Investigator Roles and Responsibilities in Clinical Device Trials A Total Product Lifecycle Approach to Medical Device Development: Responsibilities and Opportunities The Stanford Center for Clinical and Translational Education and Research Li Ka Shing Center for Learning and Knowledge September 28-29, 2010
Sonali P. Gunawardhana M.P.H., J.D., LL.M. Regulatory Counsel Food and Drug Administration Center for Devices and Radiological Health Office of Compliance Division of Bioresearch Monitoring
Disclaimer The 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 as per 21 CFR 10.85. 3
Device Clinical Research Regulations 21 CFR 50: Protection of Human Subjects 21 CFR 54: Financial Disclosure 21 CFR 56: Institutional Review Boards 21 CFR 58: Good Laboratory Practice 21 CFR 812: Investigational Device Exemptions
CDRH BIMO INSPECTIONS Fiscal Years 2005-2009 400 300 332 336 323 301 305 200 100 FY05 FY06 FY07 FY08 FY09
CDRH BIMO INSPECTIONS Fiscal Years 2005-2009 Entity 2005 2006 2007 2008 2009 Sponsor 73 53 40 57 59 CI 180 200 183 155 163 IRB 48 59 92 88 79 GLP 31 24 8 1 4
FY09 Investigator Deficiencies Follow investigational plan, investigator agreement, or protocol Document case hx/device exposure Obtain adequate informed consent Record and report protocol deviations Control of investigational device Report UADEs
FY09 Sponsor Deficiencies Monitor study Secure investigator compliance Obtain signed Investigator Agreement Provide information to properly conduct study Maintain current investigator list Inform investigators, FDA, or IRB
Sponsor-Investigator Inspections 31 Inspections of Sponsor- Investigators performed during FY 2008 and 2009 11 Warning Letters Issued = 35%
Inspection Classification 2, 6% 13, 42% NAI VAI OAI 16, 52% N = 31
Most Frequent Investigator Violations 9/11 Failure to follow investigational plan & FDA regs 8/11 Failure to maintain records 7/11 Failure to obtain informed consent in accordance with Part 50
Most IMPORTANT Violations Overall IDE Violations Failure to submit IDE [812.20] Failure to submit IDE supplement [812.35(a)] Monitoring Violations Failure to ensure proper monitoring [812.40] *10/11 Warning Letters had one, or both of these violations
Compliance Tools Untitled/Warning letter Re-inspection Informal conference 3rd party audits Rejection of site data Disqualification CI, IRB, or GLP Invoke Application Integrity Policy Revoke marketing permit Civil Money Penalties Seizure Injunction Prosecution
CDRH BIMO Warning Letters 35 30 1 3 25 8 3 5 4 20 15 4 8 4 GLP IRB Sponsor CI 10 20 18 19 16 4 5 9 0 FY05 FY06 FY07 FY08 FY09
Example Of An Inadequate Response: You enrolled and performed study surgery on at least eight subjects prior to IRB approval.
Example Of An Inadequate Response: 20 out of 25 subjects Case Report Forms (CRFs) were incomplete because information needed to determine study eligibility were missing and not available in source documents.
Example Of An Inadequate Response: Failure to adequately supervise the conduct of the study.
Example Of An Inadequate Response: Failure to properly monitor the study.
Example Of An Inadequate Response: Failure to conduct the study in accordance with the investigational plan.
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain Applies to Clinical Investigators Some clinical investigators may have already received a Warning Letter but in some cases violations discovered on the first inspection are serious enough for the Center to issue the NIDPOE.
Disqualification Of Clinical Investigators A NIDPOE letter informs the recipient clinical investigator that FDA is initiating an administrative proceeding to determine whether the clinical investigator should be disqualified from receiving investigational products pursuant to the Food and Drug Administration's regulations. Generally, FDA issues a NIDPOE letter when it believes it has evidence that the clinical investigator repeatedly or deliberately violated FDA's regulations governing the proper conduct of clinical studies involving investigational products or submitted false information to the sponsor.
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain Consent Agreements List specific responsibilities of the Clinical Investigator in terms of coming into compliance. Can last for a specific amount of time or can be an agreement the disqualification is permanent. Can be viewed as a tool to bring the Clinical Investigator into compliance which in turn serves as a way to educate the Clinical Investigator as to their regulatory responsibility for the current and future clinical trials.
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain What does disqualification mean for the clinical investigator? Their name is added to a list on the FDA website that indicates that they are disqualified from participation in any type of clinical trial. Generally it means that they have incurred legal fees and it can open them up to more eminent liability. Some might feel that it has had a negative impact on their reputations.
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain What does disqualification mean for the Sponsor? The data from the disqualified clinical site can not be used in their submission. (Monetary and Ethical considerations) Sponsor is responsible for oversight of all clinical investigators so there might be some serious issues in terms of monitoring which can lead to further regulatory action.
References CDRH Homepage www.fda.gov/cdrh CDRH Learn http://www.fda.gov/cdrh/cdrhlearn/ Device Advice www.fda.gov/cdrh/devadvice Notice of Initiation of Disqualification Proceedings and Opportunity to Explain www.fda.gov/regulatoryinformation/foi/electronicreadi ngroom/ucm092185.htm
Contact Information Sonali P. Gunawardhana, M.P.H., J.D., LL.M. Regulatory Counsel Office of Compliance Division of Bioresearch Monitoring Center for Devices and Radiological Health U.S. Food and Drug Administration 10903 New Hampshire Ave. Building 66, Room 3452 Silver Spring, MD 20993 Phone: (301) 796-5635 Fax: (301) 847-8136 sonali.gunawardhana@fda.hhs.gov