21 CFR 812.140(b)(2)}
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Other Items Needed in the Investigational Plan
Labeling Patient Consent Materials Case Report Forms IRB Information Information on other participating
institutions
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Submission Elements, Pivotal IDEs
Primary and secondary endpoints– Discussion of appropriateness of endpoint
parameters, hypotheses, and success criteria
Basic trial design– Controlled? If not, why not?– Randomized? If not, why not?– Blinded? If not, why not?
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Pivotal IDEs – Frequent FDA questions
Trial conduct and study monitoring– Data handling and adjudication process– Sponsor blinding
– Independent committees– Case report forms
• Is the right information being gathered to support the study endpoints and are investigators adequately prompted to report adverse events?
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Pivotal IDEs – Frequent FDA Questions (Cont.)
Statistical analysis plan– Type-1 error and multiplicity– Missing data handling
– Sample size calculations and assumptions– Assessment of critical covariates– Adaptive design plans
– Interim analyses and early stopping rules– Data handling
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Pivotal IDEs
Statistical analysis planProvide enough detail to avoid ambiguity once the trial has started.
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Emergency use of an approved device
Three circumstances for emergency use of an unapproved device– No IDE for the device
– Use of a device under an IDE where the physician wants to use it in a way not described in the IDE
– When the physician, who wants to use it, is not an investigator
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Criteria for emergency use
Each of the following conditions must exist– Life-threatening condition or serious disease or
condition– No generally acceptable alternative treatment is
available– No time to obtain FDA approval
• FDA expects the physician to determine whether these conditions have been met and must assess potential for benefit and have substantial reason to believe benefit will occur.
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After the emergency use
Physician must notify the IRB within 5 days If future use likely, immediately initiate effort
to obtain IDE and IRB approval If device was under an IDE, physician notifies
the sponsor, who must report to FDA within 5 days
If no IDE exists, physician notifies FDA– About the emergency use– Patient protection measures– Scientific results
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Device Advice:
http://www.fda.gov/cdrh/devadvice/
IDE Information:http://www.fda.gov/cdrh/devadvice/ide/index.shtml
Right of Reference and Master Files:http://www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2
Resource – FDA Website
