501: Successful FDA Inspections Richelle Little & Kara Morgenstern HCCA Research Compliance Conference 2012 Resource List for FDA Clinical Trial Inspections EIR policies http://www.fda.gov/iceci/inspections/fieldmanagementdirectives/ucm061430.htm. Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInf ormationSheetsandNotices/ucm113709.htm FDA Inspections of Clinical Investigators, June 2010 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf FDA Institutional Review Board Inspections, January 2006 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126555.pdf Writing an Effective 483 Response http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeeting sConferences/UCM102921.pdf FDA’s Compliance Program Guidance Manual (CPGM), Bioresearch Monitoring, Clinical Investigators and Sponsor-Investigators, Program 7348.811, December 8, 2008 http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/ucm1 33773.pdf FDA Running Clinical Trials Website http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm Materials at CDRH Learn (online videos and printable slide presentations) http://www.fda.gov/Training/CDRHLearn/ucm162015.htm WIRB Seminars (live and recorded, various topics) http://ie6.wirb.com/Pages/EducationServices.aspx ICH Guideline E6: Good Clinical Practice http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1 /Step4/E6_R1__Guideline.pdf FDA Warning Letters http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm 1
Top Ten Tips for Surviving an FDA Inspection 1 – DO respond promptly when the FDA contacts you to schedule an inspection. DON’T ever ignore or otherwise disregard any communication (written or telephone) from the FDA. DON’T get so nervous when the FDA calls that you agree to a schedule that will not allow you time to prepare or the opportunity to be readily available during the inspection. The FDA is usually willing to allow a matter of several days in order to accommodate the study team’s needs and schedules. DON’T try to otherwise delay or drag out the inspection. Doing so may arouse suspicion and inspire the inspector to dig deeper. 2 -- DO alert key institutional offices that the FDA has scheduled an inspection of your study. DON’T try to handle the inspection in a vacuum. There is good institutional support for you from the IRB and Regulatory Affairs and others. (Note that the IRB requires that it be notified of inspections of IRB- approved studies). 3 -- DO review and organize all of the documents associated with the study in order to be re-familiarized with the details and prepare to address any anticipated questions. Also make sure that memories of the study team are refreshed regarding each member’s roles and responsibilities on the study. DON’T try to manipulate or obfuscate the written records associated with the study under inspection. DON’T try to orchestrate any approach to the inspection that would represent anything other than how the study was actually conducted. 4 -- DO make adequate time to attend to the inspection before, during, and after the actual days when the inspector is on site. DON’T try to squeeze it into your normal schedule, and DON’T depend on someone else to represent you and your role/activities on the study. 5 -- DO arrange for a convenient, quiet, secure, neutral space for the inspector to review records and interview personnel. Include arrangements to carefully photocopy records as requested (make three (3) copies of any document the inspector will take - one for the inspector, one for the study team, and one for institutional offices). DON’T host the inspection in the midst of your study conduct operations (think: front parlor, not laundry room). Page 1 of 2 2
6 – DO answer the inspector’s questions in an honest and forthright manner. DO provide information responsive to the question, and then stop talking in a natural manner. DO feel comfortable answering “I don’t know off the top of my head – let me check it out” when you are not sure. DO explain or defend your position in a polite and respectful manner a limited number of times. DON’T offer speculation on what you think you would have done in place of factual recollection of what you did do. DON’T give the FDA inspector the answer you think they want to hear if you cannot support your responses. DON’T succumb to the urge to fill any silence by providing study-related information that has not yet been asked about by the inspector. DON’T become overly or repeatedly defensive or argumentative. 7 -- DO take careful notes of the inspector’s "observations" (citations) and non-citation suggestions during the inspection and exit interview. Ask questions to ensure a solid understanding of each deficiency and why the inspector has identified it as being worth pointing out. Even if it's not written on the inspection form you will receive, it will factor into the FDA report file and the eventual FDA decision about the outcome of your inspection. DON’T assume that anything you discuss with the inspector is “off the record.” 8 -- DO prepare to respond to cited "observations" within 15 days of the end of your inspection (even if the inspector tells you that it’s optional). A follow-up report in 2-3 months may also be appropriate. DO take great care in responding to the FDA. Vague, sloppy, inaccurate, defensive, or argumentative responses may result in additional scrutiny and sanctions. DO review your copies of records that the inspector took away – these will be used to support the inspector’s citations, and what they show should be considered in your response. DON’T expect that this will not take a significant amount of your time, effort, and detailed attention – as well as that of the “village” that will rally to support you. 9 -- DO take a deep breath, remember that yours is not the only study to undergo FDA inspection and realize that everyone (study team, institution, and FDA) is on the same side - working toward better, safer medical treatments through the safe, ethical, responsible conduct of clinical research. DON’T panic or agonize. Consider the occasional FDA inspection to be just another “cost of doing business” in the business of conducting clinical research. 10 -- DO focus on continuous quality improvement going forward. Do make a commitment to ensure any past mistakes are not repeated. DON’T dwell on the past. You cannot alter what has happened, sometimes “it is what it is” Page 2 of 2 3
EXAMPLE CORRECTIVE/PREVENTATIVE ACTION FORM CAPA Date: October 13, 2011 Issued to: Director of area that has the issue As required by policy – Distribution is limited Copies to: CAPA File Requested by: External - Western Institutional Review Board Response needed by: November 14, 2011 Observation: Potential Issue: On October 10, 2011 our site received an email from WIRB indicating that the signed consent form that we sent to them was not the correct version of the IRB approved consent form. WIRB has asked for more details as to why the wrong version of the consent form was signed by the subject. Objectives: 1. Determine the scope of the problem and assess how many subjects may have signed the wrong version of the consent form. 2. Compare the two documents to determine if information that is included only in Version 2 would affect a subject’s willingness to continue participation in the clinical trial. . 3. Confirm the roles and responsibilities of all research staff related to the management of clinical trial documents. 4. Assure that systems are in place to effectively manage clinical trial documents in the future and throughout the remainder of the clinical trial. Background: There are three study coordinators involved in this clinical trial. Each coordinator keeps a file with the currently approved consent documents at their work stations. The current versions of the consents are downloaded and copied by the regulatory coordinator who puts a stack on his desk and the coordinators pick up the new current versions from the stack off the regulatory coordinator’s desk and replace the consents at their workstations. The regulatory coordinator tells the coordinators when there is a new version either in person or email depending on which is convenient. Summary: The clinical trial started June 1, 2011. Version one of the consent form was IRB approved June 1, 2011. There were 35 subjects enrolled who signed version one. Version two of the consent form was approved by the IRB on September 1, 2011 and 5 subjects were enrolled after this date. Those five subjects signed version one of the consent form. Therefore, five subjects signed the wrong version of the consent form. Version one and version two of the consent forms were compared and it was determined the following differences: • Version two indicates that the subject will receive $25.00 for each office visit while version one dord not include any compensation the subjects. � Page 1 of 3 4
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