Kathy Weil Division of Bioresearch Monitoring Office of Compliance Center for Devices and Radiological Health US Food and Drug Administration

Kathy Weil Division of Bioresearch Monitoring Office of Compliance Center for Devices and Radiological Health US Food and Drug Administration Kathy.Weil@fda.hhs.gov

Follow the protocol and IDE regulations to ensure data integrity (21 CFR Part 812) Protect your human subjects (21 CFR Part 50) Disclose your financial interests (21 CFR Part 54)

A comprehensive, agency-wide program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research

Protect the rights, safety, and welfare of human research subjects Assure the quality, reliability, and integrity of data collected

Clinical Investigators Sponsors, Contract Research Organizations, and Monitors Institutional Review Boards Good Laboratory Practices

New product or indication Premarket approval (PMA) or notification (510(k)) New technology Investigational device exemption (IDE) Complaints Allegations of research misconduct Non-compliant history Previously violative (OAI) inspection Routine surveillance Institutional Review Boards

No Action Indicated (NAI) No objectionable conditions or practices Voluntary Action Indicated (VAI) Objectionable conditions or practices But not at threshold to take or recommend administrative or regulatory action Official Action Indicated (OAI) Serious objectionable conditions found Regulatory action recommended

NFC = No For Cause inspections included

CDRH BIMO Warning Letters 2006 to 2010

CDRH BIMO Warning Letters

Recidivist OAIs across program areas: CI = 38% S/M = 21% IRB = 31% GLP = 10% N = 144

N = 365

General Responsibilities of Investigators (21 CFR 812.100) Ensure that the investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations. Protect the rights, safety, and welfare of subjects under the investigator's care. Control devices under investigation. Ensure that informed consent is obtained from each subject in accordance with (21 CFR Part 50)

Specific Responsibilities of Investigators (21 CFR 812.110) 1. Await IRB approval and any necessary FDA approval before obtaining written informed consent or permitting subject participation. 2. Use investigational devices only on subjects enrolled in the study 3. Financial disclosure. 4. Dispose of the device properly.

Inspections (21 CFR 812.145) Investigators are required to permit FDA to inspect and copy any records pertaining to the investigation including, in certain situations, those which identify subjects.

Investigational Device Distribution and Tracking The IDE regulations prohibit an investigator from providing an investigational device to any person not authorized to receive it (21 CFR 812.110(c)). Monitor the shipping, use, and final disposal of the devices with good record keeping practices. Return any remaining supply of the device or otherwise to dispose of the device as the sponsor directs (21 CFR 812.110(e)).

Prohibition of Promotion and Other Practices (21 CFR 812.7) The IDE regulations prohibit the promotion and commercialization of a device that has not been first cleared or approved for marketing by FDA. Including: Promotion or test marketing of the investigational device Charging subjects or investigators for the device a price larger than is necessary to recover the costs of manufacture, research, development, and handling Unduly prolonging an investigation beyond the point needed to collect data required to determine whether the device is safe and effective Representing that the device is safe or effective for the purposes for which it is being investigated.

Annual Progress Reports and Final Reports The IDE regulations do not specify the content of the annual progress or final reports. Check with your IRB what information they need. Consider the following information: IDE number Device name & Indications for use Brief summary of study progress in relation to investigational plan Number of subjects enrolled Number of devices received, used, and the final disposition of unused devices Brief summary of results and conclusions Summary of anticipated and unanticipated adverse device effects Description of any deviations from investigational plan Reprints of any articles you ve published

Investigator s detailed report Sent to the center that issued the inspection Evidence accompanies report Center classifies the inspection and determines outcome (OAI, VAI, NAI)

Submit a prompt written response Assess the root cause of the problem Evaluate the extent of the problem Explain actions to correct the problem Implement preventative actions to avoid recurrence Timelines for implementation Supporting documentation

Rejection of data IRB restrictions Deficiency letter IDE, 510(k), or PMA withdrawal No new studies or subjects Application Integrity Policy Untitled letters Civil Money Penalties Warning letters Seizure / Detention Consent Agreement Injunction Disqualification Criminal Prosecution CI, IRB, GLP Debarment

Did not follow investigational plan and FDA regs Did not follow signed investigator agreement Inadequate documentation of case history/ device exposure Did not properly obtain informed consent Inadequate record of protocol and/or protocol deviations

Review the protocol can you realistically follow it at your site? Select qualified study personnel & ensure training Ensure the protection of your human subjects Ensure data integrity Mitigate bias

You initiate and actually conduct, alone or with others, an investigation The device is administered, dispensed, or used under your direction

General Duties Submit the IDE application to FDA Obtain both FDA and IRB approval for the investigation Select qualified investigators and provide them with the information they need to conduct the investigation properly Ensure proper monitoring of the investigation Ensure that any reviewing IRB and FDA are promptly informed of significant new information about an investigation

Selection of Investigators (21 CFR 812.43) Selecting qualified investigators (training and experience) Shipping the investigational device only to participating investigators Obtaining a signed investigator's agreement from each investigator. Selecting qualified monitors (training and experience) Providing investigators with the investigational plan and report of prior investigations of the device. (21 CFR 812.45)

Monitoring (21 CFR 812.46) Securing compliance of all investigators Evaluating all unanticipated adverse device effects Resuming terminated investigations

Monitoring Visits Monitors review records such as: IRB approvals Informed Consent Documents Source documents Case Report Forms (CRF)

Controlling Distribution and Disposition of Devices May ship investigational devices only to qualified investigators participating in the clinical investigation ( 812.43(b)). Must maintain complete, current, and accurate records pertaining to the shipment and disposition of the investigational device ( 812.140(b)(2)). Instruct investigators on their recordkeeping obligations and requirments (812.140(a)).

Prohibition of Promotion and Other Practices (21 CFR 812.7)

Supplemental Applications (21 CFR 812.35(a) and (b)) Changes in the investigational plan Addition of new institutions

Records Investigator Sponsor All Correspondence Pertaining to the Investigation X X Shipment, Receipt, Disposition X X Device Administration and Use X - Subject Case Histories X - Informed Consent X - Protocols and Reasons for Deviations from Protocol X - Adverse Device Effects and Complaints X X Signed Investigator Agreements - X Membership/Employment/Conflicts of Interest - X

Type of Report Prepared by Investigators for: Prepared by Sponsors for: Unanticipated Adverse Effect Evaluation Sponsors and IRBs FDA, IRBs and Investigators Withdrawal of IDE Approval Sponsors FDA, IRBs and Investigators Progress Report Sponsors, Monitors and IRBs FDA and IRBs Final Report Sponsors and IRBs FDA, IRBs and Investigators Emergencies (Protocol Deviations) Sponsors and IRBs FDA Inability to Obtain Informed Consent Sponsors and IRBs FDA Withdrawal of FDA Approval N/A IRBs and Investigators Current Investigator List N/A FDA Recall and Device Disposition N/A FDA and IRBs Records Maintenance Transfer Sponsors FDA Significant Risk Determinations N/A FDA

Inspections (21 CFR 812.145) Sponsors are required to permit FDA to enter and inspect (at reasonable times and in a reasonable manner) any establishment where devices are held (including any establishment where devices are manufactured, processed, packed, installed, used, or implanted or where records or results from use of devices are kept). FDA may also inspect and copy all records relating to an investigation including, in certain situations, records which identify subjects.

Did not ensure proper monitoring Inaccurate or incomplete correspondence Inadequate or no records of device shipment/disposition Did not obtain signed investigator agreement Did not inform investigators Did not secure investigator compliance Inadequate record retention Inadequate or no progress reports

Remember Correct issues before they jeopardize the study or subject safety Minimize recurring issues Practice protocol care Create an accountable organizational culture Focus on good ethics and research practices Protect your reputation Protect your subjects

CDRH Homepage www.fda.gov/cdrh CDRH Learn http://www.fda.gov/cdrh/cdrhlearn/ Device Advice www.fda.gov/cdrh/devadvice Disqualification List www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm