Presentation on theme: "IRB Review of Device Research and Other Clinical Uses of Devices"— Presentation transcript:
1IRB Review of Device Research and Other Clinical Uses of Devices Marian Serge, R.N.Nurse ConsultantDivision of Bioresearch MonitoringOffice of Compliance, CDRH, FDA(240)
2DisclaimerThe contents of this presentation are my own, and do not necessarily reflect the views and/or policies of the Food and Drug Administration or its staff. The Food and Drug Administration will not be bound by any of the comments or information contained in this presentation.
3Topics Background – FDA’s review IRB Review Humanitarian Use Devices Significant Risk DevicesNon-significant Risk DevicesExempt DevicesHumanitarian Use DevicesEmergency useCustom DeviceCompassionate UseIRB and Clinical Investigator Non-compliance
4Background FDA’s Investigational Device Exemption (IDE) Review Pre-IDE meeting (sponsor and FDA)Protocol design may be decided uponIF IRB makes changes - strongly suggest CDRH inputIDE application (sponsor submits research plans to FDA)FDA acknowledges the date it received the IDEFDA determination within 30 daysApprove, approve with modifications, disapprove“Condition of approval letter”Study may start, while sponsor responds to the conditions
5IRB review of an IDE study IRBs may review an IDE study before FDA approval but with the following risks:IRB might review again after FDA’s changes and approvalThe investigator might start study before FDA approvalStandard practice: IRB review after FDA approvalEnsure IDE application is approved by FDAAsk for a copy of FDA approval, or condition of approval letterEnsure letter states study can start
6FDA-Regulated Research Human Subject Protection & Data IntegritySponsorClinicalInvestigatorandResearchTeamIRBandInstitutionHSP is not just an IRB functionJoint effortCI/Sponsor responsibilitiesSponsors are in an unique position through their monitoring responsibilities to ensure CI compliance with HSPIRB approvalADRsCFsContinuing RvwFDA and the regs hold all parties accountable
8Significant Risk Device Study Significant risk device means an investigational device that presents a potential for serious risk to the health, safety or welfare of a subject and isan implant;for use in supporting or sustaining human life;for substantial importance in diagnosing, curing, mitigating, or treating disease or preventing impairment of health; orthe device study presents serious risk to health, safety, or welfare of a subject
9Significant Risk Device IRB Initial Review Considerations Initial Review – gathering the informationProtocol, informed consent document, device description, previous research, etc. reviewed at convened meetingMost IRBs have standard forms for completion by clinical investigators at initial review –
10Significant Risk Device IRB Initial Review Considerations More questions to ask:Monitoring plans? How often will the site be monitored?Who will implant/use the device?Who will conduct the informed consent process?Are there subinvestigators – what activities?What are the responsibilities of the research team – research activities; CRF completion; device accountability?What are the Field Clinical Engineer activities?
11Significant Risk Device IRB Review Considerations During Study Unanticipated adverse device effectClinical investigators must make UADE reports to sponsor and IRB within 10 working daysIRBs may observe the consent process and research [21 CFR (f)]Review of Amendments/changesSponsor reports to the IRB at least yearly
12Significant Risk Device IRB Continuing Review Convened meetingReview protocol, current informed consent, adverse events, sponsor info, etc.Review of IRB forms completed by CIAlso ask for monitoring reports, accountability records, and ask who is implanting the device, whether device implanted outside the study, etc.
15Non-Significant Risk Device FDA is not aware of NSR studiesIRB is only oversight body for NSR studiesSponsor will make the initial NSR determination
16IRB Review Non-Significant Risk Device IRB must determine whether the NSR device research is NSR or SRHow to make the determinationReview the SR definitionReview Sponsor’s brief explanation of why the device is not a SRReview the proposed use of the deviceReview the additional procedures - surgicalAsk FDA for assistance:
17IRB Review Non-Significant Risk Device IRB determination of whether the NSR device research is NSR or SRIf NSR, IRB may continue their review for implementation at the site. If approved, study is considered to have IDE; it may start; must follow abbreviated requirements at 812.If SR, IRB reports its determination to the CI and where appropriate the sponsor and wait for the sponsor to obtain an IDE before approving the research study at the site.
1821 CFR 812.2(b) Non-significant risk device studies Sponsor responsibilities [21CFR 812.2(b)]Label: “Caution-Investigational device limited by Federal law to investigational use.Ensure IRB approval after presenting the IRB with explanation of why device is NSR.Ensures Investigators obtain informed consentMonitoringMaintains records: name and use of device; explanation of NSR; name and address of CIs; name and address of each IRB; GMP statement, and adverse effects & complaints
19Non-significant risk device studies Sponsor responsibilities Reports to IRBs and FDA:unanticipated AEs;withdrawal of IRB approval;withdrawal of FDA approval;at least yearly submit progress reports;recalls (return, repair, disposal);submit final report w/i 6 mo;lack of informed consent to FDA; andthe IRB’s SR determinations to FDA.Ensures CIs maintain records and reportsNo promotion of the NSR device
2021 CFR 812.2(b) Non-significant risk device studies Clinical Investigator responsibilitiesObtain and document informed consentReport unanticipated adverse device effectsto IRB and sponsor in 10 working daysReport any information about the research to IRB and FDA upon request
21Research exempt from 21 CFR 812 but not from parts 50 (consent) & 56 (IRB) Several categories of exempt research510(k) devices used according to labelingIf the testing is not for determining safety or effectiveness and subjects not at riskConsumer preference testingTesting of a modificationTesting of two devices in commercial distributionDiagnostic devices, if it meets the following
22Diagnostic devices exempt, if the testing Research exempt from 21 CFR 812 but not from Parts 50 (consent) and 56 (IRB)Diagnostic devices exempt, if the testingIs non invasive (simple venepuncture is okay)Sampling procedure does not present significant riskWill not introduce energy into the bodyIs confirmed by another established diagnostic procedureOtherwise the diagnostic study must follow 812
23Informed consent process Important for device studies Ensure language understandableEnsure there is no exculpatory languageEnsure patient given opportunity to consider whether or not to participateEnsure possibility of coercion or undue influence is minimizedEnsure patient is given adequate opportunity to read it before it is signed and datedIRB: ask about the process at initial and continuing review
24IRB Review and Informed Consent FDA has no waiver ofinformed consent(except for emergency use)
27What is a Humanitarian Use Device? An HUD is a device that is intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the US per year.An HUD is a significant risk device
28Humanitarian Use Device Humanitarian Device Exemption HUD – Office of Orphan Products DevelopmentHDE – Office of Device Evaluation
29HDE application review by CDRH Bench and animal testingClinical experience: may be data, literature, investigation(s), marketing experienceApproval based on probable benefit outweighs risk of injury from its use (not reasonable assurance of safety and effectiveness – as in PMA approval)HDE label states “the effectiveness of this device for this use has not been demonstrated”The HDE allows the HUD to be sold
30What are the HDE holder responsibilities? (Federal Register) The HDE holder is responsible for ensuring that the HUD is not administered to or implanted in a patient prior to obtaining IRB approval at the health care facility.An HDE holder may wish to enforce this requirement by not shipping the HUD to the facility until it has received confirmation of IRB approval.
31What are the IRBs responsibilities IRB activities – follow Part 56Approval before HUD-HDE administered!Initial review – convened meetingContinuing reviewWithdrawal of approval
32Federal Register – IRB review of an HUD-HDE FDA believes that the approval criteria set forth in the IRB regulations can and should be interpreted to include consideration of the patient’s need for the HUD and the likelihood that the device is appropriate for the patient’s condition or disease state.(i.e., No special IRB written procedures are needed to review an HUD – use the approval criteria at )
33Federal Register – IRB review of HDE An IRB may approve the use of the HUDin general, for HUD patientsfor groups of patients (with the serious HUD disease or condition) that meet certain criteriaunder a treatment protocol for the HUDon an HUD case by case basis
34Federal Register – IRB review of HDE An IRB may specify limitations on the use of the HUD based uponone or more measures of disease progressionprior use and failure of any alternative treatment modalitiesreporting requirements to IRB or IRB chairappropriate follow up precautions and evaluationsany other criteria it determines appropriate
35Federal Register – IRB review of HDE IRB requirement to withdraw approvalFailure to follow IRB or FDA requirementsUnexpected serious harm to subjects
36What are physician responsibilities? Physician and Institution ActivitiesReport serious adverse events using Medical Device Reporting system 21 CFR 812 Subpart HInformation to PatientsRegulations do not require informed consentIRB and Institution may require consentMost HUDs have information for patients
37Humanitarian Use Device Research and off label use If safety and effectiveness data are being collected on the exact use described in approved labeling – IDE may not neededIf research is intended to prove safety or effectiveness for a new use – IDE neededOff label use of HUDFDA recommends compassionate use provision, which includes prior FDA and IRB concurrence before use.
40Emergency Use of unapproved device Points for IRBs to Remember Unapproved device (usually under IDE)Either for new use orby a physician not part of the research studyPhysician must determine:Life-threatening situation or serious disease/conditionNo other treatment availableUsed once; if potential for more uses -- IDE required and IRB review
41Emergency Use of unapproved device FDA does not have to concur before it is used.Physician makes report to the IRB and sponsor within 5 working days after useUninvolved physician’s assessmentInformed consent (if no consent - next slide)Institutional clearance, if requiredIRB chairperson’s concurrence (if time)Authorization from the sponsor (if under an IDE)
42Emergency Use and NO Informed Consent - 21 CFR 56.23 What are HSP requirements if NO consent?Physician and an uninvolved physician certify thatThe patient has life-threatening situationPatient is unable to communicateTime is not sufficient to obtain consent from patient or LARNo alternative method of approved or generally recognized therapy that provides likelihood of saving the lifeIf time not sufficient to find uninvolved physician, then Physician must make above determinations
45Custom Device All of the following criteria must be met: Necessarily deviates from performance standard or PMA requirementsNot generally available in finished form for purchase or dispensing upon prescriptionNot offered through labeling or advertisingNot generally used by other physicians, dentistsSpecific patient form (the device is formed to the individual patient’s physiological needs) or special needs of a practioner
46Custom Device IRB Awareness Rule of thumbDevice is only available through special order for an individual patientPhysician requests special design from manufacturer for unique situationPatient’s name on manufacturer’s order formTools for use by specific physician or dentist in medical practiceUsed by physicians or dentistsNo IRB review is required. No IDE needed.Institutional policy may require IRB reviewReport misuse to FDA at
47Three Examples when a device was NOT a Custom Device Hydrocephalic shunts made of some other material than silicone because patients allergic to silicone. (IDE needed)Cranial helmets for miss-shaped new-born heads. The helmets were shaped or sized i.e. “fitted” for each subject. (IDE needed)Thoracic Aortic Aneurysm graft ordered individually for each patient (IDE needed)
50Compassionate Use Compassionate use Single patient or small group Serious disease or conditionNo alternative available
51Compassionate Use Physician duties - guidance Obtain FDA concurrence of the compassionate use before it is used (FDA reviews the sponsor’s protocol or IDE supplement)Obtain IRB chair’s concurrence and follow IRB proceduresMonitors the patientReport adverse events to IRBFollow-up report to sponsor (sponsor reports to FDA)Summary information about patient outcomes
52Compassionate Use and Patient Protection Measures Guidance Physician obtains uninvolved physician’s assessment of compassionate usePhysician obtains IRB chair concurrence(chair should ask whether FDA concurred)Institutional clearancePhysician provides the patient with info and obtains consent for usePhysician monitors for problemsPhysician makes a report
54IRB Deficiencies Fiscal Years 1998 - 2005 FY19981999200020012002200320042005Inadequate initial &/orcontinuing review80%64%56%39%24%25%50%37%Inadequate minutes61%42%35%11%28%17%Lack of or incorrect SR/NSR determination52%58%57%10%16%34%22%Inadequate SOPs36%33%26%9%19%7%Inadequate membership roster32%31%30%13%20%21%12%
55To Improve compliance institutions should: Provide training to IRB members & staffProvide training to clinical investigatorsImplement a quality assurance programCorrect & prevent problems before they jeopardize subject safety and the institution’s reputationFocus institutional culture on ethics and good clinical research practices
56Investigator Deficiencies Fiscal Years 1998 - 2005 1999200020012002200320042005Failure to follow investigational plan/regs32%46%47%44%51%54%50%Protocol deviations21%8%26%40%20%38%16%9%Inadequate subject protection/IC24%19%28%29%Inadequate device accountability17%27%18%14%7%Lack of FDA &/or IRB approval11%5%13%10%
57Areas where clinical investigators or research team did not comply . . . . Did not randomize subjects; put all subjects on the investigational deviceImplanted a patient not in the research studyImplanted a “custom” device by requesting it on a “prescription pad”Failed to obtain IRB approval for modifications or amendments in protocol & ICEnrolled subjects who did not meet eligibility criteria
58Areas where clinical investigators or research team did not comply . . . . Failed to report unanticipated adverse device effects.Failed to complete CRFs, AE forms, and device accountability records.Failed to include all basic elements in the informed consent document.Failed to ensure completion of all protocol required tests (i.e., 6-month angiograms).Started research study before IRB approval.
59Areas where clinical investigators or research team did not comply . . . . Unapproved device implanted without an IDE.CI failed to sign Investigator Agreement.CI refused to give financial information to sponsor.Patients did not sign an informed consent document.Patients signed an informed consent from another hospital IRB.
60Areas where clinical investigators or research team did not comply . . . . Patients signed an old version of Informed Consent documentClinical Investigator did not maintain correspondence from IRBNo documentation about receipt of devices or distribution to subjectsLost devices