FDA Inspection Readiness Richard Angelo, Ph.D. Director, Managing Consultant October 17, 2014
Agenda Reasons for Inspections Preparing for Inspections Inspection Day Inspection Outcomes 2013 Inspection Metrics Final Thoughts References 2
Reasons for an Inspection Routinely Assigned Inspections New Product NDAs, PLAs, PMAs, BLAs Assess compliance with regulations Verification of data For Cause Inspections Issues Arising During Application Review Complaints Site termination 3
Who/What May Be Inspected? Facilities Personnel Records Systems Policies 4
How Are Investigator Sites Selected? Site Performance/Demographics Enrollment Cross-Section (high, moderate, low) Geographic Cross-Section (regional populations) Site Cross-Section (community hospitals, private practices, university hospitals, etc.) Unusual Data Trends Too consistent and uniform Dissimilar data compared to other sites High dropout rate, AE rate, protocol violations 5
How Are Investigator Sites Selected? Foreign pivotal trials Study is outside investigator s expertise Complaints Past inspection history 6
FDA Inspections May occur with or without prior notice Scheduled (Announced) Inspection typically first inspection, or if previous inspection was nonviolative Unscheduled (Unannounced) Inspection - if prior inspection was violative Duration and frequency at discretion of FDA Start time of inspection is not negotiable Notify FDA of any scheduled extraordinary events such as offsite, all day management meeting, etc. 7
What May FDA Review? Protocol/Amendments Investigator s Brochure Informed Consent Forms Correspondence IRB Sponsor FDA Investigational Product Receipt/Storage Dispensing Accountability Quality Systems Laboratory Credentials Form FDA 1572 DOR Log/Site Signature List Monitoring Log CRFs Source Documents Staff Qualifications CVs Training Files/Records Adverse Events/SAEs SOPs Investigator Agreements 8
What May FDA Not Review? Financial data not required by 21 CFR Part 54 (Financial Disclosure) Personnel information other than qualifications Studies not covered by the notice of inspection (Form FDA 482) Non-study data and/or records Internal audit reports 9
Preparing for an FDA Inspection
Getting the Call Establish who should receive calls from FDA Request the following information Nature and scope of the visit Expected arrival (date and time) Number of FDA Investigators coming Anticipated length of stay List of studies/documents they wish to review Notify QA, staff, administrators Notify the sponsor 11
Planning Ahead Have Available A Responsible Person to receive Inspector(s) A senior official (President, CEO, COO, Head of QA, etc.) Understands Company Policies Accountability for Facility Operations Legally answerable regarding compliance Accept the Notice of Inspection (Form FDA 482) Identify a point person and a back-up to escort the Inspector(s) and contact other parties as needed 12
Planning Ahead Have Available A designated work space for FDA Quiet, comfortable, devoid of confidential information Knowledgeable staff for interviews Company/facility operations Study participation and conduct Company policies Standard Operating Procedures (SOPs) Work Practices 13
Begin Document Preparation Study files Regulatory binder(s) List of all studies conducted by PI Protocol number(s) and title(s) IND/IDE number(s) Sponsor(s) Dates of study(ies) 14
Begin Document Preparation Investigator agreements Training records Study logs Delegation of Responsibility Monitoring Drug/device accountability Screening/enrollment Protocol deviations SOPs (e.g., table of contents) 15
Begin Document Preparation Gather source/supporting documents Ensure they are complete and legible Adequately document exposure to investigational product Adequately document all concomitant medications and AEs Request medical records, if applicable CRFs Completed by authorized staff (see DOR log) Corrections were made appropriately If EDC was used, ensure someone can access ecrfs 16
Begin Document Preparation Informed Consent Form All original, fully executed forms (all pages) are present Correct versions(s) were used (IRB approved) Consent was obtained prior to study participation Consenting conducted by an authorized person (see DOR log) Study subjects received copies of ICFs Regulatory binder completeness Drug accountability records Reconcile and corroborate subject dosing/exposure 17
Inspection Day
Inspection Day Assure that any/all receptionist locations are aware of the procedure: Whom to notify (the order of alternates) when FDA arrives Ask (do not insist) the inspectors to sign-in Ask inspectors to wear visitor badges Do not offer information or answer inappropriate questions Keep the inspection team in the reception area 19
Inspection Day The Inspector(s) must present their credentials (identification) Assure this is accomplished for all FDA personnel Do not attempt to photocopy their identification credentials You may write down their names and ID numbers The Inspector(s) must present a signed Notice of Inspection (Form FDA 482) to the highest responsible official available Escort the Inspector(s) to the pre-designated workspace 20
Inspection Day Even if you think you know, ask the Inspectors: The reason for the inspection What they will need to see and in what order Normal courtesies may be offered to the Inspectors (e.g., coffee, soft drinks, food, etc.) If the Inspectors want to pay for these, don t disagree. Notify others of FDA presence and location Key areas may be visited during a facility tour (e.g., pharmacy, clinic, laboratory, server room, document storage, etc.) 21
Inspection Day Inspector may explain the logistics of the inspection. Afterwards, if it is not clear: Ask inspectors if they plan to meet at the end of each day to review findings If not practical, ask to be briefed of significant findings Ask that the closeout meeting be conducted at a time when RP is available Do not leave FDA unsupervised at any time when reviewing documentation, it is acceptable to leave them in the designated room and check on their progress regularly 22
Inspection Day FDA may request a facility tour Always escort the Inspectors when they leave the workspace Predetermine who will participate in the tour Include knowledgeable people who can answer facility questions Make sure designated staff are prepared to answer questions if the tour comes into their area(s) FDA requests for documents Bring in documentation as it is requested by the Inspectors Maintain a log of all documents requested by FDA 23
Inspection Day FDA requests for copies of documents Maintain a log of all copies requested by FDA Assign a designated person to make copies Make a duplicate set of all copies requested, one set for you Stamp all requested copies CONFIDENTIAL FDA questions Maintain a log of all questions asked by FDA Predetermine who will address questions on specific subjects If that person is not present, send for him/her 24
Responding to FDA Questions The Do s: Be friendly and cooperative Be willing to say I don t know or I can find the answer for you Avoid conditional terms such as usually, typically, generally Stop talking once the question is answered Ask for clarification when needed Control your emotions Maintain eye contact Resist uncomfortable silence 25
Responding to FDA Questions The Don ts: Volunteer information that has not been requested Be sarcastic, argumentative, defensive or evasive Guess or hypothesize Point out deficiencies, errors Apologize for issues or deficiencies Express personal opinion Ramble Respond to comments made by FDA 26
Affidavits May be prepared by FDA during the inspection A written recount of what took place May be used as a basis for issuance of search and seizure warrants FDA may request executive signatory Never read, review or sign an affidavit Do not sign any generated written statements or inspection recount documents that may constitute an admission of error Do not provide oral confirmation of truthfulness of any statement 27
Closeout Meeting At the conclusion of the inspection a closeout meeting will be held Include key operational and management staff Inspectional findings will be presented by FDA If inspectional observations are noted, review each one for clarity and accuracy If you believe an observation is erroneous, discuss why and request the Inspector change it or note the disagreement in their report 28
Closeout Meeting A Form FDA 483 may be issued if objectionable findings were discovered If you do not understand a finding, ask for clarity If possible, make corrections before the Inspector leaves and allow him/her to verify (may result in a verified correction annotation on the Form FDA 483) If you agree, and a corrective action (CA) has been identified, explain what will be done and when If you do not yet know what the CA will be, say so Your responses will be included in the Inspector s report 29
Closeout Meeting If you disagree with the Form FDA 483 Explain why and discuss with Inspectors (do not argue) Don t promise a CA if you disagree with the observation Your responses will be included in the Inspector s report At the conclusion of the meeting: Thank the Inspector(s) for the time and effort they spent at your site Conduct a debriefing and planning session with inspection participants shortly after the Inspector(s) depart 30
Inspection Outcomes
After the Inspection - You A written response to all 483 items should be prepared and sent to the issuing FDA office within 10 business days FDA usually allows up to 15 days (be safe, not sorry) The response(s) will then track with the EIR (Establishment Inspection Report) process Enables FDA to consider these responses prior to release of the inspection outcome letter 32
After the Inspection - FDA Inspector will write an Establishment Inspection Report (EIR) within 30 days The EIR will be reviewed by the FDA District Office and a classification will be recommended NAI (no action indicated) No objectionable conditions or practices VAI (voluntary action indicated) Objectionable conditions exist; not at threshold to take or recommend administrative or regulatory action OAI (official action indicated) Serious or numerous objectionable conditions found. Regulatory action(s) recommended 33
After the Inspection - FDA FDA letter arrives 30-90 days after inspection: NAI states FDA observed basic compliance with regulations. However, FDA does not always send a letter when no significant deviations were observed. VAI identified deviations that do not meet the threshold of regulatory significance. May require a written response. OAI identifies significant regulatory violations and may result in a Warning Letter or Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) Share letter with senior management and QA 34
2013 Inspection Metrics
2013 BIMO Inspection Metrics Bioresearch Monitoring Program Conducts inspections of sponsors, clinical investigators, IRBs, animal research facilities, bioanalytical laboratories Inspections in 2013 Clinical Investigator (48%) Bioequivalence (27%) IRBs (12%) Sponsors (9%) GLP (4%) 36
2013 BIMO Inspection Metrics Clinical investigator inspections CDER (361; 56%) CBER (91; 14%) CDRH (193; 30%) Clinical investigator inspection outcomes NAI (54%) VAI (43%) OAI (3%) 37
2013 BIMO Inspection Metrics Most Prevalent Deficiencies (all investigator inspections) Protocol Deviations 34% Drug Accountability 5% Records 21% Adverse Events 5% Informed Consent 9% IRB Communication 3% 38
2013 BIMO Inspection Metrics Most Prevalent Deficiencies (investigator OAI inspections) Protocol Deviations 73% Records 64% Informed Consent 9% Submitting False Information 9% IRB Communication 9% 39
Final Thoughts
Final Thoughts Be prepared, not scared 41
Final Thoughts Document, Document, Document If it wasn t written down, it didn t happen 42
Resources International Conference on Harmonization E6 Guideline for Good Clinical Practice http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinicalpractice.html FDA Guidance for Industry E6 Good Clinical Practice, Consolidated Guidance http://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf FDA Information Sheets http://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/guidancesi nformationsheetsandnotices/ucm113709.htm 43
Resources Bioresearch Monitoring Program Compliance Manuals http://www.fda.gov/iceci/compliancemanuals/complianceprogrammanual/ucm2556 14.htm 44
Thank You!