The FDA Inspection Process February 17, 2010

Topics Discuss the FDA inspection process Describe the type of outcomes Review material that is reviewed during an inspection

Who Performs the Inspections? Office of the Commissioner Office of Regulatory Affairs Bioresearch Monitoring Program (BIMO) 6 Region Offices CDER 20 District Offices CBER 130 Resident Posts CDRH

FDA Inspections in Clinical Research BIMO INSPECTION PROGRAM (CDER) Good Laboratory Practice (GLP) * In vivo Bioequivalence Good Clinical Practice (GCP) * Institutional Review Boards * Clinical Investigators * Sponsor-Monitors, CROs

Essential Pieces

Project Cohesiveness

Complete Application

BIMO Inspections Inspections can be performed during any phase of the development process “Directed” inspections are typically assigned during the IND phase Inspections conducted during the NDA phase can be “Routine”, “For Cause”, or “Directed”

Regulatory Authority to Conduct Inspections/Audits 21 CFR 312.68 “An investigator shall upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to 312.62.”

General Goals of Inspection: Clinical Investigator Program Adherence to applicable regulations with respect to Good Clinical Practice Validity of studies in support of marketing applications Ensuring that rights, safety and welfare of study subjects have been protected

Inspection Preparation

Preparing Ahead For an FDA Inspection General Tips The time to start preparing for an FDA inspection is at the beginning of a study! Keep all records and documents current and appropriately filed (easily accessible) Keep all communications from different studies separate from each other

Preparing Ahead For an FDA Inspection General Tips (continued) Document and file all pertinent communication with key sponsor personnel and with other external personnel (vendors, project partners, etc.) Conduct periodic QC reviews to ensure data integrity Identify/know team/personnel who will interact/respond to FDA during an inspection Ensure all staff are educated on proper conduct during an FDA inspection Know GCPs, regulations/guidelines, SOPs and study specific information (or at least know how to access resources to get the information)

Preparing Ahead for an FDA Inspection General Tips (continued) -Use an “adequate” NTF system to explain situations or provide information that doesn’t fit nicely into other categories. The NTF should have the following elements: Identify and correct the problem Record changes in procedure to prevent future occurrences Follow through – document that a new process/procedure is in place

FDA Inspection Outcomes No inspectional findings FDA 483 Observations Documents non-compliance with regulations only (can not cite for non-compliance with guidelines) May be left at the site at the end of the inspection or sent later EIR (Establishment Inspection Report) Will list findings: non-compliance with both regulations and guidelines Site/Organization may or may not receive a copy

FDA Compliance Program Guidance 7348 FDA Compliance Program Guidance 7348.111 Bioresearch Monitoring Clinical Investigators

What will FDA Inspect? Determining facts surrounding study Who performed specific tasks Degree of delegation of authority Where study procedures were performed How and where data was recorded How test article accountability was maintained How monitor communicated with investigator How monitor evaluated the study’s progress

What will FDA Inspect? Subjects exist and have disease Study data Subjects exist and have disease Subjects meet inclusion/exclusion criteria Protocol followed AEs reported and all reports adequate Consent obtained IRB approval obtained CRFs accurate Dropout subject documentation Retention of study blind

What will FDA Inspect? The Investigator Authority and Administration How investigator was notified of study specifics Was delegation appropriate? What laboratory was used. If local, was laboratory facility adequate Determine if and why investigator discontinued study before completion Protocol Compliance Test Article Accountability Electronic Records and Signatures Consent of Human Subjects IRB Interactions

What will FDA Inspect? Subject Records AE Documentation and Reporting Records Retention Sponsor Was copy of ICF provided to sponsor? Were periodic reports submitted? Determine if and how AEs were reported to sponsor Timeliness of CRF submission to sponsor Were all intercurrent illnesses/concomitant therapies reported to sponsor How was study monitored; method and frequency Review all 1572’s

Fair game for the inspection? ECGs Videos (i.e. 2nd. Look laparoscopic procedures) Diaries Electronic records X-rays Flyers/Radio Ads Post-it-notes Audit Reports

Key Areas to control PI Involvement Adequate Staffing/time Well documented screening Processes to assure protocol compliance Documentation, Documentation, Documentation AEs taken seriously

Title 21 CFR Part 11 Validation Record generation and copying Record protection Access Audit Trails Operational system checks Authority checks Device/Terminal Checks Training/User accountability System document control Controls for open systems Electronic Signatures

GCP Tips VERY POPULAR ACRONYM (ALCOA) A – Attributable L – Legible C – Contemporaneous O – Organized A – Accurate

GCP Tips cont. (RARE) R – reproducible A – accurate R – reliable E – (able to be) evaluated

Compliance Classifications NAI – No Action Indicated Inspected firm is in compliance VAI - Voluntary Action Indicated Deviation(s) from the regulations Voluntary correction is requested OAI - Official Action Indicated Because of serious non-compliance requiring regulatory or administrative action by FDA

Violative Actions Revision to the protocol without obtaining the sponsor’s written concurrence Failure to submit revised protocol to IRB for approval Failure to obtain written informed consent and provide oral explanation of the study Failure to update consent forms to reflect changes in the protocol Over-delegation to non-physicians (e.g., diagnosis that qualifies/determines eligibility for entry into the study) Improper corrections to essential documents - Erasures, white-out or obliteration of original data entered on either CRFs or medical charts Changes made to study data without checking the source documents or without justification for change Back dating consent forms and signatures Failure to obtain IRB approval of consent form revisions Changes to study data without the investigator’s concurrence, especially after the investigator has “signed-off” the completed CRF

Violative Actions Creation of fake records or patients by using demographic data or using blood, urine and tissue samples from other subjects Patients’ diaries altered to reflect a positive outcome Using site personnel as subjects to which they did not meet inclusion criteria for study article under investigation Destruction of study records

Consequences of non-compliance (not all inclusive) Warning Letters NIDPOE Letters Disqualification Untitled Letters

Clinical Investigator Deficiencies CDER Inspections (all) – FY 2006 35% of the deviations related to protocol deviations 23% related to records maintenance 9% related to drug accountability documentation 6% related to consent process 5% were related to reporting of AEs

Adequate FDA 483 Response Submit a prompt written response -assess the root cause of the problem -Explain actions to correct the problem -Evaluate the extent of the problem -Implement preventative actions to avoid recurrence -include supporting documentation -provide REALISTIC timelines for implementation and correction

Questionable Research Scientific Misconduct Percentage in survey of US based scientists who engaged in questionable research practices 15.5% - Changed a study's results to satisfy a funding source 15.3% - Dropped data from analysis based upon a "gut feeling" 12.5% - Overlooked other's use of flawed/questionable data 10.8% - Withheld research results 7.6% - Circumvented minor rules protecting humans subjects Source: Nature June 2005 n = 3247

Warning Letter Failure to personally conduct or supervise the clinical investigation [21 CFR 312.60]. “Specifically, during the FDA inspection you informed the FDA investigators that you did not personally meet with at least two sub-investigators … who conducted the study, nor reviewed their research or clinic records regarding the subjects they enrolled. You also informed FDA investigators that you were not aware that all the screening x-rays obtained by the two sub- investigators were re-interpreted by a second radiologist at the end of the study and that you were also not aware that only the results from the second radiologist were reported to the sponsor.”

Warning Letter Citations Failure to secure investigator compliance with the investigational plan and applicable FDA regulations [21 CFR 312.56(b)] -”…despite several clinical monitoring visits from …monitors, …and [your] own audits documenting serious protocol violations and regulatory noncompliance by multiple clinical investigators, these violations persisted. -”there were overwrites on several subjects’ signature dates; thus, the actual date the subject signed the consent document was not clear”

Warning Letter Citations Failure to secure investigator compliance with the investigational plan and applicable FDA regulations [21 CFR 312.56(b)] “We note that generation of numerous memos to file after all subjects have completed the study does not adequately secure compliance of an investigator.” “… method for securing compliance (i.e., the generation of more than 125 memos to file for protocol and informed consent deviations noted at the site) was not adequate.”

Quality Assurance & Regulatory Compliance Contact Information Al Chester Quality Assurance & Regulatory Compliance 919-668-8690 Alfred.chester@duke.edu