Investigational Plan Workshop on FDA Product Life Cycle of an ...

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  • Describe the type/design (e.g., open-label, observational) of the proposed clinical study. Provide a general description of the characteristics of the proposed subject population(s). Provide a justification for the suitability of this (these) population(s) for the purpose of the investigation. Specify the estimated total number of subjects to be enrolled into the clinical study and the anticipated number of subjects expected to complete the study. Indicate that “enrollment” into the investigation is defined as providing informed consent for study participation (i.e., as per University IRB policies). List the specific criteria for including subjects for participation in the clinical study. Note that these criteria should be inclusive of diagnostic criteria and, where appropriate, confirmatory laboratory tests applicable to the specific disease or condition to be treated or diagnosed by the investigational device.
  • Describe or list the procedures that will be performed to verify subject eligibility for participation in the clinical study. Describe the plan and procedures for allocating subjects to the various treatment or diagnostic arms of the study so as to ensure comparability between test groups and any control groups with regard to pertinent variables such as gender, severity or duration of disease, and use of therapy other than the investigational device Breaking the blind : (Incorporate only if the proposed clinical study is blinded). Describe the procedures for breaking the blind should a given subject suffer a serious adverse event wherein knowledge of the identity of the study treatment or diagnostic product received by the subject is necessary for effective emergency treatment of the event. Specify, if applicable, the parameters (i.e., observations and/or measurements) that will be used to evaluate the efficacy of the study treatment or diagnostic product(s); to include the methods and timing for assessing, recording, and analyzing these parameters. If the proposed clinical study does not involve evaluation(s) of the efficacy of the investigational device, state this. Procedures to assess safety : Specify the parameters (i.e., procedures, laboratory tests, or other measures) that will be used to evaluate the safety of the study treatment or diagnostic product(s); to include the methods and timing for assessing, recording, and analyzing these parameters.
  • Summarize the primary and, if applicable, secondary endpoints or outcomes that will be evaluated in the clinical study. Sample size determination. Specify the number of subjects planned to be enrolled into the clinical study (i.e., to complete the clinical study) and the reason(s) for the choice of this sample size. Include, if applicable, calculations of the power of the study or provide an alternate explanation for the proposed sample size. For example, if the purpose of the proposed clinical study is to obtain pilot data upon which to base a subsequent pivotal study of the investigation device, state this and provide a clinical justification for the sample size selected. Describe the composition and operations of the Data and Safety Monitoring Committee that will provide oversight of the clinical study.
  • Describe all increased risks to which the subjects (patients-subjects and normal controls, if applicable) will be exposed as a result of their participation in the clinical study. Address the steps that will be taken to minimize these risks. Provide an analysis of the benefit-to-risk ratio of study participation (i.e., for each of the study populations, if applicable) and a corresponding justification for conducting the clinical study.


  • 1. Investigational Plan Workshop on FDA Product Life Cycle of an Investigational Device Exemption NHLBI June 24, 2010 Tara A. Ryan, MD, MS, MBA Interventional Cardiology Devices Branch ODE/DCD
  • 2. 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
  • 3. 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
  • 4. 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?
  • 5. 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
  • 6. 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
  • 7. 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)
  • 8. Study Design
    • General study design
    • Proposed subject population
    • Anticipated number of subjects
    • Inclusion criteria
    • Exclusion criteria
  • 9. Study Procedures
    • Screening procedures
    • Study treatment (allocation, breaking the blind)
    • Follow-up assessment methods including the schedule of testing
  • 10. 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
  • 11. 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?
  • 12. 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.
  • 13. Monitoring Procedures
    • Two major issues:
      • Who can be a monitor?
      • What constitutes adequate monitoring?
  • 14. 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)
  • 15. 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)}
  • 16. Other Items Needed in the Investigational Plan
    • Labeling
    • Patient Consent Materials
    • Case Report Forms
    • IRB Information
    • Information on other participating institutions
  • 17. 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?
  • 18. 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?
  • 19. 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
  • 20. Pivotal IDEs
    • Statistical analysis plan
      • Provide enough detail to avoid ambiguity once the trial has started.
  • 21. 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
  • 22. 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.
  • 23. 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
  • 24.
    • Device Advice:
    • IDE Information:
    • Right of Reference and Master Files:
    Resource – FDA Website
  • 25. Questions/Comments
    • [email_address]
    • Direct: 301-796-6352